ImmunoSensation the immune sensory system Bonn cluster of excellence

ANNUAL REPORT 2013

G Ap(3’-5’)G

Gp(2’-5’)A A cGAMP

DNA cGAS

pppGp(2'-5')A GTP ATP

universitätbonn ANNUAL REPORT 2013

Preface p. 8 OVERVIEW Overview: Science and Structure p. 12 Scientific Reports – Research Highlights DNA Sensing and Oxidative Damage p. 16 Local Immune Regulation in Tissues p. 24 Sterile Inflammation in the Nervous System and Metabolism p. 36 Immune Sensing and Responses in Tumor Biology p. 50 Feature Article: Immunity and Aerospace Medicine p. 56

Interviews p. 60 Dean of the Medical Faculty: Prof. Max Baur, MD p. 61 Speaker: Prof. Gunther Hartmann, MD p. 64 Vice-Speaker: Prof. Waldemar Kolanus, PhD p. 66 Postdoc: Katharina Hochheiser, PhD p. 68 PhD Student: Larisa Labzin p. 72 Head of the Flow Cytometry Core Facility: Dr. Elmar Endl p. 76

Cluster Coordination Reports p. 80 Family Support & Gender Equality p. 81 Young Investigator Support p. 86 Public Relations p. 90

Events p. 92 First Retreat of the ImmunoSensation Cluster in St. Goar p. 93 Cluster Seminars p. 95 ImmunoSensation visits ELSC/Israel p. 98 Cluster Science Day p. 102 Prizewinners of the Cluster Science Day p. 104

List of Publications p. 110

Seminars & Meetings p. 124

Prizes & Distinctions p. 128

List of Cluster Members p. 132

Biosketches p. 140

Impressions Retreat St. Goar p. 168

Organigram – Structure of the Cluster p. 170

Participating Institutions p. 172

Cluster Coordination Office (CCO) p. 174

Imprint p. 176 Preface Preface

We can now look back on the first year just at the edge of a profound ­conceptual of funding of our Cluster of ­Excellence advance arising from new interactions ­ImmunoSensation by the German within the Cluster, such as the one ­Research Foundation, DFG. Within the presented in the Feature ­Article. One Cluster, we presented a conceptually example of the focus areas of the Cluster new view of an immune sensory system research is illustrated on the cover ­image. beyond the boundaries of classical immu- It is the identification of the founding nology, and it is truly exciting to see that member of a new family of metazoan our concept has found so much reso- cyclic heterodinucleotide second mes- nance within the international community. sengers, a key molecule in the DNA We also coined the term immune ­sensing sensing pathway. One distinguishing to draw attention to the parallels with feature of this new molecule is the 2´- ­other sensory systems, and what was 5´ linkage, which differs from the 3´-5´ initially deemed unconventional has now cyclic dinucleotides that are already well entered the immunological parlance. known in bacteria. This molecule is the Immune sensing is now frequently used long-sought missing piece in the ­puzzle worldwide and has almost eclipsed the of immune sensing of DNA (Gao et al., former term “pattern recognition”. 2013a; Ablasser et al 2013a; Civil et al., 2013; Gao et al.,2013b). In the context Within our first year, we have made of this new second messenger molecule, substantial progress in establishing a Cluster researchers also discovered a widely visible center for immunology in novel principle in innate immunity – that Bonn. Structural measures include the innate immune signals can be transferred recruitment of the first Cluster professor- via gap junctions. Gap-junction ­mediated ship funded by the DFG (W2 Vascular transfer of cGAMP to bystander cells Immunology, Dr. Wolfgang Kastenmüller allows a rapid transcriptional-­independent from the NIH, USA), the formation of antiviral response in neighboring cells a ­central organizational structure, the protecting them instantly from virus in- Cluster ­Coordination Office, the estab- fection (Ablasser et al., 2013b). Another lishment of the International Immunology publication in this context clarified how Training Program, IITB, and the creation oxidation of self DNA can lead to autoin- of ­support programs such as soft skill flammatory disease (Gehrke et al., 2013). courses for students and young scientists Altogether, DNA sensing was one of the and instruments for family and gender most important topics in innate immunity ­support. In scientific terms, we are proud in 2013, and the contributions made by to present what has been achieved ­ImmunoSensation Cluster were promi- in 2013, including groundbreaking nent at an international level. ­discoveries as well as the development of innovative concepts and strategies which We could not have had such a success- we expect will yield novel insights in the ful year without the collaborative effort of coming years. all our members. We would like to thank our scientists, young and “old”, for their Exciting work has been done in the enthusiasm and hard work in 2013. We ­Cluster, some of which is published in thank the managerial team behind the 2013 and reported in the ­following chap- Cluster for its great track record after only ters. Other innovative project ­areas are one year. We are grateful for the support

9 that we have received from the DFG and This is comparable to other classical from the University of Bonn, specifically sensory systems that operate constantly Picture the Faculty of Medicine and the Faculty of without us taking notice of them. Intact Prof. Dr. Gunther Hartmann Mathematics and Natural Sciences. The and synchronized communications and cooperation within the Cluster between connections of the immune system to the University and our two extramural other processes and ­structures of our institutions, the Max Planck Society-­ body, like metabolism or the nervous associated center of advanced european system, are crucial to balance immune studies and research (caesar) and the activity and to maintain health. German Center for Neurodegenerative Diseases (DZNE) has been central to To efficiently investigate the­complex breaking new ground in research on the network of the immune sensory immune sensory system. Finally, there ­system, research groups from different is a great sense of scientific ­community ­disciplines are working together with- in Bonn that extends beyond group, in the ­ImmunoSensation Cluster. The institutional and national borders. It is Medical Faculty is leading this initiative this atmosphere that makes science at jointly together with LIMES (Life and ImmunoSensation so vibrant, dynamic Medical Sciences Institute) of the Faculty and enjoyable. of ­Mathematics and Natural Sciences. (For references see Cluster publication list 2013.) Immunologists closely work together with groups of genetics, biochemistry, biophysics, cell biology, neuroscience, Overview Science and Structure and mathematics. The participation of research groups from the clinical de- The concept of the ImmunoSensation partments foster translational research. Cluster is to address the immune ­system Besides the University of Bonn, the Max as a complex, yet incredibly efficient Planck Society-associated center of sensing device, which displays ­multiple advanced european studies and research characteristics of a sensory organ. (caesar) and the German Center for ­Specialized receptors are in charge of Neurodegenerative Diseases (DZNE) are sensing damage or danger, such as the equal partners of the Cluster. The ­German receptors of the innate immune sys- Aerospace Center (DLR) and the Hebrew tem, which are inherited and present University in Israel are Cluster-­associated from birth on. In addition, there are the institutions. The Cluster ­closely cooper- ­highly ­variable receptors of B- and T ates with international research ­partners cells that are acquired later in life, and and institutions from the USA, UK, which are characterized by constant ­Ireland, Israel, and Japan. renewal. ­Immune sensing receptors are not restricted to immune cells. Some Prof. Dr. med. Gunther Hartmann of them are expressed in a wide range Speaker of human somatic cell types. They rep- resent the center core of a multimodal sensory ­system that is well-equipped to ­distinguish self from non-self as well as harmless from harmful. An exact ­analysis and signal integration of the sensed information is essential in order to coordi- nate and execute an appropriate immune reaction and to protect the organism from damage. In healthy organisms, these sensing mechanisms are continuously active beyond the level of our awareness.

10 11 Overview: ImmunoSensation Cluster of Excellence Science and Structure an Introduction: Interview with Prof. Gunther Hartmann Speaker of the ImmunoSensation Cluster

ImmunoSensation: and mathematics at the University of Interview with Prof. Hartmann, what is the research Bonn collaborate closely with research ­focus of the ImmunoSensation Cluster of on neurodegeneration at the DZNE and Prof. Dr. med. Excellence? the research on biophysics and molecular Gunther sensory systems at caesar. We also work Hartmann Gunther Hartmann: together with international collaboration Our approach is to view the immune partners in the USA, UK, Ireland, Israel ­system as an immune sensory system, and Japan. in other words as an organ of perception that uses receptors to sense pathogens and cellular damage. This system should ImmunoSensation: be seen in a broader context than just im- What exactly is meant by “the immune mune cells, since these immune sensing system as a sensory organ”? What is the receptors are not restricted to immune connection to the other systems in the cells and therefore this concept reaches body? beyond the classical immune system. We are also beginning to understand the Gunther Hartmann: ­extent to which the immune system is For most sensory organs, the signal inte- linked with the other functional systems in gration takes place in the central ­nervous our bodies, such as the metabolism and system. The immune system is also the nervous system. linked with the nervous system. However, its signal integration does not take place in the CNS but rather within the immune ImmunoSensation: organs themselves. Most immune cells Which academic fields are involved in this are mobile, and our research focuses on type of research? how these immune signals, how all of the information derived from multiple mobile Gunther Hartmann: cellular units, can be integrated in a way A leading academic role has been ­taken that the appropriate immune response is by two facilities at the University of elicited. The immune response has to be Bonn: the Faculty of Medicine and the sufficiently specific and directed to the Life and Medical Sciences Institute cause of damage but not cause damage (LIMES), which is part of the Faculty of in this process. One particularly important ­Mathematics and Natural Sciences. In ad- topic within the cluster is sterile inflamma- dition, two extramural institutions are also tion, in other words inflammation in the part of ImmunoSensation: the German absence of microbial infection. Centre for Neurodegenerative ­Diseases (DZNE) and the center of advanced ­european studies and research (caesar), ImmunoSensation: which is associated with the Max Planck What has changed in our understanding Society. Within the cluster, scientists in of the Immunsystem in comparison with the fields of immunology, neuroscience the previous models!

13 Interview with Gunther Hartmann: are endogenous to the human host, when ImmunoSensation: Prof. Dr. med. Over the last few years, the field of these are found at an unusually high con- What effect has the ImmunoSensation ­Immunology has experienced several centration or have acquired molecular Cluster of Excellence had on research in Gunther waves of research focuses. Until 1965 changes. One important example is the Bonn in general? Hartmann or so, researchers focused mainly on misidentification of endogenous nucleic the humoral immune system, including acids, a process that is closely linked with Gunther Hartmann: B cells and the antibodies they produce. the development of several autoimmune There are sizeable number of techniques Then it became evident that B cells are diseases. that are important to basic and clinical mainly guided by T cells during the im- ­research but require equipment with mune response. Both B- and T cells have six-figure prices. No one lab can afford the ability to recombine new genes within ImmunoSensation: this kind of instrumentation. Sharing a human’s lifetime. This is the learning Does this research offer new perspectives equipment and technical platforms does process through which new receptors for therapeutic approaches to disease? not only make machinery available. It are produced that are able to recognize also allows us to share and develop a ­specific viral or bacterial structures even Gunther Hartmann: high level of expertise. Often, the coop- if the host has never been in contact with Sterile inflammation plays a central role erative use of equipment also leads to them before. This is also known as the in several widespread diseases, which scientific collaboration. Shared seminars adaptive immune system. as atherosclerosis, Alzheimer’s disease, and conferences also create a common rheumatic diseases, gout and type 2 space for intensive scientific discussions The next conceptual advance was that diabetes. There are also genetic sterile and exchange. Our programs to promote cells of the innate immune system, in inflammatory diseases that often have a gender equality also make Bonn particu- ­particular dendritic cells, control and devastating course without treatment, larly interesting for women in science. We modulate the responses of the adaptive such as Muckle-Wells disease. In recent are devoting considerable resources to immune system. Immune sensing recep- years, these diseases have become the training of young scientists, but also tors recognize pathogens and activate ­eminently treatable but only because we support for simple everyday problems, T cells or induce tolerance. We see ­innate understand the molecular mechanisms such as daycare. All this is important for immune sensing receptors as well as T- behind them. Since we now know how the success of our scientists, and it also and B cell receptors, including ­antibodies, endogenous stimuli can trigger inappro- makes Bonn a highly attractive place for as part of the immune sensory ­system priate immune responses, we can also talented researchers. because all of these receptors are ­highly block these mechanisms. Thus, we can specialized to detect danger and specifically suppress the inflammatory ­damage. process and restore balance within the Interview by the immune sensory system. By “restoring Cluster Coordination office balance”, I mean that we can treat the ImmunoSensation: autoinflammation and still largely preserve What roles do the receptors of the im- the immune sensing of pathogens. mune sensory system play in disease? What processes are beneficial and which Our new understanding of the mech- are harmful for the host? anisms that control and modulate the immune system also lead us to new Gunther Hartmann: possibilities for the treatment of malig- There are many different families of nant tumors. One particularly promising ­receptors. Some receptors recognize viral approach is the activation of the immune ­nucleic acids. Others recognize molecules receptor RIG-I. In conjunction with the that are specific to bacteria. They detect Cluster, we have established a biotech the presence of microbial pathogens via company, Rigontec GmbH, which is their contact with specific molecules that working to translate RIG-I-based tumor are uniquely found in microbes but not in therapy into clinical application, specifi- their human hosts. Thus, these receptors cally for cancer treatment. This is one ex- can activate an “early warning system” ample of a potential direct benefit of our against a particular microbe and disease. research for patients. Other receptors recognize molecules that

14 15 DNA Sensing and Cytosolic DNA Sensing via the Oxidative Damage Innate Immune System

The Innate Immune System tantly, the endosome is usually free of en- DNA Sensing ­Distinguishes Friend from Foe dogenous DNA or RNA. However, in the course of an autoimmune disease, if there and Oxidative The most important role of the immune is an accumulation of endogenous nucle- Damage Prof. Veit Hornung, MD system is to preserve the integrity of the ic acids in the endosomal compartment, Institute of Molecular Medicine organism in the face of danger both from this can also activate these TLRs and Medical Faculty without and within, i.e. from both envi- their pathways and initiate or aggravate ronmental pathogens and endogenous the pathogenesis of the disease. In addi- University of Bonn danger signals. To this effect, the immune tion to changes in localization or concen- Dr. Andrea Ablasser, MD system has developed a fascinating tration, structural modifications of endog- ability: it can reliably identify potentially enous molecules can also be indicative of Institute of Clinical Chemistry & Clinical Pharmacology dangerous microbes and eliminate them cellular damage and lead to the activation Medical Faculty without misidentifying and damaging the of a particular immune-sensing receptor. University of Bonn body of the host. The underlying principle of this is a system of ­germline-encoded Dr. Winfried Barchet, PhD ­receptors that recognize molecular How can the Immune Sensory System Institute of Clinical Chemistry & Clinical Pharmacology ­patterns intrinsic to dangerous organ- Recognize that DNA is Foreign? Medical Faculty isms or processes, also known as im- University of Bonn mune-sensing receptors. As the name Since endogenous DNA is normally “innate” literally suggests, the host is born confined to the nucleus of the cell, the Prof. Gunther Hartmann, MD with these pattern-recognition receptors. cytosolic localization of DNA is indicative Institute of Clinical Chemistry & Clinical Pharmacology As a whole, these receptors form an im- of either cellular damage or the presence Medical Faculty mune-sensory system. of pathogens. While it has been known University of Bonn for decades that the detection of cyto- Some of these receptors recognize invari- solic DNA leads to the release of type-I ant elements within microbial pathogens interferon, the precise receptors and that are clearly distinguishable from the mechanisms involved in cytosolic DNA endogenous structures of the host, e.g. recognition have remained elusive until several immune- sensing receptors rec- very recently. At the end of 2012, James ognize elements of bacterial cell walls. Chen (University of Texas) and his col- Moreover, in the last few years, it has also leagues were able to identify a previously been discovered that they can detect en- uncharacterized cytoplasmic enzyme dogenous molecules. Here, the specific that creates a second messenger cyclic spatiotemporal subcellular localization of guanosine monophosphate–adenosine the receptors can play an important role. monophosphate, or cGAMP, after bind- This means that under physiological con- ing DNA. Accordingly, the DNA-binding ditions, immune-sensing receptors and enzyme was named cGAMP synthetase, their endogenous ligands are usually sep- or cGAS (Figure 1). Before the discovery arated. This spatiotemporal principle is of of cGAMP, bacterial cyclic dinucleotides particular importance for receptors that were already known to be potent acti- detect microbial nucleic acids, such as vators of the ER-adaptor protein STING certain members of the Toll-like Receptor (stimulator of interferon genes). STING (TLR) family. TLR3, TLR7, TLR8 and TLR9 activation initiates an antimicrobial “de- are all found in the endosome, where they fense program”, which protects the cell can come into contact with the nucleic against bacterial and viral infection. In- acids of phagocytosed microbes. Impor- terestingly, the importance of STING for

17 Figure 1 Three-dimensional Prokaryotic cyclic dinucleotide Metazoan cyclic dinucleotide structures of cyclic di-GMP cyclic-di-GMP cGAMP(2’-5’) and cGAMP(2’-5’). Carbon atoms are shown in beige, DNA viruses, nitrogen in blue, oxygen reverse transcribing viruses in red, and phosphorus in endogenous sources orange. RNA viruses B-forB-formm A-form dsRNAA dsDNADNA

AllostericAllosteric Allosteric OAOAS cGAS activation activation GTP + ATP Prokaryotes 2’-OH 3’-OH c-ddi-AMP 2’-5’ OAs cGAMPP c-didi-GMP-

RNase-L DNA Sensing DNA-recognition was also well known the research groups of Hornung/Ablasser STING before the discovery of cGAS. What and Hartmann/Barchet were both able Ribosome and Oxidative inhibiton of ­remained unclear was how the DNA was to show that there was an important IKK Translocon viral propagation, complex Damage actually recognized and how this recogni- ­molecular distinction between the meta- gap junction apoptosis TBK1 Nucleus tion could lead to STING activation. Thus, zoan second messenger formed by cGAS ERER IκB the discovery of cGAS and its second and previously discovered bacterial cyclic IRF3 p65p50 p65p50 messenger cGAMP finally allowed the dinucleotides. In collaboration with Din- IRF3 puzzle to be solved: the enzyme cGAS shaw Patel at the Rockefeller University in antiviral gene catalyzes the formation of cGAMP after New York, Hartmann/Barchet were able p65p50 expression binding ­cytosolic DNA; then, cGAMP can to examine the crystal structure of DNA, STING subsequently bind to STING and ­initiate cGAS and cGAMP, in order to more pre- the antimicrobial immune response. cisely characterize the cGAMP synthesis spreading of antiviral ­Experiments with cGAS or STING-­ and its structure. Hornung/Ablasser used immunity through gap junctions deficient cells confirmed the importance a mass-spectrometry approach, in vitro of this newly discovered axis of signal enzyme activity assays and NMR tech- transduction. In the absence of cGAS or niques to characterize the exact molecu- STING, certain DNA viruses are no lon- lar structure of cGAS-sythesized cGAMP. ger identified as “foreign” and trigger an Both complementary approaches came ­immune response. Thus, these viruses to the same conclusion: metazoan cGAS can replicate rampantly and ­unopposed dependent cGAMP demonstrates an by the immune system. unusual phosphodiester linkage. The Figure 2 Schematic view of the OAS-RNase L pathway and the cGAS-STING axis. Upon recognition of double-stranded A-form RNA, OAS produces 2’-5’ linked oligoadenylates (2’-5’ OAs) that in turn bind and activate the latent endoribonuclease RNase L. ­researchers discovered that one phos- Activated RNase L then degrades cellular RNAs and possibly also viral RNAs to induce cell death and to inhibit viral propagation. phodiester linkage in cGAMP is between cGAS detects double-stranded DNA of the B-form configuration and subsequently produces the second messenger molecule The Truth is in the Detail the C2’-atom of the ribose in GMP and cGAMP(2’-5’) using ATP and GTP as substrates. cGAMP(2’-5’) binds to and activates the ER-resident receptor STING, which the C5’-atom of the ribose in AMP while results in its translocation to a perinuclear compartment where it achieves its signaling-competent state. This in turn results in the Several members of the ImmunoSen- the second phosphodiester linkage is 3’- activation of antiviral and pro-inflammatory transcription factors that initiate antiviral gene expression. Next to its role in sensing sation Cluster of Excellence were able 5’, as is typically found in nucleic acids. the endogenous, cGAS-derived cyclic dinucleotide cGAMP(2’-5’), STING also functions as a PRR for exogenous, prokaryotic to make significant contributions to the Not only is this molecule the first example cyclic dinucleotides. Beyond its role in initiating a cell-intrinsic antiviral response, cGAMP(2’-5’) can also diffuse to neighboring characterization of the cGAS – cGAMP – of a combined 2’-5’ / 3’-5’ phosphodi- cells in a gap-junction dependent manner.. STING signal transduction cascade (Gao ester linkage in a natural nucleic acid, but et al., 2013a; Ablasser et al., 2013a; Civil this unusual linkage is also responsible for et al., 2013; Gao et al., 2013b). In two the more potent effect of DNA-dependent independent experimental approaches, cGAMP on its receptor STING.

18 19 Figure 3 Microscopic ­image of a cGAMP-­ producing HEK cell loaded with calcein (bright green) co-cultured with HEK STING cells (red). Highlighted are cGAMP ­bystander cells, in which producing STING has been activated cell (white arrows) by gap-­ junction dependent transfer of cGAMP(2’-5’).

Bystander cells, in which STING has been activated by gap-junction dependent cGAMP transfer from cGAMP producing cell (green).

DNA Sensing Further studies in structural biology many different input signals, and they are could also show that cGAS displays a themselves usually upstream of several and Oxidative striking resemblance to oligoadenylate signaling pathways. Damage synthetases (OAS). This enzyme family is activated by double-stranded RNA and However, the team of Veit Hornung was produces oligoadenylates, short chains of able to find a mechanism which offers a 2’-5’ linked adenosine monophosphates. plausible explanation for this unusually These oligoadenylates then activate strict signaling pathway (Ablasser et al., RNase L, an effector enzyme of the anti- 2013b). Upon examining the activation of viral immune response, which degrades STING at a single-cell level, the research- viral RNA when activated. These discov- ers discovered that not only the cells with eries demonstrate intriguing parallels in a direct cGAS activation showed STING- the innate immune response to intracellu- induced antiviral activity but also their lar nucleic acids: double-stranded nucleic neighbors. In other words, the activation acids activate enzymes with polymerase of the cGAS-STING signaling pathway activity that produce 2’-5’ second mes- was not restricted to the one cell where sengers and then initiate a very specific cGAS had been activated, but rather the antiviral immune response (Figure 2). activation was “propagated” to neighbor- Figure 4 Oxidative damage of DNA confers resistance to TREX1 degradation and potentiates cGAS/STING ­dependent ing cells in the tissue. In further studies, immune sensing Upon entering the cytosol, DNA is degraded by exonuclease TREX1, which limits potential­ immune it could be show that this local activation activation (left panel). However, DNA that has incurred oxidative modifications e.g. as a consequence of UV damage A Neighborhood Watch Against was communicated by the transfer of or ROS exposure becomes largely resistant to TREX1 mediated degradation. Accumulating oxidized DNA engages Viruses cGAMP through small intercellular ­canals the cytosolic DNA receptor cGAS, which via the second messenger 2’,3’-cGAMP activates the STING dependent known as gap junctions. This newly dis- signaling cascade. STING signaling via TBK1 and IRF3/7 eventually leads to the secretion of type I IFN and other pro-­ One distinctive feature of the cGAS- covered mechanism allows the host to inflammatory cytokines (right panel). This mechanism provides a potential explanation for UV-light induced phototoxicity cGAMP-STING signaling pathway is the directly and rapidly warn neighboring cells prevalent in autoimmune lupus erythematosus (LE), and suggests that oxidative modifications of self DNA may act as fact that the second messenger cGAMP about a viral threat without ­waiting for trigger for the induction of LE skin lesions. can only be produced by cGAS and ­cytokine production and release. This most likely uniquely serves as a ligand for ­crucial time advantage allows for the STING. This lack of “signaling promiscu- more efficient containment of a viral ity” is rather unusual. Most second mes- ­infection (Figure 3). sengers are generated downstream from

20 21 Oxidatively Damaged DNA Sounds an our immune system to distinguish endog- Liu Y., Jones R.A., Hartmann G., ­Tuschl even Louder Alarm enous and foreign DNA. Situations that T., Patel D.J. Cyclic [G(2‘,5‘)pA(3‘,5‘)p] lead to misidentification of endogenous Is the Metazoan Second Messenger DNA in the cytosol and outside of the DNA, such as the oxidative damage to Produced by DNA-Activated Cyclic GMP- nucleus is usually degraded rather rapidly DNA in lupus patients, lead inevitably to AMP Synthase. Cell. 153(5):1094-107. by a variety of DNAses. Thus, unmodi- unnecessary inflammation and eventually 2013b. fied DNA is a relatively weak stimulus for to inflammatory disease. the cGAS-STING signaling pathway, and Gehrke N., Mertens C., Zillinger T., DNA Sensing unphysiologically high concentrations Thus, DNA sensing was a central theme Wenzel J., Bald T., Zahn S., Tüting T., and Oxidative of DNA are necessary to investigate the of several important research projects Hartmann­ G., Barchet W. Oxidative cGAS-STING pathway in vitro. The group and a core research area of the Immu- Damage of DNA Confers Resistance to Damage of Hartmann/Barchet has discovered noSensation Cluster of Excellence. In Cytosolic Nuclease TREX1 Degradation that oxidatively damaged DNA is a much 2013, our researchers were able to make and Potentiates STING-Dependent Im- more potent activator of the cGAS path- discoveries in this field which were both mune Sensing. Immunity. 39(3):482-95. way than unmodified DNA (Gehrke et al., clinically relevant and groundbreaking on 2013. 2013). This oxidative damage can occur international level. in physiological conditions via contact with UV-radiation from the sun or oxygen radicals after the activation of immune Reference Publications 2013 cells. Ablasser A., Goldeck M., Cavlar T., Picture DNA Sensing One important modification to DNA in an Deimling T., Witte G., Röhl I., Hopfner Dr. Andrea Ablasser and Oxidative oxidative environment is the presence of K.P., Ludwig J., Hornung V. cGAS pro- 8-hydroxyguanosine. The researchers duces a 2‘-5‘-linked cyclic dinucleotide Damage could show that this modification does second messenger that activates STING. not change its binding to cGAS but rather Nature. 498(7454):380-4. 2013a. inhibits its eventual degradation via the cytosolic DNAse TREX1. This reduced Ablasser A., Schmid-Burgk J.L., Hem- degradation leads to an accumulation of merling I., Horvath G.L., Schmidt T., Latz oxidized DNA in the cytosol and thus a E., Hornung V. Cell intrinsic immunity heightened activation of the cGAS path- spreads to bystander cells via the in- way (Figure 4). tercellular transfer of cGAMP. Nature. 503(7477):530-4. 2013b. This mechanism has important con- sequences for our understanding of Civril F., Deimling T., de Oliveira Mann both physiological immune sensing and C.C., Ablasser A., Moldt M., Witte G., pathological autoinflammation. The group Hornung V., Hopfner K.P. Structural of Hartmann/Barchet could show that mechanism of cytosolic DNA sensing by Picture (f.l.t.r.) exposure to UV-irradiation leads to the cGAS. Dr. Winfried Barchet, Prof. Gunther Hartmann, presence of oxidized DNA in the skin of Nature. 498(7454):332-7. 2013. Prof. Veit Hornung, patients with cutaneous lupus erythema- Thomas Zillinger tosus and that the ensuing inflammation Gao P., Ascano M., Zillinger T., Wang contributes to the disease pathology. W., Dai P., Serganov A.A., Gaffney Moreover, they demonstrated that bac- B.L., ­Shuman S., Jones R.A., Deng L., terial and viral DNA could be better iden- Hartmann­ G., Barchet W., Tuschl T., tified if the DNA had been previously ex- Patel D.J. Structure-Function Analysis of posed to an oxidative environment, such STING Activation by c[G(2‘,5‘)pA(3‘,5‘)p] as reactive oxygen species produced by and Targeting by Antiviral DMXAA. immune cells. Cell. 154(4):748-62. 2013a.

Thus, the researchers were able to identi- Gao P., Ascano M., Wu Y., Barchet W., fy an important novel criterion that allows Gaffney B.L., Zillinger T., Serganov A.A.,

22 23 Local Immune Introduction Regulation in Tissues Local Context Sensing

Immune cells located in peripheral ­organs a ­novel IFN-γ dependent pathway which Local Immune are exposed to microenvironmental regulates production of the chemokine ­signals from neighboring non-immune CCL17 by dendritic cells differentially Regulation in cells, which may dramatically alter in the spleen versus the lymph nodes. Tissues Prof. Irmgard Förster, PhD ­recruitment and mobility of immune cells, Whereas organ-resident splenic dendritic Immunology and Environment their ability to elicit an immune response cells were susceptible to IFN-γ depen- Life and Medical Sciences Institute and its quality. Our aim is to better dent suppression of CCL17 expression, ­understand how local particularities are ­migratory dendritic cells in the lymph University of Bonn integrated by the immune system when it nodes specifically downregulated the Prof. Percy Knolle, MD decides which effector mechanisms are IFN-γ receptor and expressed much to be activated. This knowledge is critical larger amounts of CCL17, a ­chemokine Institute of Molecular Medicine for designing locally targeted immuno- which promotes T cell-dendritic cell University of Bonn therapies that cause less adverse effects ­interactions and inflammation (see Institute of Molecular Immunology in other organs. ­Globisch et al., 2014). Technical University Munich Migration of immune cells is guided by The liver constantly receives immunosti- Prof. Christian Kurts, MD localized expression of chemoattrac- mulatory signals from the gut through Institute of Experimental Immunology tants and cell adhesion molecules. The ­microbial components or food constitu- Medical Faculty ­expression of these immune ­regulators ents and plays an important role in detox- University of Bonn varies enormously between the ­different ification of low molecular weight chem- tissues of our body. Dendritic cells icals. To avoid unwanted overshooting Prof. Natalija Novak, MD (DC) are attracted to peripheral organs immune responses in the liver, this organ Department of Dermatology and Allergy through the action of chemokines and has developed an immunosuppressive Medical Faculty cell ­adhesion molecules. Upon ­activation microenvironment, which is of major im- University of Bonn through PRR ligands, dendritic cells portance for induction of immunologic change their chemokine receptor ex- tolerance. On the other hand, in the case pression to follow different ­chemokine of acute or chronic viral infection of the ­gradients in order to move to local liver, local expansion of virus-specific ­draining lymph nodes and induce an ap- ­cytotoxic T cells is highly desirable, also propriate immune response. The Kurts in the liver. P. Knolle and coworkers made group discovered an unusually high the striking observation that cytotoxic T ­number of dendritic cells in the cortex of cells were able to proliferate in microana- the kidney, which were recruited through tomical niches formed within the liver by the local expression of the chemokine TLR-activated intrahepatic myeloid-cell

CX3CL1 (fractalkine) by the kidney stro- aggregates, so called iMATEs (Huang et ma. Immigration of dendritic cells into al., 2013). the ­kidney but not other organs was

dependent on expression of the CX3CR1 Regulation of immune responses through chemokine receptor. Blockade of CX- communication between immune and

3CR1-dependent chemokine responsive- non-immune cell types also plays an im- ness selectively depleted dendritic cells portant role in neuro-immune ­interactions. in the kidney cortex and protected mice The group of N. Novak in the Department from development of glomerulonephritis of Dermatology and ­Allergy now dis- (see article by Hochheiser et al., 2013). covered that neurotrophins ­released by In addition, the group of I. Förster in co- sensory neurons are able to stimulate the operation with J.L. Schultze discovered proliferation and migration of mast cells,

25 which in turn are able to ­produce neuro- T cells to antigen-presenting dendritic CCL17 ­expression in the spleen. The between organ-resident and migratory trophins themselves. cells but also positively ­influences the only stimulus known so far to be able to dendritic cells. Alternatively, the local A dysregulation of this circuit appears to migration of dendritic cells themselves. induce CCL17 in the spleen is systemic microenvironment of the spleen versus be responsible for a hereditary disease Using various mouse models, it has been CD1d-dependent NKT cell activation by lymph node may regulate organ-specific called mastocytosis, which leads to the shown previously that CCL17 promotes glycolipid antigens, e.g. α-galactosylce- gene expression programs. Obviously, the abnormal accumulation of mast cells in the pathogenesis of several allergic and ramide (αGalCer). In collaboration with spleen as a filter of systemic blood borne the skin or gastrointestinal tract (Peng et inflammatory diseases, such as atopic the group of J.L. Schultze, we performed antigens may have different requirements al., 2013). dermatitis, inflammatory bowel disease, global gene expression analysis to further for initiation and control of immune re- More detailed summaries of the main and atherosclerosis. However, CCL17 explore the differential, organ-specific sponses than peripheral organs and their findings reported in the four selected key has also been shown to enhance cross-­ expression of CCL17. For this purpose, local draining lymph nodes. publications in 2013 are given below. presentation of exogenous antigens by CCL17-negative dendritic cells from the CD8-positive splenic dendritic cells and spleen and CCL17-expressing dendritic thereby may support anti-microbial or cells from lymph nodes were purified by Reference Publication 2013 Organ-specific Cytokine Responsive- anti-viral immune responses. fluorescent cell sorting and characterized ness and Expression of the Chemokine by global mRNA expression analysis. This Globisch T., Steiner N., Fülle L., ­Lukacs- CCL17 Interestingly, the expression of CCL17 analysis revealed a striking differential Kornek V., Degrandi D., ­Dresing P., (by Irmgard Förster) by dendritic cells is strongly influenced expression of IFN-γ inducible genes as Alferink J., Lang R., Pfeffer K., ­Beyer M. by the local tissue context. In the steady well as the IFN-γ receptor (IFN-γR) itself, Weighardt H., Kurts C., Ulas T., Schultze Local Immune Dendritic cells are important sentinels of state, organ-resident splenic DC ­generally which were strongly downregulated in J.L. and Förster I. Cytokine-­dependent the immune system and direct the quality fail to express CCL17, ­whereas ­migratory, the lymph node compared with splenic regulation of denditic cell differentiation Regulation in and strength of adaptive immune re- CD103-positive dendritic cells in lymph ­dendritic cells, indicating the cytokine in the splenic microenvironment. Eur. Tissues sponses in an organ-specific manner. The nodes are strong CCL17 producers. IFN-γ may be responsible for suppression J. ­Immunol. 44, 500-510, 2014. Epub Förster group has characterized a subset In barrier organs, such as the skin or of CCL17-expression in the spleen. To 2013 Dec 12. of dendritic cells that produces the inflam- ­intestinal mucosa, CCL17 expression test this hypothesis, CCL17 reporter mice matory chemokine CCL17, a ligand of the is induced by Toll-like receptor stim- expressing the green fluorescent protein chemokine receptor CCR4. CCL17 not ulation or allergic sensitization, even under control of the CCL17 promoter Local Regulation of T Cell Immunity in only mediates the attraction of activated though the same stimuli do not induce were bred with IFN-γR-­deficient mice, the Liver rendering all dendritic cells insensitive (by Percy Knolle) to IFN-γ. Whereas IFN-γR deficiency, as such, did not lead to a major up- The liver is constantly exposed to bacteri- Local Immune regulation of CCL17 expression in the al degradation products derived from the Figure Differential ex- Regulation in spleen, a large proportion of splenic gastrointestinal tract. The Knolle group pression of the IFN-γR Tissues on splenic versus lymph IFN-γR-­deficient DC upregulated CCL17 has characterized the consequences of node dendritic cells. IFN-γ ­expression by 50-fold when mice were TLR-signaling locally in the liver. It is well ­mediates suppression of stimulated with αGalCer. This positive known that the liver contains many cell CCL17 expression in the ­induction of CCL17 was dependent populations that provide strong ­innate spleen, whereas GM-CSF on the cytokines IL-4 and GM-CSF, as ­immunity since they are equipped with and IL-4 lead to upregula- shown by the application of IL-4- or immune sensory receptors. Moreover, tion of CCL17 expression, GM-CSF-specific neutralizing ­antibodies since the liver harbors scavenger cell in particular in the absence as well as the analysis of GM-CSF-­ populations such as Liver Sinusoidal of IFN-γR signaling. deficient mice. In contrast, absence of ­Endothelial Cells and Kupffer cells, these the type I IFN receptor did not impact cell populations have a prominent role on the level of CCL17 expression. Thus, in eliminating pathogen-associated ­dendritic cells locally regulate production ­molecular patterns from the circulation, of CCL17 through differential expression and, at the same time, they can mount of the IFN-γR. potent innate ­immunity triggering local inflammation. As splenic dendritic cells are organ-­ resident and may develop from local The Knolle group made the unexpected precursor cells, it is possible that the discovery that uptake of agonistic ligands differential expression of the IFN-γR is for TLR4 and TLR9 in the liver and local determined by developmental differences inflammation in the liver both lead to a

26 27 dramatic expansion of CD8 T cells locally against viral infection suggesting that T Exclusive CX3CR1 Dependence of The Kidney Depends on Fractalkine to in the liver. TLR-ligands did not act on T cell expansion within iMATE is an import- Kidney DCs Impacts Glomerulonephri- Recruit Dendritic Cells cells directly to facilitate this enormous ant part anti-viral immunity. Since, during tis Progression local expansion but instead facilitated chronic viral infection of the liver, no (by Christian Kurts) Recently, the Kurts group discovered that Local Immune the recruitment of myeloid cells to the iMATEs are observed, we reasoned that DCs depend on a particular chemokine liver. Comprehensive phenotypic analysis therapeutic iMATE induction by TLR9-L As many as 4 million people in ­Germany receptor, known as the fractalkine recep- Regulation in revealed that inflammatory monocytes application might overcome chronic infec- suffer from chronic kidney disease (CKD), tor, or CX3CR1, in order to infiltrate the Tissues were recruited to liver sinusoids and dif- tion. Indeed, in combination with adop- and its incidence is on the rise. For many kidney. Even though DCs are present in ferentiated into inflammatory dendritic tive cell therapy or DNA vaccination, the patients, CKD eventually leads to kidney virtually every organ, this dependence cells under the influence of continuous induction of iMATE formation suffices to failure and the need for external blood on CX3CR1 is specific to the kidneys, TLR-signaling. Interestingly, myeloid cells control and eradicate chronic viral infec- filtration, known as dialysis. However, this where it has a dramatic influence on DC accumulated in cocoon-like structures tion. Thus, hepatic immune sensing has treatment is not only extremely ­expensive influx. In mice deficient in CX3CR1, the that formed within 24 hrs of TLR signaling an important role for adaptive immunity but also reduces the life expectancy and number of DCs in the kidney is reduced and disappeared again after 6 to 8 days. by promoting strong proliferation of T the quality of life of patients. Currently, by 75% while other organs in the body T cells migrated into these structures cells outside of lymphoid tissues. the only alternative to dialysis available remain unaffected. Since DCs in other and proliferated locally. Since T cells did is ­kidney transplantation, which ­requires organs also express CX3CR1, this finding not proliferate elsewhere in liver tissue major surgery followed by lifelong was initially quite surprising. However, but only in these structures formed by Reference Publication 2013 ­immunosuppression and, thus, carries its further analysis revealed that the kidney myeloid cells, we termed them iMATE for own risks. ­expresses exceptionally high levels of intrahepatic myeloid cell aggregates as- Huang L.R., Wohlleber D., Reisinger F., CX3CL, the ligand of CX3CR1. CX3CL sociated with T cell expansion. Jenne C.N., Cheng R.L., ­Abdullah Z., CKD is often the result of a misguid- levels are higher in the kidney than in any Schildberg F.A., Odenthal M., Dienes ed ­autoimmune response directed at other organ with the exception of the Local Immune iMATEs were not only formed in response H.P., van Rooijen N., Schmitt E., Garbi­ the ­basic filtration unit of the kidney small intestine. This expression of CX3CL to application of TLR-ligands but were N., Croft M., Kurts C., Kubes P., ­Protzer and known as glomerulonephritis (GN). promotes the infiltration of the kidney with Regulation in also observed during viral infection of the U., Heikenwalder M., Knolle P.A. ­However, CKD can also result from other DCs and could explain the extraordinarily Tissues liver by RNA or by DNA viruses indicating ­Intrahepatic myeloid-cell aggregates underlying conditions, such as diabetes high number of DCs found in this organ. that iMATE formation is a physiological ­enable local ­proliferation of CD8(+) T cells mellitus and high blood pressure. None- ­response to viral infection. ­Importantly, and ­successful immunotherapy against theless, even if diabetes and hypertension In collaboration with the Institut ­national prevention of iMATE formation by ­chronic viral liver infection. Nat Immunol., are not ­primary autoimmune diseases, the de la santé et de la recherche ­médicale ­elimination of inflammatory monocytes 14(6): 574-583, 2013. ­immune system still plays an important (Inserm) in Paris and the ­University also abrogates protective T cell immunity role in their pathology in that it induces ­Hospital Eppendorf in Hamburg, Kurts chronic inflammation and thus promotes and his group could show that ­CX3CR1- the destruction of the renal parenchyma deficient mice were largely protected from and its replacement with scar tissue. crescentic GN in their model. Crescentic GN, also known as rapidly progressive Figure Accumulation of In their previous work (Hochheiser et al., GN, is a type of GN ­characterized histo- inflammatory monocytes 2011), the Kurts group was able to show pathologically by the presence of cellular locally within the liver leads that dendritic cells (DCs) play a central crescents and ­clinically by its rash pro- to formation of iMATEs that role in the development of kidney disease. gression and loss of renal function. This serve as expansion hub for DCs are the “sentinels” of the immune form of GN can ­develop idiopathically, i.e. activated CD8 T cells. system that collect and process antigens without a known underlying cause, or as in the body and then present them to a clinical manifestation of several different T cells in the lymph nodes. In addition, autoimmune diseases, including systemic tissue resident DCs in the kidney and lupus erythematodes and Goodpasture other organs modulate local immune syndrome. Thus, if an inhibitor of CX- ­responses via the regulation of infiltrating 3CR1 could be used to selectively reduce T-cells (Heymann et al., 2009; Riedel et the number of DCs in the kidney without al., 2012; Wakim et al., 2008). affecting other organs, such a therapy would not only be promising for the treat- ment of GN but also for many other sys- temic diseases that also affect the kidney.

28 29 Local Immune A New Approach to Treatment found in the renal cortex, the site of the Other References ated by the neuro-immunologic network glomeruli and thus GN, and not in the play an ­important role. Both activation Regulation in The striking selectivity of CX3CR1 ­renal pelvis, where pyelonephritis occurs. Heymann F., Meyer-Schwesinger C., as well as recruitment and migration Tissues ­dependence to the kidney makes this Hamilton-Williams E.E., Hammerich L., of mast cells from the bone marrow therapeutic approach particularly prom- Initial epidemiological studies indicate Panzer U., Kaden S., Quaggin S.E., via the blood to the peripheral organs ising. Conventional immunosuppressive that these processes are conserved Floege J., Gröne H.-J., and Kurts C. Kid- are directed by soluble mediators therapy for autoimmune GN and other in ­humans, meaning that CX3CR1 ney dendritic cell activation is ­required for and corresponding ­surface receptors. autoimmune diseases brings unwanted is ­extremely promising as a potential progression of renal disease in a mouse ­Neurotrophins are growth factors that systemic effects including a reduction ­target for GN therapy in human patients. model of glomerular injury. The Journal were initially ­discovered in the nervous of the general immune competence of ­Clinical studies are now needed to verify of Clinical Investigation 119, 1286, system and contribute to the develop- the patient. The kidney itself can also be the role of CX3CR1 in human patients 2009. ment, ­maintenance and regeneration prone to infection under immunosuppres- and hopefully translate this finding from of nerve fibers (Arevalo and u,W 2006). sive treatment, in particular to a bacterial the bench to the bedside. Hochheiser K., Engel D.R., Hammerich, They include nerve-growth factor (NG- infection of the renal pelvis, known as L., Heymann F., Knolle P.A., Panzer U., F)-β, brain-derived neurotrophic factor pyelonephritis. As shown by previous and Kurts C. Kidney Dendritic Cells Be- (BDNF), neurotrophin (NT)-3 and -4 (A). work from the Kurts group (Tittel et al., Reference Publication 2013 come Pathogenic during Crescentic Glo- NTs promote the chemotaxis, maturation 2011), DCs play a central role in com- merulonephritis with Proteinuria. Journal and survival of MCs (Tam et al., 1997). batting pyelonephritis. Thus, despite the Hochheiser K., Heuser C., Krause T.A., of the American Society of Nephrology NT-expressing nerves are in close contact lack of systemic effects, one potential Teteris S., Ilias A., Weisheit C., Hoss F., 22, 306–316, 2011. with mast cells, and mast cells, them- problem with CX3CR1 inhibition could still Tittel A.P., Knolle P.A., Panzer U., Engel selves, are also capable of ­producing be a potentially increased risk for kidney D., Tharaux P.-L., Kurts C. ­Exclusive Riedel J.H., Paust H.J., Turner J.E., Tittel NTs (Bruni et al., 1982; Groneberg et infections. However, Kurts and his group CX3CR1 dependence of kidney DCs im- A.P., Krebs C., Disteldorf E., Wegscheid, al., 2005; Nilsson et al., 1997; Peters were able to show that the inhibition of pacts glomerulonephritis progression. J. C., Tiegs, G., Velden, J., Mittrucker, H.W., et al., 2007; Quarcoo et al., 2009). This CX3CR1 does not diminish the ability of Clin. Invest. 123, 4242–4254, 2013. et al. Immature ­Renal Dendritic Cells Re- ­bidirectional interaction of NTs and mast the immune system to combat pyelone- cruit Regulatory CXCR6+ Invariant Natu- cells ­suggests a contribution by NTs to phritis. This surprising finding is due to a ral Killer T Cells to Attenuate Crescentic diseases such as mastocytosis. fortunate anatomic detail: the DCs that GN. Journal of the American Society of depend on CX3CR1 are predominantly Nephrology 23, 1987–2000, 2012. The three tropomyosin-related kinases, Local Immune tropomyosin-related kinase A (TrkA), B Tittel A.P., Heuser C., Ohliger C., Knolle (TrkB) and C (TrkC) are all high-affinity Regulation in P.A., Engel D.R., and Kurts C. Kidney neurotrophin receptors. TrkA is a receptor Tissues Dendritic Cells Induce Innate ­Immunity for NGF-β; TrkB is a receptor for BDNF Figure A renal corpuscle against Bacterial Pyelonephritis. Journal and NT-4, and TrkC is a receptor for NT- from a kidney with glomer- of the American Society of ­Nephrology 3. In this context, we were able to report ulonephritis: the Bowman’s 22, 1435–1441, 2011. for the first time the expression of TrkA, capsule and glomerulus TrkB and TrkC on human skin mast cells (both red) are surrounded by Wakim L.M., Waithman J., van Rooi- (SMCs) as well as their increased expres- dendritic cells (green). jen N., Heath W.R., and Carbone F.R. sion on human SMCs of patients with ­Dendritic Cell-Induced Memory T Cell mastocytosis. In addition, we observed ­Activation in Nonlymphoid Tissues. that the intestinal mast cells of patients ­Science 319, 198–202, 2008. with mastocytosis expressed TrkA and TrkC but not TrkB.

Local regulation of mast cell migration We also investigated the expression of and activation in the skin and gut by Trk isoforms in controls and mastocytosis neurotrophins in mastocytosis patients. Full-length TrkA was not found (by Natalija Novak) on human SMCs. Only the exon-lacking TrkA I splice variant was expressed, both Mastocytosis is characterized by a on SMCs from controls and from patients ­rapid mobilization of mast cells through with mastocytosis. However, TrkB was exogenous and endogenous ­stimuli expressed in both full-length (FL-TrkB) (Pardanani, 2012). Here, signals medi- and truncated (TrKB-T1) isoforms on the

30 31 SMCs of both populations (B). Patients ­stimulation and differentiation of mast with mastocytosis nonetheless displayed cells, mediated by NT-3 and NT-4 (C). Figure (A): Overview differences in their gene expression As we and others could show that mast of ­neurotrophins and profile of TrkB on human SMCs when cells themselves both represent a source ­respective tropomyosin- compared with controls (Stoilov et al., of NTs as well as expressing the respec- related kinase receptors. 2002). Exons 1- through 4 and a major tive functional receptors, mast cells might (B): Schematic drawing part of exon 5 encode the conventional augment these effects in an autocrine of TrKB-FL and TrkB-T1 5´untranslated region (UTR) of the human fashion. ­isoforms expressed by TrkB gene and serve as transcription start human skin mast cells. sites. We ­detected a higher expression Altogether, we could provide evidence (C): Summary of the of the 5´UTR in SMCs of mastocytosis for a crucial role for NTs in ­mastocytosis, ­proposed mast cell – ­neurotrophin network in patients. However, SMCs of patients and we elucidated a sophisticated net- mastocytosis. with mastocytosis and controls had the work ­allowing communication between same mRNA expression level of exon mast cell progenitors in the blood, 24, which encodes part of the FL-TrkB mast cells in the skin and gut as well as receptor containing the tyrosine kinase ­soluble ­mediators of the nervous system. domain (exons 21-24). Although both ­Further know-ledge about mechanisms FL-TrkB and TrKB-T1, the receptor vari- promoting mast cell infiltration will help ant without exon 22, were expressed on to identify structures which might be human SMCs, TrKB-T1-mRNA expres- targeted in therapeutic approaches to sion was increased in SMCs of patients prevent unwanted tissue infiltration by with mastocytosis. In addition, SMCs of mast cells and mast cell overactivation, in patients with mastocytosis displayed a ­mastocytosis and in other mast cell driven higher mRNA expression of extracellular diseases, as well. domain of TrkB than controls. Although the full-length isoform of TrkC was not expressed on SMCs of patients with Reference Publication 2013 mastocytosis or on control mast cells, a truncated isoform was detected in the Peng W.M., Maintz L., Allam J.P., Raap SMCs of both populations. Moreover, the U., Gutgemann I., Kirfel J., Wardelmann expression of this truncated isoform of E., Perner S., Zhao W., Fimmers R., TrkC was significantly higher on the SMCs ­Walgenbach K., Oldenburg J., Schwartz of patients with mastocytosis L.-B., and Novak N. Increased circulating levels of neurotro- Local Immune NTs have been shown to exert chemo- phins and elevated expression of their Regulation in tactic effects on different cells. In line with high-affinity receptors on skin and gut these observations, we demonstrated mast cells in mastocytosis. Blood 122, Tissues a significantly increased migration of 1779–1788, 2013. CD117+ mast cell progenitors toward an NGF-β gradient via TrkA, which was ex- pressed by mast cells of the skin and gut, Other References organs which are frequently infiltrated by mast cells in mastocytosis. Arevalo J.C., and Wu S.H. Neurotrophin signaling: many exciting surprises! Cell. In addition, we could show for the first Mol. Life Sci. 2006 Jul, 63 (13) 1523-37, time higher circulating levels of NGF-β, 2006. NT-3 and NT-4. Together with the in- creased migration of CD117+ progenitors Bruni A., Bigon E., Boarato E., Mietto L., from the blood toward an NGF-β gra- Leon A., and Toffano G. ­Interaction be- dient via TrkA, NTs might contribute to tween nerve growth factor and lysophos- the augmented tissue infiltration by mast phatidylserine on rat peritoneal mast cells. cells mediated by NGF-β as well as the FEBS Letters 138, 190–192, 1982.

32 33 Local Immune Groneberg D.A., Serowka F., and skin homeostasis in health and disease. ­Peckenschneider N. Gene expression Horm. Metab. Res. 39, 110–124, 2007. Regulation in and regulation of nerve growth ­factor Tissues in atopic dermatitis mast cells and the Quarcoo D., Fischer T.C., Peckenschnei- human mast cell line-1. Journal of der N., Groneberg D.A., and Welker P. ­Neuroimmunology. 161 (1-2): 87-92, High abundances of neurotrophin 3 in 2005. atopic dermatitis mast cell. J Occup Med Toxicol 4, 8, 2009. Nilsson G., Nilsson K.F., and Xiang Z. Human mast cells express functional TrkA Stoilov P., Castren E., and Stamm S. and are a source of nerve growth factor. Analysis of the human TrkB gene European Journal of Immunology. ­genomic organization reveals novel TrkB 27(9): 2295-301, 1997. isoforms, unusual gene length, and splic- ing mechanism. Biochem. Biophys. Pardanani A. Systemic mastocytosis: dis- Res. ­Commun. 290, 1054–1065, 2002. ease overview, pathogenesis, and treat- ment. Hematol. Oncol. Clin. North Am. Tam S.Y., Tsai M., Yamaguchi M., Yano 26, 1117–1128, 2012. K., Butterfield J.H., and Galli S.J. Expression of functional TrkA receptor Peters E.M.J., Raap U., Welker P., Tanaka ­tyrosine kinase in the HMC-1 human A., Matsuda H., Pavlovic-Masnicosa S., mast cell line and in human mast cells. Hendrix S., and Pincelli C. ­Neurotrophins Blood 90, 1807–1820, 1997. act as neuroendocrine regulators of

Picture (f.l.t.r.) Prof. Christian Kurts, Prof. Natalija Novak, Prof. Irmgard Förster, Prof. Percy Knolle © UKB / Katharina Wislsperger

34 35 Sterile Inflammation Sterile Inflammation in Nervous System in Nervous System and and Metabolism Metabolism One of the crucial functions of the ­innate and eliminating pathogens also makes it Sterile immune system is the initiation and an intrinsically destructive force. Reactive execution of the acute ­inflammatory ­oxygen species, porines, metalloprote- Inflammation ­response. This response is our “first line ases, etc. are not only highly effective in Nervous Prof. Michael Heneka, MD of defense” against invading ­pathogens, means of targeting invading pathogens, System and Clinical Neuroscieces Unit and it is rapid, powerful, inherently but they also destroy host cells and scar Metabolism Medical Faculty non-specific and incredibly effective. parenchymal tissue. Nonetheless, this incredible effectiveness University of Bonn and efficiency also comes at a cost. The In sterile inflammation, or inflamma- Prof. Eicke Latz, MD PhD non-specificity of the acute inflammatory tion in the absence of an infectious, response enables the immune system ­microbial trigger, this destruction more Institute of Innate Immunity to efficiently recognize new pathogens, often drives the pathology of the disease Medical Faculty yet it also inherently harbors the ­potential than curing it. There are a plethora of University of Bonn of misidentifying threats and caus- sterile stimuli that cause inflammation: ing ­inappropriate immune responses. crystals such as monosodium urate or Prof. Joachim L. Schultze, MD ­Moreover, the very effectiveness of the cholesterol, ischemia, other types of cel- Genomics & Immunoregulation acute inflammatory response in killing lular damage, aluminum salts, oxidized Life and Medical Sciences Institute University of Bonn

Prof. Veit Hornung, MD Institute of Molecular Medicine Domains: Figure 1 ­Inflammasome AIM2 Pyrin Medical Faculty proteins. Pictured are several different multim- LRR CARD University of Bonn BIR eric protein complexes formed via homotypic Caspase-1 AIM2 Pyrin domain interactions, e.g. p10 / p20 NACHT HIN200 Pyrin-Pyrin or CARD- ASC ASC CARD. All of the inflam- FIIND masomes can binding and activate of pro- PYD procaspase-1 caspase-1 via CARD- B30.2/SPRY procaspase-1 CARD interaction.

NLRP1 NLRP3 NLRC4 NLRP6 procaspase-1/5 ?

NLRP3 NLRC4 NAIP2 NLRP6 NLRP1 or ? NAIP5

NOD2 ASC ? ASC ASC ASC

procaspase-1 procaspase-1 procaspase-1 procaspase-1

37 DNA. Since these stimuli often do not closely ­regulated and requires the forma- Atherosclerosis Alzheimer Disease pose an ­inherent threat, the inflamma- tion of the ­inflammasome, a multiprotein Gout tion and ­ensuing ­destruction is often “for ­molecular platform. There are different Type 2 Diabetes naught”. If ­intentionally applied in a limited inflammasome complexes that respond ­quantity as an adjuvant, sterile inflamma- to a variety of sterile and infectious stimuli tory ­stimuli can be used to purposefully with the activation of caspase-1, which in boost the adaptive response. However, turn activates IL-1b (Figure 1). these ­stimuli in larger quantities are rarely “cleared” by the immune system and are Although several inflammasomes most Lysosome often the result of continuous ­processes likely play an important role in sterile within the host. Without clearance of ­inflammation, e.g. AIM2 recognizes the inflammatory trigger, there is also no ­cytosolic dsDNA both of endogenous ­possibility for the inflammation to resolve. and microbial origin, the NLRP3 inflam- Inflammasome β masome has been implicated in the IL-1 greatest number of human pathologies ASC Sterile Inflammation and the to date. The precise mechanism of ­Inflammasome NLRP3 activation still remains unknown. inactive NLRP3 Caspase-1 However, the NRLP3 inflammasome is Pro-caspase-1 Sterile Many sterile inflammatory stimuli induce downstream of any process that results Inflammation the release of the pro-inflammatory in ­potassium efflux, such as bacterial ­cytokines IL-1a and IL-1b. Activation of toxins or extracellular ATP via the P2X7 Pro-IL-1β active in Nervous the IL-1 receptor, which is expressed on ­receptor. In addition, it can be activated Caspase1 System and a wide variety of immune and somatic by a ­process known as lysosomal de- Metabolism cells, enables the movement (diapedesis) stabilization. The lysosome is a digestive Pyroptosis of immune cells to the site of inflamma- ­compartment in cells. In immune cells tion. It also causes fever, vasodilatation such as macrophages, it is where phago- and hyperalgesia, which are respon- cytosed ­material, whether pathogens sible for the typical clinical symptoms or simply debris, is degraded. However, of inflammation. IL-1b is expressed as crystalline material as well as the accu- an inactive pro-form, pro-IL-1b, which mulated ­aggregated proteins associated must first be transcriptionally upregu- with several diseases are all “difficult to lated, e.g. via NF-KB, and then cleaved digest” leading to lysosomal rupture and Figure 2 The accumulation of crystalline material is associated with many „lifestyle diseases“. to achieve ­bioactivity. This cleavage is NLRP3 activation (Table 1 and Figure 2). Phagocytosis of this material activates NLRP3 via lysosomal destabilization.

In 2013, the list of materials known to information, please see page 43 of this Sterile ­initiate sterile inflammation via NLRP3 chapter.) was expanded to include the Amyloid-B Inflammation protein found in the senile plaques of Another publication from the ­Immuno- in Nervous Alzheimer’s patients. ­ImmunoSensation Sensation Cluster focused on ­developing System and members Michael Heneka, Annett the tools necessary to execute high- Metabolism ­Halle and Eicke Latz were not only able throughput screenings for pharmaco- to show that Amyloid-β can activate logical inhibitors. Cluster members Veit NLRP3 but also that the progression of Hornung and Eicke Latz have developed ­Alzheimer’s disease is NLRP3 dependent. a proteolytic luminescent reporter for * ImmunoSensation Cluster Members have published important research on these mechanisms. This discovery is of particular clinical rele- caspase-1 and IL-1b activation, allow- Table 1 Sterile inflammation contributes to the pathology of many diseases. Here, a list of diseases where vance since it raises the possibility of the ing the measurement of inflammasome NLRP3-mediated inflammation is involved and the corresponding NLRP3 stimulus. use of pharmacological NLRP3 inhibitors ­activation in high-throughput. Currently, to halt Alzheimer’s progression. (For more both scientists are screening for new

38 39 ­cytokines after TLR activation. Thus, the ­Abela G.S., Franchi L., Núñez G., Schnurr Sterile anti-inflammatory effect of HDL is not only M., Espevik T., Lien E., Fitzgerald K.A., Inflammation the result of its ability to remove pro-in- Rock K.L., Moore K.J., Wright S.D., flammatory cholesterol crystals, but also Hornung­ V., Latz E. NLRP3 inflam- in Nervous via a direct stimulation of anti-inflamma- masomes are required for atherogenesis System and tory processes. This discovery is not only and activated by cholesterol crystals. Metabolism important for our understanding of sterile ­Nature 464, 1357–1361, 2010. inflammation in atherosclerosis but is a promising therapeutic approach for other Heneka M.T., Kummer M.P., Stutz A., inflammation-mediated diseases of both Delekate A., Schwartz S., Vieira-Saecker infectious and sterile origin. A., Griep A., Axt D., Remus A., Tzeng T.-C., Gelpi E., Halle A., Korte M., Latz E., Golenbock DT. NLRP3 is activated in Reference Publications 2013 Alzheimer’s disease and contributes to Table 2 Human TLRs, their known ligands and downstream immune response after activation. pathology in APP/PS1 mice. Nature 493, (Based on Kawai and Akira, 2011. Bartok E., Bauernfeind F., Khaminets 674–678, 2012. M.G., Jakobs C., Monks B., Fitzgerald K.A., Latz E., and Hornung V. iGluc: Hornung V., Bauernfeind F., Halle A., a luciferase-based inflammasome and Samstad E.O., Kono H., Rock K.L., protease activity reporter. Nat. Methods ­Fitzgerald K.A. and Latz E. Silica crystals 1–10, 2013. and aluminum salts activate the NALP3 Sterile ­inflammasome-relevant pharmacological pro-inflammatory cytokines such as IL-6 inflammasome through phagosomal Inflammation therapies. (For more information, please are also part of the acute phase reaction De Nardo, D., Labzin L.I., Kono H., ­destabilization. Nat Immunol 9, 847–856, see page 46 of this chapter.) and central to sterile and infectious in- Seki R., Schmidt S.V., Beyer M., Xu D., 2008. in Nervous flammation. ­Zimmer S., Lahrmann C., Schildberg System and F.A., Vogelhuber J., Kraut M., Ulas T., Kawai T. and Akira S. Toll-like Receptors Metabolism Sterile Inflammation and the TLRs Thus, the mediation of TLR-­mediated ­Kerksiek A., Krebs W., Bode N., Grebe and Their Crosstalkwith Other Innate transcriptional effects is a feasible A., ­Fitzgerald M.L., Hernandez N.J., ­Receptors in Infection and Immunity. “switch-point” for controlling inflam- ­Williams B.R., Knolle P., Kneilling M., ­Immunity 34, 637–650, 2011. The Toll-Like Receptor (TLR) family is mation. After stimulating the release of Röcken M., Lütjohann D., Wright S.D., a part of an ancient immune sensory pro-inflammatory cytokines, TLR activa- Schultze J.L., Latz E. High-density li- Rock K.L., Latz E., Ontiveros F. and Kono ­system, which has analogs in insects and tion is often accompanied by a second poprotein ­mediates anti-inflammatory H. The Sterile Inflammatory Response. plants. All 10 currently known TLRs in wave of cytokines, lead by IL-10 which reprogramming of ­macrophages via the Annu. Rev. Immunol. 28, 321–342, humans are thought to each be responsi- downregulates the release of further transcriptional ­regulator ATF3. Nature 2010. ble for the detection of a distinct group of ­cytokines. The resolution and endoge- Publishing Group 15, 152–160, 2014. molecules that are not normally found in nous downregulation of TLR-mediated Epub releases 2013 Dec. healthy cells. (See Table 2) inflammation are currently important fields of research. Understanding the Latz E., Xiao T.S. and Stutz A. Activation The most important pathways down- ­resolution of inflammation would create and regulation of the inflammasomes. stream of the TLRs are NF-KB ­signaling, the ­possibility for therapeutic approaches Nat. Rev. Immunol. 13, 397–411, 2013. AP-1 signaling and IRF-dependent type-I that inhibit autoinflammation but still allow interferon production. The production adequate host defense. of type-I interferon is essential for the Other References ­initiation of an anti-viral state in immune ImmunoSensation Cluster members and somatic cells and is also downstream Eicke Latz and Joachim Schultze have Bauernfeind F., Ablasser A., Bartok E., of cytosolic DNA sensing (p. 17). NF-KB ­discovered a novel mechanism of TLR Kim S., Schmid-Burgk J., Cavlar T., and and AP-1 are responsible for the tran- inhibition via High-density Lipoprotein Hornung V. Inflammasomes: current scription of pro-inflammatory cytokines. (HDL), commonly known as “good cho- ­understanding and open questions. Cell. The transcriptional regulation of pro-IL1B lesterol”. The researchers discovered Mol. Life Sci. 68, 765–783, 2010. and NLRP3 is of particular importance that HDL upregulates the transcriptional for sterile inflammation in response to modulator ATF3, which in turn represses Duewell P., Kono H., Rayner K.J., Sirois crystalline material (see above). However, the transcription of pro-inflammatory C.M., Vladimer G., Bauernfeind F.G.,

40 41 Sterile Metabolic Regulation of Immunity by Using unbiased genomics approaches These studies have great relevance for Reference Publication 2013 Sterile Inflammation High-density Lipoproteins (HDL) and bioinformatics analysis, Dr. Dominic the pharmaceutical industry as current Inflammation De Nardo and Ms Larisa Labzin from efforts focus on the development of De Nardo D.*, Labzin L.I.*, Kono H., in Nervous High-density lipoprotein (HDL) has the Latz laboratory, together with the HDL-based therapies for the treatment Seki R., Schmidt S.V., Beyer M., Xu in Nervous System and ­protective functions in various ­diseases ­laboratory of Prof. Joachim L. ­Schultze, of ­inflammatory diseases, particularly D., Zimmer S., Lahrmann C., ­Schilberg System and Metabolism including atherosclerosis and type II have identified how HDL can affect the atherosclerosis. For example, ­successful F.A., Vogelhuber J., Kraut M., Ulas Metabolism ­diabetes. HDL is best known for its output of macrophages in response in vivo treatment could potentially be T., ­Kerksiek A., Krebs W., Bode N., ­essential role in reverse cholesterol to various inflammatory stimuli, such ­evaluated by measuring the induction of Grebe A., ­Fitzgerald M.L., Hernandez ­transport (RCT). During this important as ­Toll-like receptor (TLR) ligands. In ATF3 in blood cells of patients. N.J., ­Williams B., Knolle P.A., Kneiling process HDL removes excess choles- a ­concerted effort involving scientists M., Rocken M., Lutjohann D., Wright terol from peripheral cells and transports from Germany, Japan, China, the USA S.D., Schultze J.L.*, Latz E.*. HDL it to the liver, thus promoting ­cholesterol and Australia, we identified the inducible ­mediates anti-­inflammatory ­transcriptional ­excretion into the digestive tract. In ­transcriptional modulator, ATF3 as the key ­reprogramming of macrophages via ­addition to its role in RCT, HDL displays factor that mediates HDL’s anti-inflamma- ATF3. Nature immunology, 2014 15(2), remarkable anti-inflammatory properties, tory activities in macrophages. We could 152-160, 2014. Epub 2013 Dec 8. which also likely contribute to its pro- show that incubation of macrophages tective nature. However, the molecular with HDL results in an upregulation of *equal contribution mechanisms by which HDL can reduce ATF3, which then acts to repress the inflammatory responses in immune cells transcription of key inflammatory cyto- have remained elusive. kines, including IL-6, IL-12p40 or TNF.

Picture (f.l.t.r.) Larisa Labzin, Prof. Eicke Latz and Dr. Dominik De Figure HDL treatment Nardo from the Institute of macrophages does HDL of Innate Immunity not affect TLR-induced Pam3Cys LPS © Barbara Frommann / signaling, but rather Uni Bonn induces the expression of the transcription- al modulator, ATF3, SR-B1 TLR which then acts to Free cholesterol directly inhibit the gene expression of numer- CpG DNA ous pro-inflammatory cytokines. ? p65p50 NFκB

ATF3 NLRP3 is Activated in Alzheimer’s with Alzheimer’s, little is known about the

p65p50 Disease and Contributes to Pathology molecular mechanisms determining the Inflammatory in APP/PS1 Mice disease’s development. ATF3 genes Three members of the ­ImmunoSensation ATF3 cytokine Alzheimer’s disease is the most common Cluster of Excellence, Prof. Eicke Latz Nucleus cause of dementia worldwide. Moreover, (page 159), Prof. Michael Heneka (page Cytoplasm as our life expectancy increases, the 148) and Dr. Annett Halle (page 146), prevalence of this disease is only have approached Alzheimer’s ­disease expected to rise further. Although much research from an interdisciplinary per- is known about the clinical symptoms spective and discovered that sterile Macrophage and histopathological findings associated ­inflammation is of central importance to

42 43 its pathogenesis. As they have discov- mation by microglia is responsible for the Caspase-1 Activation in Human 1-induced sterile inflammation and Sterile In- ered, Alzheimer’s is not only a neurolog- progress of Alzheimer’s disease. ­Alzheimer’s Patients ­Alzheimer’s disease. There are BfArM-­ flammation ical disease but also an immunological approved medications that are known one, as well. Therefore, the team of scientists exam- In order to corroborate these results to inhibit NRLP3, and screenings of in Nervous ined the role of NLRP3 and caspase-1 in human patients the cleavage of new compounds is ongoing. Thus, via System and in a murine model of Alzheimer’s disease caspase-1 in the brain of patients with drug ­repurposing or discovery, NRLP3 Metabolism β-Amyloid Causes Sterile Inflammation (APP/PS1 mice). These transgenic mice Alzheimer’s disease was also examined. ­inhibition is a novel and promising express mutated versions of the amyloid Alzheimer’s disease patients ­exhibited ­approach to ameliorate the symptoms Sterile In- One of the most prominent histopatholog- precursor protein (APP) and presenilin-1 increased cleavage of caspase-1 in of Alzheimer’s disease. flammation ical findings in Alzheimer’s disease is the (PS1) which both highly correlate with their hippocampus and frontal cortex. accumulation of the β-amyloid peptide in the early development of Alzheimer’s in The hippocampus is responsible for the in Nervous senile plaques in the brain parenchyma. humans. These modified mice develop ­consolidation of memories and is one Reference Publication 2013 System and However, it is less clear how these senile senile plaques and show memory loss, of the first regions of the brain to be Metabolism plaques actually cause brain damage. cognitive dysfunction and hyperdynamic ­affected in Alzheimer’s disease patients. Heneka M.T., Kummer M.P., Stutz A., In their previous work, Annett Halle, a locomotion at the age of 6 months. The frontal cortex is associated with Delekate A., Schwartz S., Vieira-Saecker ­neurologist by training, and Eicke Latz, an short-term memory, attention, planning, A., Griep A., Axt D., Remus A., Tzeng immunologist, discovered that β-amyloid In order to investigate the role the reward and motivation, and it has been T.-C., Gelpi E., Halle A., Korte M., Latz peptide can in fact provoke an inflamma- NLRP3/caspase-1 pathway in ­Alzheimer’s shown in several studies that the frontal E., Golenbock DT. NLRP3 is activated in tory response in vitro from immune cells ­disease, NLRP3 and caspase-1 defi- cortex also undergoes volumetric decline Alzheimer’s disease and contributes to known as microglia. ciency were each crossed with APP/ in ­Alzheimer’s disease patients. Thus, pathology in APP/PS1 mice. Nature 493, PS1 mice, respectively. Lack of NLRP3 these areas of the brain are exactly where 674–678, 2013. These cells are the resident macrophages was sufficient to largely protect mice one would expect to find Alzheimer-in- of the central nervous system. As phago- from memory loss and behavior deficits. duced inflammation. Since APP/PS1 cytes, microglia engulf debris and patho- In ­particular, NLRP3-deficient APP/PS1 mice ­precisely recapitulate these findings, Other Reference gens, including the β-amyloid aggregates mice performed as well as wild-type mice there seems to be a clear association found in senile plaques. Ideally, phagocy- in the Morris-water maze test (­spatial between Alzheimer’s disease and sterile Halle A., Hornung V., Petzold G.C., tosis should lead to the removal of extra- memory formation) and in the object ­inflammation in the brain in humans, as Stewart C. R., Monks B.G., ­Reinheckel cellular debris by delivering the engulfed ­recognition test. well. T. Fitzgerald K.A., Latz E., Moore material into a specific intracellular com- K.J., ­Golenbock D.T. The NALP3 partment, known as the lysosome, where A priori, these findings could simply be ­inflammasome is involved in the innate they are digested. However, as Halle and explained via the decreased sterile inflam- A New Approach to Alzheimer’s immune response to amyloid-β. Nature Latz discovered, in the case of aggre- mation found in NLRP3-deficient APP/ ­Therapy ­Immunology, 9(8), 857–865, 2008. gated β-amyloid the cells are unable to PS1 mice. However, Michael Heneka fully digest this substrate. The incomplete and his colleagues also discovered that Altogether, these results show a clear removal of aggregated β-amyloid results NLRP3-deficient APP/PS1 mice in fact association between NLRP3/Caspase- in a destruction of the lysosomal com- have less senile plaques than APP/PS1 partiment. This in turn results in a leaking mice. Upon further investigation, the of lysosomal acidic content into the cy- researchers could show that APP/PS1 toplasm. Some of the released proteins mice deficient in NLRP3 or caspase-1 Picture represent potent danger signals causing could are in fact better able to phagocy- Prof. Michael Heneka the activation of an intracellular inflamma- tose and ­dispose of β-amyloid. This may © Bruna Guerra Franklin tory pathway, the NLRP3-inflammasome. be the ­result of macrophage polariza- (For more information on the inflam- tion or the enhanced survival of NLRP3 masome, please see the introduction to or caspase-1 deficient macrophages Sterile Inflammation page 37.) ­after contact with β-amyloid. (Activation of NLRP3 normally kills macrophages ­triggering a special form of cell death NLRP3 and Caspase-1 Activation in known as pyroptosis.) vivo

Up to now it has remained unknown whether NLRP3-dependent sterile inflam-

44 45 Sterile In- iGluc: a luciferase-based Nonetheless, despite this impressive flammation ­inflammasome and protease ­arsenal of regulatory possibilities, ­IL-1b in Nervous ­activity reporter can still be inappropriately ­activated in organisms. For example, acute System and The Role of IL-1 and the Inflam- ­IL-1b release plays a central role in Metabolism masome in Sterile Inflammation the ­pathogenesis of sepsis. However, ­chronic, lower-level activation of IL-1b The cytokine IL-1b is the most ­potent and also significantly contributes to ­endogenous pyrogen known in ­mammals. sterile inflammatory processes found However, it is also one of the most ­closely in ­Alzheimer’s, atherosclerosis, dia- regulated. The cytokine itself must be betes mellitus and gout (see figure 2 transcriptionally upregulated and ­undergo on page 39). Needless to say, better proteolysis via caspase-1 and the so- ­understanding both how IL-1b release is called inflammasome complex before it regulated and how it can be modulated can bind to its receptors. At the same pharmacologically would make a vital time organisms are equipped with decoy contribution to the development of new receptors and receptor antagonists for treatment strategies for many widespread IL-1b. illnesses. Figure 2 iGluc reporter macrophages screened for inhibitors of NLRP3 activity using the Prestwick commercial library. Approximately 1.5% of compounds demonstrated a significant inhibition of NLRP3 activation.

6 x 10 AIM2 titration in 293T cells iGluc as a Sensor for Caspase-1 and standard” read-out for inflammasome 10.0 Sterile Inflammasome Activity activation, immunoblotting for cleaved Inflammation caspase-1, is a time-consuming tech- a 5 inactive b 5.0 x 10 in Nervous Ctrl. Gaussia AIM2 Veit Hornung (page 152) and his nique. luciferase lab members Eva Bartok and Franz 6.0 + Caspase-1 1.5 System and ASC ­Bauernfeind, in collaboration with In contrast, gaussia luciferase activity 5.0 Metabolism pro-IL-1β Caspase-1 1.0 Eicke Latz (page 159) have developed can be easily read in a luminometer after 4.0 a ­proteolytic biosensor for activators the addition of its substrate. In addition, iGLuc

Luminescence [RLU] 0.5 ­upstream of IL-1b. The biosensor is the use of luciferases as reporters for 3.0 + Caspase-1 based on murine IL-1b fused to a ­gaussia transcriptional activity has a well-estab- 2.0 0.0 luciferase construct, known as iGLuc lished methodology for high-throughput ­(Figure 1). Surprisingly, the gaussia screenings (HTS). Thus, there is a clear 1.0 AIM2: 0 (ng pDNA) Luminescence [RLU] 0.78 1.56 3.12 6.25 12.5 25.0 50.0 100 ­luciferase in iGluc has little activity when rationale for the development of a gauss- (0.78 ng pDNA) 0.0 cleaved active ASC: fused to the full-length form of mmIL-1b. ia-based proteolytic assay for inflam- Caspase-1: (1.56 ng pDNA) pro-IL-1β Gaussia However, upon proteolytic cleavage of masome activation. iGluc luciferase iGLuc: (100 ng pDNA) EGFP-Gluc WB: IL-1b, iGLuc exhibits a robust gaussia cleaved iGluc anti-GFP AIM2 signal. To this end, Veit Hornung and his ­colleagues decided to create a cell- anti-HA ASC The activation of IL-1b is a complex based assay to measure inflammasome anti-Flag iGLuc iGluc process involving the formation of a ­activation. Wild-type immortalized murine EGFP-GLuc cleaved iGLuc ­multimeric protein complex known as the macrophages and cell lines deficient in

1 3 inflammasome. This complex activates inflammasome proteins were ­transduced Activity: 15 78 [fold induction] 243 469 677 781 821 caspase-1, which in turn cleaves IL-1b. to stably express the iGluc reporter. (For more information on the “inflam- Upon inflammasome stimulation, these masome”, please see the introduction cells ­secrete active iGLuc into the ­cellular to this chapter.) However, measuring supernatant where they activity can Figure 1 (a) iGluc only exhibits luciferase activity after proteolytic cleavage by caspase-1. (b) iGluc can be used as a readout for ­inflammasome formation is ­technically be rapidly measured using a standard inflammasome activation. Aim2 inflammasomeeconstitution r via transient transfection in 293T HEK cells shown. challenging, and the current “gold ­luminometer.

46 47 Sterile Screening the Inflammasome Other Reference Inflammation Thus, it is now possible to screen Bauernfeind F., Ablasser A., Bartok E., in Nervous ­thousands of novel compounds and Kim S., Schmid-Burgk J., Cavlar T., and System and clinically-approved medications for in- Hornung V. Inflammasomes: current un- Metabolism flammasome activation and inhibition. derstanding and open questions. Cell. This approach has enormous potential for Mol. Life Sci. 68, 765–783, 2010 drug repurposing and new drug ­discovery for all of the illness related to inflam- masome activation. Given the prevalence and prognosis of these diseases (See figure 2 on page 39), new therapies could be of major clinical significance. Currently, Veit Hornung and his colleagues are us- ing iGLuc to search for new therapeutic ­approaches to treating sterile inflamma- tion (Figure 2).

Reference Publication 2013

Bartok E., Bauernfeind F., Khaminets M.G., Jakobs C., Monks B., Fitzgerald K.A., Latz E., and Hornung V. iGluc: a luciferase-based inflammasome and protease activity reporter. Nat. Methods 1–10, 2013.

Picture Prof. Veit Hornung, Dr. Eva Bartok © Dr. S. Putz

48 49 Immune Sensing and Introduction Responses in Tumor Biology The immune system communicates ­cytokines and growth factors, includ- Immune with virtually all of the cell types in our ing TNF-α, IL-6, HGF and TGF-β are body and is constantly surveying its crucial soluble mediators of the physio- Sensing and ­integrity. Tissue injury causes the release logical wound response and their aber- Responses in Prof. Michael Hölzel, MD of alarm signals, or DAMP molecules rant ­release and activation is frequently Tumor Biology Institute of Clinical Chemistry and Clinical Pharmacology (­Damage-Associated Molecular Pattern), ­detected in tumor tissues. Medical Faculty that are sensed by patrolling immune cells and upon their recruitment initiate In this sense, cancers can be consid- University of Bonn and coordinate a wound repair response. ered to be chronically wounded tissues Prof. Thomas Tüting, MD This physiological program is not only that nevertheless manifest a metastable essential for the integrity and survival of organization with established reciprocal Department of Dermatology and Allergy multicellular organisms, but it also plays interdependencies between neoplastic Medical Faculty a critical role in several pathological and non-malignant cells. From that point University of Bonn ­conditions including chronic inflammatory of view, the cytoreductive therapies used diseases and cancer. It is well estab- in the clinic such as genotoxic chemo- lished that genomic alterations are key therapies, targeted inhibition of oncogenic drivers of neoplastic cell proliferation. signaling or immunotherapies not only However, over the years, it has become cause profound acute onset injury to the clear that tumors also critically require tumor tissue but also massively exacer- the presence of non-transformed cells bate the preexisting inflammation (Krysko in their ­neighborhood for their survival. et al., 2012). Dying cancer cells release Cancer-associated fibroblasts and certain large amounts of DAMPs that rapidly subsets of immune cells are of pivotal ­attract immune cells to the regressing and ­importance to this interplay among the collapsing tumor tissue. This infiltration various cell types present in the tumor subsequently establishes a cytokine-­ microenvironment. Proinflammatory driven regenerative proinflammatory

Figure 1 Links therapy between therapy-induced tumor tissue injury, innate immune sensing and the development of therapy resistance. A proinflam- matory microenviron- ment supports different ­scenarios of therapy resistance.

51 ­tumor microenvironment that is believed Report on key contributions 2012/13 ­resistance in colon cancer patients and to though a gradual loss of CTL effector Immune to pave the ground for the survival of a EGFRi in lung cancer. From a translational functions contributed to tumor relapses Sensing and few remaining tumor cells and ultimately Huang S., Hölzel M., Knijnenburger T., perspective, blocking TGF-βR signaling in this model, reactivating these ­memory lead to the relapse of the disease (Figure Schlicker A., Roepman P., ­McDermott may be a promising target to enhance T cells via a booster vaccination only Responses in 1) (Hölzel et al., 2013). U., Garnett M.J., Grernrum W., Sun and restore multimodal drug responsive- temporarily enhanced tumor control, Tumor Biology C., Prahallad A., Groenendijk F.H., ness in different cancers by abrogating and we ultimately observed relapses in Therefore, it is important to ­understand ­Mittempergher L., Nijkamp W., Neefjes protective regenerative wound ­responses. all cases. Importantly, we noticed a loss how therapy-related tumor tissue ­injury J., Salazar R., Ten Dijke P., Uramoto H., Our study is in line with other reports of the ­target antigen gp100 that was is sensed by the immune ­system and Tanaka F., Beijersbergen R.L., Wessels showing an important contribution of the linked to an inflammatory microenvi- to identify the critical innate immune L.F., Bernards R. MED12 controls the re- tumor microenvironment to resistance to ronment. ­Surprisingly, serial transplan- ­signaling cascades and cell types sponse to multiple cancer drugs through cancer therapy (Straussman et al., 2012). tation experiments and in vitro studies ­involved. This knowledge may help to regulation of TGF-β receptor signaling. revealed that melanoma cells switch substantially improve current ­cancer Cell, 151, 937–950, 2012. Landsberg J., Kohlmeyer J., Renn M., between differentiated and dedifferen- ­treatments by specifically targeting the Bald T., Rogava M., Cron M., Fatho M., tiated subpopulations with or without microenvironmental survival ­signals Lennerz V., Wölfel T., Hölzel M., Tüting T. ­melanocytic antigen ­expression, respec- sensed by remnant tumor cells ­after Therapy-induced tumor tissue injury Melanomas resist T-cell therapy through tively. Subsequent ­experiments identified a ­cytoreductive therapy. However, and inflammation is a trigger for regen- inflammation-induced reversible dediffer- the ­proinflammatory cytokine TNF-α as ­despite this unified initial approach to erative wound responses, and EMT-like entiation. Nature, 490, 412–416, 2012. major cause for the reversible shift of ­understanding the outgrowth of resistant phenotype transitions at relapse have both mouse and human melanoma cells tumor cells in a proinflammatory environ- been linked to the activation of the from a melanocytic to a non-melanocytic ment, the scenario surrounding a par- TGF-β ­signaling pathway in the tumor In order to understand how melanomas phenotype. Thereby, inflammation leads ticular tumor remains quite complex as microenvironment. Targeting the ALK become resistant to immunotherapy, we to TNF-α secretion by tumor-infiltrating Immune different cancers are phenotypically and and EGF receptor tyrosine kinases with used a genetically engineered mouse immune cells and selectively impairs the Sensing and genetically heterogeneous ­(Gerlinger et specific inhibitors (EGFRi, ALKi) causes melanoma model that recapitulates recognition of the melanocytic antigens al., 2012; Meacham and Morrison, 2013). profound but transient responses in lung ­clinical courses of regression, remission by the CTLs (Figure 2). However, it does Responses in Another layer of complexity is ­added by cancers harboring EML4-ALK transloca- and relapse following adoptive transfer not affect the recognition of non-mela- Tumor Biology the inherent phenotypic plasticity of the tions or activating mutations of EGFR. A of cytotoxic T cells (ACT). Our model nocytic tumor antigens as demonstrated tumor and immune cells themselves in re- ­significant subset of EGFRi resistant tu- allowed us to successfully treat estab- by matched pairs of human melanoma sponse to proinflammatorysignals ­ ­(Aktipis mors indeed exhibits EMT-like transitions lished primary melanomas with cytotoxic cell lines and respective cytotoxic T cells et al., 2013). A ­prominent ­example of in clinical specimens at recurrence. In T cells (CTLs) that specifically target isolated from melanoma patients. Our adaptive and protective cancer cell phe- this study, we used an unbiased large- the melanocytic differentiation antigen work exemplifies the importance of the notype switching is the acquisition of scale RNAi in vitro screen and identified gp100 (Kohlmeyer et al., 2009). Even phenotypic plasticity of melanoma cells mesenchymal traits by ­therapy-resistant that loss of MED12, a component of the epithelial tumors, termed as EMT-like transcriptional MEDIATOR complex and states (epithelial-­mesenchymal transi- known mutated cancer gene, confers tion), with cancer stem cell-like properties resistance to ALK and EGFR inhibitors (Zhang et al., 2012). Despite these ad- (Huang et al., 2012). Unexpectedly, we Figure 2 Model summa- vances, little is known about the in vivo could establish a novel link between rizing the mechanism of dynamics of different tumor and immune MED12 and TGF-β signaling, and we inflammation-induced re- cell subpopulations and how they interact found that cytoplasmically localized versible dedifferentiation that with each other. MED12 negatively regulates TGF-βR2 contributes to resistance to by direct binding. Reducing MED12 T cell therapy in melanoma. T cells killing the melanoma In conclusion, the innate immune sens- ­expression enhanced TGF-βR signaling, cells via the target antigen ing of DAMP release after tissue injury which is both necessary and sufficient gp100 provoke a proin- has emerged as a critical aspect of for drug resistance. In this context, flammatory response in the tumor biology in the context of tumor TGF-β was able to activate MEK/ERK tumor microenvironment development and therapy resistance. signaling, and hence MED12 loss also that in turn leads to revers- The resulting inflammation is a potent reduced sensitivity to MEK and BRAF ible dedifferentiation (antigen ­influence leading to the “rewiring” of inhibitors in other cancers. In parallel, loss) and upregulation of the the ­phenotypes of neoplastic and non-­ MED12 ­suppression caused an EMT- lineage precursor marker malignant cells in the tumor microenviron- like ­phenotype switch, which we could NGFR on the surface of the ment. also functionally link to chemotherapy melanoma cells.

52 53 as a rapid adaptation to therapy-induced complex tumor tissue. In keeping with Reference Publications 2012/13 ­multiregion sequencing. N Engl J Med Immune inflammatory signals in the microenviron- this ­analogy, we have integrated the 366, 883–892, 2012. Sensing and ment (Landsberg et al., 2012). Further- concepts and terminology of ecological Hölzel M., Bovier A., and Tüting T. more, it establishes a link between the approaches and applied them both to Plasticity of tumour and immune cells: a Kohlmeyer J., Cron M., Landsberg Responses in loss of T cell effector functions with the specific cell populations as well as the source of heterogeneity and a cause for J., Bald T., Renn M., Mikus S., Bon- Tumor Biology immunoselection of reversible antigen tumor environment, as a whole. Cell therapy resistance? Nat Rev Cancer 13, dong S., Wikasari D., Gaffal E., Hart- loss variants through dynamic inflamma- populations can be regarded in terms 365–376, 2013. mann, G., et al. Complete Regression tion-induced phenotype switching of im- of their “fitness” and ability to survive in of ­Advanced Primary and Metastatic mune and tumor cells. the “­niches” provided within the tumor Huang S., Hölzel M., Knijnenburg T., Mouse ­Melanomas following Combina- environment. Furthermore, we discuss Schlicker A., Roepman P., McDermott U., tion ­Chemoimmunotherapy. Cancer Re- Hölzel M., Bovier A., Tüting T. Plasticity strategies to mathematically model the Garnett M., et al. MED12 controls the re- search 69, 6265–6274, 2009. of tumour and immune cells: a source of dynamics of these heterogeneous sub- sponse to multiple cancer drugs through heterogeneity and a cause for therapy populations that are both genetically and regulation of TGF-β receptor ­signaling. Krysko D.V., Garg A.D., Kaczmarek A., resistance? Nat Rev Cancer 13, 365-76, phenotypically ­diverse. Using our T cell Cell 151, 937–950, 2012. Krysko O., Agostinis P., Vandenabeele, 2013. therapy resistance model as a template, P. Immunogenic cell death and DAMPs we have simulated the cell ­population Landsberg J., Kohlmeyer J., Renn M., in cancer therapy. Nat Rev Cancer 12, dynamics with an adaptive Markovian Bald T., Rogava M., Cron M., Fatho M., 860–875, 2012. Immune In this opinion article, we discuss con- model (Figure 3). We also ­discuss how Lennerz V., Wölfel T., Hölzel M., et al. Sensing and cepts that reconcile the inflammation-in- we aim to ­incorporate our experimen- Melanomas resist T-cell therapy through Meacham C.E., and Morrison S.J. duced adaptive plasticity of tumor and tal results into such ­models in order inflammation-induced reversible dedif- ­Tumour heterogeneity and cancer cell Responses in immune cells with the genetic heteroge- to more ­comprehensively ­understand ferentiation. Nature 490, 412–416, Oct. plasticity. Nature 501, 328–337, 2013. Tumor Biology neity of cancers in the context of therapy the ­evolution of complex ­tumor micro- 2012. resistance. Following a careful review of environments ­consisting of tumor and Straussman R., Morikawa T., Shee K., experimental and clinical research, we ­immune cells during ­therapeutic ­selection Barzily-Rokni, M., Qian Z.R., Du, J., Davis were able to delineate similarities among ­pressure. This ­approach ­provides a Other References A., Mongare M.M., Gould J., Frederick the therapeutic approaches to different ­mathematical framework for modeling D.T., et al. Tumour micro-­environment tumor types including chemotherapy, T cell activation that may help us to better Aktipis C.A., Boddy, A.M., Gatenby R.A., elicits innate resistance to RAF inhibitors oncogenic signaling inhibition and immu- understand both endogenous antitumor Brown, J.S., and Maley, C.C. Life history through HGF secretion. Nature 487, notherapy. We propose that the course immunity and T cell based immunother- trade-offs in cancer evolution. Nat Rev 500–504, 2012. of regression and relapse represents apies by ­inhibition of negative immune Cancer 13, 883–892, 2013. a fast-track evolutionary setting as an checkpoints such as PD-1 or targeted Zhang Z., Lee J.C., Lin L., Olivas V., Au approach to studying the interactions immune-cell activation with RIG-I ligands. Gerlinger M., Rowan A.J., Horswell S., V., LaFramboise T., Abdel-Rahman M., between different cell populations in a Larkin J., Endesfelder D., Gronroos E., Wang X., Levine A.D., Rho J.K., et al. Martinez P., Matthews,N., Stewart A., Activation of the AXL kinase causes resis- Tarpey P., et al. Intratumor ­heterogeneity tance to EGFR-targeted therapy in lung and branched evolution revealed by cancer. Nat. Genet. 44, 852–860, 2012.

Figure 3 Results of a simulated T cell ­therapy using an adaptive Picture (f.l.t.r.) ­Markovian ­dynamics Prof. Michael Hölzel, model. A future Prof. Thomas Tüting goal is to implement ­mathematic modeling in therapeutic models to understand interactions between different cell populations.

54 55 Feature Article: Salt Metabolism and Macrophages: Immunity and Of Astronauts and Normal People Aerospace Medicine Manned space flight is not only expen- “store” salt in their bodies during manned Salt Metabolism sive. It also causes a number of serious space flight, meaning that they don’t and Macrophages: health problems for astronauts due to life ­excrete enough of the NaCl taken up at zero gravity for prolonged ­periods of with their meals. This was then confirmed Of Astronauts and Prof. Waldemar Kolanus, PhD time and exposure to intense ­radiation. and extended by statistical analyses led Normal People Molecular Immunology & Cell Biology Such issues - amongst others - are by the physiologist Jens Titze (Erlangen investigated at the DLR, the German ­University/Vanderbilt University, Nashville) Life and Medical Sciences Institute Space Agency, at their site in Cologne. using a real-life simulation of a manned University of Bonn In the course of a number of studies, Mars mission, which took place in Berlin. the ­immune system and immune cells Here, the would-be astronauts lived for have also come into focus. It turned 500 days in a completely contained and out, for ­example, that ROS production, controlled environment (the ­so-called which is one of the major anti-­microbial “Mars 500 mission”). A very similar defense mechanisms of innate ­immune ­observation was made here, as well: cells, is strongly altered in macrophages test persons apparently store salt in their at ­conditions of zero-gravity. Such tissues. And this happens in a manner, ­conditions are not only available in space which does not involve concurrent ­water but may also be caused during ­parabolic uptake or a rise in aqueous volume. It flights of aircrafts, because “free fall” thus remains “invisible” to the kidneys – e.g. when the aircraft nosedives for (Rakova et al., 2013). Where are these a while - equals zero gravity. With the stores and how are they regulated? Titze help of stationary devices that simulate and colleagues had shown before that the conditions of constant free fall for tissue macrophages might play a role in cells through the use of rotation and by this process (Machnik et al., 2009). Upon employing centrifuges, which can easily stimulation with high concentrations of generate conditions of excessive weight, salt (a 40mM excess, to be precise), skin it was then shown that gravity-dependent macrophages induce the expression of alterations of ROS production of macro- the transcription factor NFAT5 (also called phages can also be observed in “normal” TonEBP), which is known to play a role laboratories, as well (Adrian et al., 2013). in renal physiology, as well. The result This raises ­important questions about of NFAT5 expression is the production the anti-bacterial ­defense mechanisms of the lymphangiogenic growth factor of ­astronauts during manned spaceflight VEGF, and lymphangiogenesis is indeed and is the subject of further investigation. observed in the skin of rats that are fed on a high-salt diet (Machnik et al, 2009; Another related area in which my lab ­ ­Izzedine et al., 2009). became involved is the general metabo- lism of astronauts (and, as will be shown, We hypothesized that macrophages of ordinary people, too!). ­Specifically, I’m might be able to sense salt stored in referring here to salt and water metab- ­tissues in the form of gradients and olism. Salt uptake is a long-known risk ­devised a very simply system to test this factor for systemic high blood pressure idea. A so-called transwell system was disease, which plays a major role in the employed by Silke Müller, a grad student development of atherosclerosis and can at the lab of Dr. Ruth Hemmersbach at damage countless other organs in the the DLR in the department of Prof. Rupert body. It was observed, that astronauts Gerzer. In the course of these studies,

57 Silke was trained by Dr. Thomas Quast in same conditions in which they would at the molecular structures of immune Other References Salt Metabolism my team at the LIMES Institute. ­normally migrate towards chemokines. cells to treat high blood pressure. With the help of Jens Titze, we were Izzedine, H., Ederhy, S., Goldwasser, and Macrophages: Salt Metabolism The observations made by Silke were ­finally able to show that macrophages F., Soria, J.C., Milano, G., Cohen, A., Of Astronauts and quite striking (Müller et al., 2013). derived from mice which lack NFAT5 Reference Publications 2013 ­Khayat, D., and Spano, J.P. Normal People and Macrophages: ­Macrophages from several sources (cell expression in macrophages (such mice Blood pressure control: salt gets under Of Astronauts and lines, bone marrow derived and ­peritoneal acquire higher blood pressure when fed Adrian A., Schoppmann K., Sromicki J., your skin. Nat Med 20, 807–815, 2009. Normal People macrophages) selectively ­migrated on a high salt diet!) surprisingly showed Brungs S., Wiesche von der, M., Hock ­towards excess concentrations of salt a normal migratory response to high B., Kolanus W., Hemmersbach R., and Machnik A., Neuhofer W., Jantsch J., present in the lower chambers of the salt concentrations (Müller et al., 2013). Ullrich O. The oxidative burst reaction in Dahlmann A., Tammela T., Machura K., transwell inserts. This was not due to ­Apparently, macrophages possess a mammalian cells depends on gravity. Cell Park J.-K., Beck F.-X., Müller D.N., Derer osmotic stress since these cells did not ­second, NFAT5-independent sensor Commun Signal 11, 98, 2013. W., et al. Macrophages ­regulate salt-de- migrate towards equi-osmolar concentra- ­system for the detection of high salt pendent volume and blood pressure by a tions of other solutes, such as the sugar ­levels. And this seems at the very least to Müller S., Quast T., Schröder A., Hucke vascular ­endothelial growth factor-C-de- mannitol. Also, these cells only became be related to their migratory ­responses S., Klotz L., Jantsch J., Gerzer R., pendent buffering mechanism. Nat Med motile when the high salt conditions were in vitro. Our future studies of course Hemmersbach­ R., Kolanus W. Salt-de- 15, 545–552, 2009. present in the lower chamber, indicating aim at the elucidation of this ­sensor pendent chemotaxis of macrophages. a bona-fide chemotaxis. This response ­system. Macrophages appear to deal PLoS ONE 8, e73439, 2013. appears to be highly cell-specific, since with a ­number of other (surprising) things, dendritic cells, which are closely related ­besides their well-known role in the killing Rakova N., Jüttner K., Dahlmann A., to macrophages, are not able to perform of pathogenic microorganisms. Maybe, Schröder A., Linz P., Kopp C., Rauh M., salt-dependent chemotaxis under the one day, clinicians will direct their efforts Goller U., Beck L., Agureev A., ­Vassilieva G, Lenkova L, Johannes B, Wabel P, Moissl U, Vienken J, Gerzer R, Eckardt KU, Müller DN, Kirsch K, Morukov B, Luft FC, Titze J. Long-term space flight Figure Current simulation reveals infradian rhythmicity model of the role in humanNa(+) balance. Cell Metab 17, of ­macrophages 125–131, 2013. in the regulation of ­interstitial NaCl ­balance (modified from Izzedine et al, 2009)

Picture (f.l.t.r.) Dr. Thomas Quast, Prof. Waldemar Kolanus, Dr. Silke Müller (all LIMES), Prof. Rupert Gerzer, Dr. Ruth Hemmersbach (both DLR)

58 59 Interview with Prof. Max P. Baur Interviews Dean of the Medical Faculty

Prof. Max P. Baur, PhD Dean of the Medical Faculty University of Bonn

Prof. Gunther Hartmann, MD Institute of Clinical Chemistry & Clinical Pharmacology Medical Faculty University of Bonn

Prof. Waldemar Kolanus, PhD Molecular Immunology & Cell Biology Life and Medical Sciences Institute University of Bonn Prof. Max P. Baur, PhD ImmunoSensation: science of all the university faculties into Dean of the Medical Faculty, The University Hospital Bonn and its diagnostics, therapy and prevention for University of Bonn Dr. Katharina Hochheiser ­Faculty of Medicine connect and integrate both patients and the general population Since 04/2011 Institute of Experimental Immunology medical departments, research institutes at large. Dean of the Medical Faculty, Medical Faculty and teaching institutions. Thus, they can University of Bonn University of Bonn be seen as a “center of competence” for 2004 – 2008 Vice-President (Prorektor) patient care, research and education. ImmunoSensation: for Science and Research, Larisa Labzin What is the significance of the Immuno- University of Bonn Institute of Innate Immunity In your opinion, what is the role of the Sensation Cluster of Excellence for the 1974 - present Medical Faculty Faculty of Medicine in terms of its status Faculty of Medicine? 16 Projects (DFG, BMFT, BMG, BMBF, EU) 3.1 Mio € University of Bonn and its significance? Max Baur: personal funding; Two large research Dr. Elmar Endl The decision to grant funding to the ­structures founded & led Head of the Flow Cytometry Core Facility Max Baur: ­ImmunoSensation Cluster of Excellence (DFG FOR 423, GEM Institute of Molecular Medicine The North-Rhine Westphalian Education awarded recognition to the long-term platform in the National Act defines universities and university ­investment that has already been made ­Genomics Research Net- Medical Faculty work NGFN) hospitals as two different and indepen- in the creation of an internationaly-­ Total funding of 21.7 Mio € University of Bonn dent public legal entities. The Medical renowned center of immunological Faculty is one of the seven faculties of ­research. Through academic appoint- the University of Bonn, meaning that ments, the creation of degree ­programs its ­primary focus is on teaching and and their ­investments in research ­research. However, medical education ­infrastructure, both the Faculty of and research are also inherently and ­Medicine and the ­Faculty of ­Mathematics ­inextricably linked to patient care at and Natural Sciences have made Bonn the University Hospital. As a result, the a center of unrivaled immunological ­Medical Faculty represents the most ­expertise. Our outstanding partner insti- ­essential link in the integration of patient tutions (DZNE, caesar, DZIF, etc) have care, research and education. We see our also made ­significant contributions to role as one of translation from the basic the research landscape. Awarding fund-

61 ing to the ­Cluster of Excellence is not these outstanding women, because, for only the reward for the strategy we have ­personal reasons, they decide not to pursued so far but also the obligation to ­pursue a ­career in academic science. make a continuing, enduring contribution This is a great loss both for science and in the future. Immunology is a field that for our greater society. Obviously, in our ­impacts many others, e.g. neurosciences, ­society, it still is not adequately recog- ­infectious diseases, translational medical nized for couples to choose to take on research. Thus, for both faculties, im- three great responsibilities, i.e. pursuing munological research is a considerable two careers and raising children at the impetus driving both external funding same time. The University Hospital, the (DFG, BMBF, EU, et al) as well as the University of Bonn and the Cluster of recruitment of outstanding students and Excellence all go to great lengths to help scientists. outstanding ­women pursue careers in academic science through dual career programs, day care and numerous other ImmunoSensation: programs. What are the advantages associated with a Cluster of Excellence? ImmunoSensation: Max Baur: The University Hospital has significantly The advantage of a Cluster of Excel- expanded in recent years and continues lence lies in its focus on the creation of to grow. Currently, the building of a new long-term, sustainable programs. The site for the German Center for Neurode- ­Cluster has enabled the recruitment of generative Diseases (DZNE) and a new new ­professors, the establishment of Mother and Child Center (ElKi) are in junior ­research groups and the creation progress. of an outstanding graduate program. Even if this funding comes to an end, the A second biomedical center (BMZ) is also investment has a long-term value and in planning. What is the current stage of will ­continue to provide for outstanding these plans? research and the excellent support of ­students and young investigators. Max Baur: During the application period for the ­Cluster of Excellence, the Faculty of ImmunoSensation: ­Medicine pledged to provide new The Faculty of Medicine, the University ­professors with sufficient space for their Hospital and their associated institutions research groups. We are ­especially proud all make every effort to recruit outstanding that we have been able to ­advance and physicians and scientists. In your opinion, expedite the building of a second bio- why are there so few female professors medical center (BMZ II) in close ­proximity in science and what could and should be to the first BMZ. ­Currently, architects and done to improve the situation? the future ­occupants of the BMZ II, inclu- ding the Cluster of ­Excellence, are in the Max Baur: process of ­designing a new 5000-square- This problem is fundamental to our meter building with laboratories, ­offices, ­society in general. Women are well ­seminar rooms and core facilities. If all ­represented at the undergraduate and goes ­according to plan, the building graduate level, where they make up should be ready for use by the end of significantly more than 50% of­students 2016. and are at least as successful as their male counterparts. However, after interviewed by they ­complete their PhD, we often lose Cluster Coordination Office

62 63 Interview with Prof. Gunther Hartmann research groups, and to fill the­respective come to the conclusion that family and Prof. Gunther Hartmann ­positions with young female scientists. an ­academic career at the forefront of Speaker of the One of them now moved on as ­professor science are mutually exclusive. We very ImmunoSensation Cluster Speaker of the ImmunoSensation Cluster of of Excellence in ­Switzerland. Furthermore, the first W3 often see that in principle women with Winner of the Gottfried- Excellence ­professorship funded by the Cluster was young families want to stay in science but Wilhelm-Leibniz-Preis given to Irmgard Förster, a renowned they decide to turn to less ­competitive 2012 ­immunologist from ­Düsseldorf. We ­areas like scientific management and ­decided that of the other four advanced coordination. In some cases, the male career positions, at least two will be partner may step back and takes most filled with female scientists. In addition, duties of daily family life, but this is the we ­offer financial support for child care. ­exception. Now, is there a solution to Young mothers receive information and this? I think yes, and we as a Cluster have special offers for nursery as well as a special responsibility to advance female ­financial benefits. Moreover, there is a free academic careers. However, it is very nursing and child care service outside the clear that it requires a ­substantial amount core working hours. The Cluster offers of money to enable both ­partners to stay special seminars on career ­opportunities, in science. It clearly requires ­specific the coordination of family life and ­research measures, and it will cost an ­additional and soft skill courses. Altogether, 400,000 amount of money. Different levels of € are available for these measures. In ­personal support have to make sure that addition, 50 % of the graduate stipend parents see their children receive good program (2 million Euro) will be used to care and attention to grow up the best recruit female students. possible way despite the time ­constraints of their parents. Important ways to ­support young parents are ­optimal day ImmunoSensation: care, support in routine duties of daily life, Prof. Gunther Hartmann ImmunoSensation: cruitment of excellent female scientists. In your opinion, what are the reasons for and child care in situations of late hours Speaker of the What is the quota of women within the For example, Andrea Ablasser, the most the low number of women at professor- of lab work or during times of ­travel. ImmunoSensation Cluster ImmunoSensation Cluster? successful female group leader in our ship level? A political decision has to be made to of Excellence Cluster, just left and has been appointed ­provide the additional funds to young University of Bonn Gunther Hartmann: a professorship at the ETH in Lausanne. Gunther Hartmann: ­female scientists. An excellence Cluster Institute of Clinical Right now about 331 students and We will further increase our efforts to This is a topic of intense discussions. is the ideal vehicle to spearhead such ­Chemistry and Clinical Pharmacology, Director ­researchers are involved in the ­Cluster. ­offer women the best conditions for their The current picture looks as follows: with an ­initiative. Surely, questions will arise © Rolf Müller/ukb The percentage of female scientists ­career development. no doubt there are as many ­excellent such as who personally and scientifically is 47%. As in other research areas, young male and female scientists. There qualifies for this additional support, and the ­quota of women decreases with is no difference in talent or capabilities. for how long? But the Cluster can explore ­advanced career stages. At the student ImmunoSensation: ­However, all scientists face the fact the best options, and establish the role and postdoc level, the percentage of Is the ImmunoSensation Cluster support- that research is one of the most ­highly model for other disciplines. Therefore, we women is 54% and 48%, ­respectively. ing women in a focused manner? ­competitive jobs and requires 100 % as a Cluster will use parts of our ­Cluster At the group leader level (including personal commitment. First, cutting funds to establish such a role model eight scientists with advanced degrees, Gunther Hartmann: edge lab research takes long hours. which specifically fosters the careers of ­Habilitation), the percentage declines Supporting women in their career de- Second, there is a high level of risk since female scientists and at the same time to 23%. The 12% of Cluster professors velopment is a central task for the Clus- ­advanced careers or professorships are generate an even beneficial situation for ­exactly match the percentage of female ter. In this respect, we are working on not ­guaranteed. In fact, the number of their children. professors at the Rheinische-­Friedrich- improving all aspects of career support ­attractive positions is rather limited, and Wilhelms Universität Bonn. The Cluster and already started to develop the cor- there are many examples where even aims to significantly increase the quota of responding structures in the preparation greatest commitment in time and efforts interviewed by women. We decided to fill 50 percent of phase of our application. Approximately does not lead to an independent ­position Cluster Coordination Office the advanced academic positions of the 60 percent of the start-up money from in science. On the other hand, there Cluster (group leaders and professors) the state of North Rhine-Westphalia is the wish to found a family and have with female candidates. However, there before our application was approved, children. In many cases, calculating the is a strong competition regarding the re- were already used to implement three risk of a scientific career, many women

64 65 Interview with Prof. Waldemar Kolanus scientific cultures of these fields are quite by UV-driven inflammation. This study different and it is therefore not always is also a good example for cooperation Vice Speaker of the ImmunoSensation Cluster easy to establish good links. The only ­because it was only made possible by approach to this is to meet often and the ­contributions of many other Cluster of Excellence to communicate as openly as possible. ­members, including Irmgard Förster, Sometimes, listening to somebody from ­Michael Hölzel, Wolfgang Kastenmüller a different area can get you much further and Bernd Fleischmann. than talking to your bona-fide “expert”, Prof. Waldemar Kolanus who will usually share most of your views. Vice Speaker of the For my taste, international ­scientific ImmunoSensation: ImmunoSensation Cluster ­conferences are too frequently put Prof. Dr. Max P. Baur, dean of the Medical of Excellence ­together around fairly narrow ­subjects, Faculty Bonn, stated that the advantage Life & Medical Sciences ­although such meetings are important, of a Cluster of Excellence lies in its focus Institute (LIMES) too. We are changing this. A narrow on the creation of long-term, sustainable Molecular Immunology & ­perspective is not what the Cluster is programs. Do you think that the interdis- Cell Biology, Director about. ciplinary co-operations will be continued beyond the Cluster’s framework?

ImmunoSensation: Waldemar Kolanus: Are there particular outstanding examples Excellence Cluster initiatives are to a Prof. Waldemar Kolanus for interdisciplinary co-operations within large degree structural programs, which and his group are inter- ested in intracellular signal the ImmunoSensation Cluster? means that it is one of our prime goal to transduction events which convince excellent colleagues to come control leukocyte adhesion, Waldemar Kolanus: to Bonn, so that they can work in close migration, and effector The quality of the scientific productivity in association with us. This was already functions. the Cluster is very high and I could go on quite successful and underscored by One focus of their current ImmunoSensation: single cells. It becomes quite obvious that with this for a while. However, I take the the recent successful recruitments of research activities is the elucidation of the role of The aim of the ImmunoSensation Cluster nobody can do all of this alone anymore. liberty to highlight two recent examples. Irmgard Förster, Wolfgang Kastenmüller integrin adhesion receptors is to efficiently investigate the complex Interdisciplinary research does not only In the recent collaborative effort of Eicke and Michael Hölzel. The establishment of and the cytoskeleton in the network of the immune sensory system. have strong advantages – it has become Latz’s and Joachim Schultze’s groups it new permanent structures already means functional adaptation of Therefore, research groups from different a necessity. was discovered how HDL (low-density sustainability. As a program, the Cluster leukocyte motility to specific microenvironments. disciplines are working together. In your lipoprotein) triggers anti-­inflammatory needs to acquire outside funds and I opinion, what are the advantages of that responses in macrophages via ATF think we are on a good way to position interdisciplinary approach? ImmunoSensation: ­transcription factors, and this paper ourselves strongly for reapplication. And According to your experience, are there was published in Nature Immunology. It even if different funding schemes emerge Waldemar Kolanus: specific challenges concerning com- was the combination of elegant in vivo in the future, the novel scientific concepts The scope of the life sciences reaches munication that come along with an models and an unbiased genomics and generated within “ImmunoSensation” are very far these days. Our not so small ­interdisciplinary structure/program like the bioinformatics approach that led to the very likely to prevail and make their way. ambition is to understand life from ImmunoSensation Cluster? right targets and thus was a ­perfect the atomistic detail of e.g. an isolated mutual fit. Another example is the latest ­immune-receptor to the intricacies of Waldemar Kolanus: Nature ­publication from ­Thomas Tüting’s interviewed by systems biology both at the cellular and The Cluster was well prepared for lab, which showed that UV ­radiation Cluster Coordination Office the organismic level. In a way this has this. Many of the Cluster scientists are strikes twice in melanoma. As a first always been the case, but the exciting ­members of the SFB 704 on “­Local event UV generates mutations, and this thing is that the tools are now becoming ­Immune Regulation and Chemical is what we knew. But UV also drives available to actually meet such formidable ­Modulation” and a strong hallmark of this cancer ­progression and development challenges. This encompasses e.g. the initiative is the co-operative approach. of ­metastases through the induction of structural resolution of complex receptor/ But of course with the introduction of the inflammatory responses - and this was signaling aggregates, the in vivo imaging Cluster, the scope widens even further completely novel. My lab was able to of motile cells interacting with each other and brings in neurobiologists, structural contribute valuable new assays to prove in their normal environments, and goes as biologists, biophysicists and mathema- that the angiotropic, migratory response far as carrying out genomic analyses from ticians. The communication styles and of the melanoma cells were modulated

66 67 Interview with Dr. Katharina Hochheiser ImmunoSensation: in a ­glomerulonephritis model. The And you continued there, first as a PhD ­previously published literature was rel- student and now as a postdoc. What atively ­contradictory and controversial. made you decide to stay even longer? We were able to show that DCs can take on ­different roles in the kidney de- Katharina Hochheiser: pending on the ­context. In homeosta- Dr. Katharina Hochheiser I had received excellent training during sis, DCs have a more ­regulatory role. is a postdoc in the labo- my diploma thesis but also knew that I In ­glomerulonephritis, they mature and ratory of Prof. Christian could still learn a lot in the Kurts lab. I also take on proinflammatory functions. eW Kurts, where she also found the research focus or rather foci were already able to publish these results completed her PhD and diploma theses. Her PhD in the lab particularly interesting, and I during the second year of my PhD. was awarded a summa ­wanted to continue working on them. cum laude in 2013. However, this brought up a different, Dr. Katharina Hochheiser Now, as a postdoc, I am still following up ­rather fascinating question. Most DCs is first and corresponding author on a publication in on a few interesting questions that came in the kidney express CX3CR1, yet no 2013 in the Journal of up during my PhD. In addition to the one had ever looked at the function Clinical Investigation, work on CX3CR1, I still have a second of this ­receptor. When we looked at “Exclusive CX3CR1 project from my PhD that I’m working ­CX3CR1-deficient mice, we saw that ­dependence of kidney on. I’m also an advisor to a new PhD the number of DCs in the kidney were DCs impacts glomerulone- phritis progression” 2013 student, who has just started and who ­drastically reduced. This effect was the Oct 1;123(10):4242-54. will ­continue on my projects when I go most pronounced in the renal ­cortex abroad by the end of the year. ­exactly where the DCs responsible for glomerulonephritis are also found. ImmunoSensation ImmunoSensation: The DCs in the renal medulla weren’t Katharina, what made you decide to go And why did you decide to go into ImmunoSensation: ­really influenced that much by the lack into science? ­immunology? Where are you going? of CX3CR1, and this DC population is ­responsible for the immune response Katharina Hochheiser: Katharina Hochheiser: Katharina Hochheiser: to infection. What’s more, this CX3CR1 I’d been fascinated with biomedical During my studies, we had several good I’m planning to start a second postdoc ­dependence also seems to be absent ­research for a long time, but it wasn’t the lecture courses on immunology. I found in Thomas Gephardt’s lab in Melbourne, from other organs with the exception of only thing I was interested in. At the end it fascinating. The body manages to Australia. During my diploma thesis, I the small intestine. of my time at school, I started looking at ­develop immune responses to all sorts of also got the chance to spend some time degree programs online and found out different pathogens in all sorts of ­different in Melbourne as an exchange student that Bonn had a relatively new program places. It manages to discover them, in Richard Kitching’s lab. The focus was ImmunoSensation: “Molekulare Biomedizin” or molecular ­distinguish friend from foe and eliminate also on nephrological research, and it was So this brings us back to the idea of biomedicine. I talked to my parents about the threat. The right cells have to get to a great experience. That’s why I decided ­having the “right cells in the right places”, it. They’re not researchers, but they still the right places. It’s a very complex, but to go back to Australia for a postdoc. doesn’t it? encouraged me to pursue whatever I was very effective, choreography. interested in. Katharina Hochheiser: ImmunoSensation: Exactly. CX3CR1 seems to be a ­kidney- ImmunoSensation: That sounds great. Congratulations! Not specific homing receptor. However, in ImmunoSensation: What brought you to Christian Kurts’s lab? only on the postdoc in Australia, you ­glomerulonephritis, we actually don’t Is that why you came to Bonn? finished your PhD in 2013 summa cum want these DCs in the renal cortex. Katharina Hochheiser: laude and published a really interesting They’re responsible for inflammation and Katharina Hochheiser: In our degree program, there were quite a paper in JCI as first and corresponding destruction of renal tissue. But we’d still Yes, at the time, there weren’t that many few lab rotations. Some were ­mandatory. author. Could you tell us a bit about your like to keep the DCs in the renal medulla programs available that specialized in Some were optional. My first otationr PhD project and the JCI paper? to protect us from infections like pyelone- ­biomedical research, and Bonn had a in Christian Kurts’s lab was a required phritis. Since these DC populations differ good website. I became a student in the one, but I really enjoyed it, so I decided Katharina Hochheiser: in their dependence on CX3CR1, it’s a second year of their program. to come back for a second, optional The project first started a couple of ­really promising target for glomerulone- ­rotation. After that, I decided to stay for years earlier, when we decided to phritis therapy. Inhibiting it could keep my diploma thesis. look at the role of dendritic cells, DCs, DCs out of the renal cortex but have few

68 69 side effects on other organs or on im- look at and that their answers may be of research even if they can’t come into the mune defense in the kidney. ­immediate practical relevance to patients. lab for a period of time. The other really For me, it’s an excellent combination of important thing is daycare. Women can’t basic and applied research. get back to the lab if there is no room in ImmunoSensation: the daycare center. However, I know that Are you following up on this? ImmunoSensation is working on providing ImmunoSensation: their female scientists with these services, Katharina Hochheiser: Your PI, Christian Kurts, and a co-author, and I think it will be of great help to them. This is one of the projects I’ve continued Percy Knolle, are both members of the on as a postdoc. Currently, I’m looking at ImmunoSensation Cluster of Excellence. whether specific inhibitors or antibodies How was the Cluster involved in the CX- ImmunoSensation: against CX3CR1 can also prevent DC 3CR1 project? As someone who has chosen to stick influx in glomerulonephritis or whether this with academic science, do you have any effect is somehow specific to CX3CR1 Katharina Hochheiser: advice for the PhD students reading this knockout mice. The technical platforms were of great interview? importance for the project, in particular “Flow Cytometry” and “Transgenic ­animal Katharina Hochheiser: ImmunoSensation: models”. The core facilities are really Don’t give up! Everyone has a time during DCs have gotten a lot of attention in ­helpful. their PhD when things just don’t work. ­recent years. Steinmann won the Nobel When that happens, take a break, keep Prize in 2011 for the discovery of their A second aspect, which is difficult to your sense of humor and try to remember role in adaptive immunity. What made you quantify, is the scientific exchange that the fun side of doing research. If you try decide to look at their role in the kidney? occurs in the Cluster. This exchange is to work day and night for 3 or 4 years, what gives you new ideas and impulses, you’ll lose perspective. Take time to catch Katharina Hochheiser: whether it’s during official talks or informal your breath and clear your head. It often DCs are really fascinating cells. They exist conversations. helps you get a new perspective on a somewhere between innate and ­adaptive problem and that’s when the best ideas immunity. They integrate the signals occur to you. ­coming from the innate immune system, ImmunoSensation: the first line of defense, and ­present The fact that we decided to interview them to the adaptive immune system. you and Larisa Labzin has nothing to interviewed by Dr. Eva Bartok ­Depending on their maturity, they can do with you being women. Rather, be regulatory or proinflammatory, which it was because you were both quite makes them a kind of central switchboard ­successful in 2013. However, the dean for the immune response. By ­influencing commented in his interview that the lack the function and migration of these cells, of women in academic science isn’t the we could also potentially control the ­enrolment numbers at university, but broader immune response. rather that so few women choose to pur- sue ­academic science as a career after- wards. As a ­female postdoc, do you feel ImmunoSensation: ­supported by the Faculty of Medicine? By And why in the kidney? ­ImmunoSensation?

Katharina Hochheiser: Katharina Hochheiser: For quite a few reasons. Kidney disease To be fair, I haven’t really needed any ex- affects many people because it can tra support so far. However, I do think that ­result from other widespread illnesses like will become relevant later when I have ­diabetes and hypertension. It’s clear that children and take maternity leave. When the immune system plays an ­important that time comes, I would like to have role here, but the exact mechanisms support from my employer. It would be still aren’t understood. This means that good if technical assistants can be hired, there are a lot of open questions for us to so that young mothers can continue their

70 71 Interview with Larisa Labzin, PhD Student ­immunity and metabolism, with a focus Larisa Labzin: on transcriptional regulation, so I could We chose to look at the role of HDL in work on a few fields that I’ve always normocholesterolemic macrophages found interesting. where the effect of cholesterol efflux wouldn’t be as important. We tested a wide variety of TLR activators instead of Larisa Labzin is in the ImmunoSensation: just looking at LPS. And we found that fourth year of her PhD That brings me to my next question. HDL inhibited TLR-signaling for all of in Prof. Eicke Latz’s You’ve obviously made the right ­decision them! Our gut feeling was that there was ­laboratory. A native of coming to Bonn, and you’ve had a very no way that HDL could just happen to Brisbane, Australia, Larisa successful year. Could you tell us some- bind this incredibly broad spectrum of completed her B.Sc. thing about the ATF3/HDL paper? ligands. Then, when we investigated the Hon. at the University the TLR signaling pathways, we found of Queensland while Larisa Labzin: that HDL didn‘t affect them, indicating working in the laboratory Of course. The short version is: we that the lipid rafts were still intact, despite of Matthew Sweet (TLR/ NLR research). ­discovered a specific anti-­inflammatory general cellular cholesterol depletion. We role for HDL that is separate from its also saw that HDL reduced intracellular Picture Larisa Labzin ­direct role in cholesterol transport. cytokine levels, indicating that it wasn‘t an © Bruna Guerra Franklin effect on secretion. So we basically tried Just about everyone knows what HDL is to narrow down where in the pathway Larissa Labzin and that it’s somehow “good ­cholesterol” HDL was mediating its effect. and Dr. Dominic DeNardo as opposed to “bad cholesterol” or shared first authorship LDL. There have been countless studies of a recent publication in Nature Immunology ImmunoSensation: assistant after finishing my bachelor’s in ­showing that high HDL levels correlate ImmunoSensation: “High-density lipoprotein So, Larisa, what brings an Australian all Australia and though I’d continue that with a lower risk of cardiovascular events. Where did you go from there? mediates anti-inflam- the way to Bonn? here and see if I wanted to pursue a Mainly, this has been attributed to the matory reprogramming PhD. However, after 3 months here, I HDL’s role in cholesterol efflux. However, Larisa Labzin: of macrophages via the Larisa Labzin was ­pretty sure that I was ready for that there have also been studies that have Our working hypothesis was that HDL transcriptional regulator Eicke Latz. I came to Bonn because I challenge. I asked Eicke if he had room shown that HDL is anti-inflammatory in was somehow involved at the transcrip- ATF3” Epub 2013 Dec 8. definitely wanted to work in his ­laboratory. for another PhD student, and he changed general. tional level. The earliest inhibitory effect However, I had thought about coming to my contract immediately. of HDL that we saw was in cytokine Europe before that. I spent a ­semester Our first question was if this effect is only mRNA levels. We thought that HDL might abroad in Berlin while studying for my due to cholesterol efflux or, ­perhaps, a then repress a transcriptional activator bachelor’s degree, and so I already ImmunoSensation: more specific anti-inflammatory ­pathway. or ­activating a transcriptional repressor. knew some German. I thought it was a So, you’ve been in innate immunity since Although there are previous studies that That’s when Eicke approached Joachim great way to combine spending time in your bachelor’s degree. What made you show that HDL somehow dampens Schultze’s lab about a collaboration. ­Germany and working in a great lab. interested in it in the first place? TLR-signaling, this has been attributed to non-specific effects. HDL really does bind Larisa Labzin: LPS (lipopolysaccharide), which of course ImmunoSensation: ImmunoSensation: During my studies, there were lots of limits TLR4 ­signaling ­because it just The paper was the result of a real Cluster If I remember correctly, you first worked fields that I found interesting: cell­biology, ­removes the ligand. ­Another ­theory was Collaboration, wasn’t it? What role did in Prof Latz’s lab as a research assistant. genetics, ­particularly ­epigenetic regula- that the cholesterol efflux­simply ­disrupts Joachim Schultze and his lab play in the Then, after a few months, you decided to tion, the biology of gene transcription. lipid rafts, and the TLRs just can’t ­signal publication? start your PhD here. What influenced your However, the ­biggest ­influence were the properly. However, we ­wanted to investi- decision? professors ­themselves. Some professors gate if HDL had a ­specific, pathway- Larisa Labzin: just exude this ­contagious enthusiasm mediated anti-inflammatory ­effect. They’ve been just brilliant, and the Larisa Labzin: for their ­research. That’s why I started ­collaboration has been incredibly Well, when I came here, I already knew in immunology, at least, but I’ve stuck fruitful. We started with a microarray I was interested in immunology. My with it because it’s a field of research that ImmunoSensation: ­experiment in wild type macrophages ­previous advisor was Matthew Sweet, ­touches on just about everything else That’s quite a broad question. What was to look for the global effect of HDL on who is also in innate immunity and a in biomedical ­research. Our paper was your approach? CpG ­induced gene expression. They TLR researcher. I worked as a research about the intersection between innate saw that HDL treatment induced a num-

72 73 ber of ­transcription factors, and then, ­inflammatory conditions like bacterial advice to students thinking about coming ­using various bioinformtaics ­approaches, ­sepsis. to Bonn for our graduate program? were able to identify ATF3 as a potential HDL inducible transcriptional ­repressor. Larisa Labzin: We confirmed that HDL did indeed ImmunoSensation: You should come! I‘ve grown to really like ­induce ATF3 in our lab, and then we One of your other successes in 2013 Bonn. It‘s quite small, but it’s pretty and did some more experiments in ATF3-­ was winning one of the first prizes at the that means you can walk and ride your deficient mice to confirm that ATF3 was ­ImmunoSensation Science Day. How bike everywhere. And, if you like having the key ­mediator of HDL‘s anti-inflam- was the meeting for you? Would you the big city life every once in a while, matory ­effect. We even did ChIP-seq ­recommend it to other students? ­Cologne is only a half an hour away. I’ve (­chromatin ­immunoprecipitation followed also found that learning German has by DNA ­sequencing) using the ATF3-­ Larisa Labzin: been a great experience for me. I‘ve deficent macrophages as a background It was actually a really cool meeting. It is made some really great friends here, and control, which gave us really clean, always good to get experience ­presenting I‘m glad I can understand German and ­comprehensive data about where ATF3 data in front of large audiences. And I can appreciate some of the Rheinlandish binding was being induced by HDL was really impressed by my ­competition! humour. across the genome. That was amazing! There’s so much great research going on We had so many hypothesis at the start, in the other groups, and it was great to The program for the students in the and we could never investigate them all, meet students from other institutes. The ­Cluster is also great. I’ve attended a so it was really nice to use an unbiased other important thing was seeing what ­communications seminar arranged by approach to identify ATF3 - and we could a broad field immunology is. ­Normally, Astrid Draffehn, which was really helpful. never have got that far without Joachim ­conferences deal with relatively narrow There are technical courses. You meet Schultze and his lab. topics, but the meeting had ­everything other students from other labs. from neuroscience to drosophila to ­molecular immunology. It’s rare as a And, of course, come for the research! ImmunoSensation: ­student to have the chance to give a talk Within the Cluster, there is funding, Where does it go from here? HDL seems in front of so many different professors. support and expertise that you can find to have quite a therapeutic potential. The questions and input were great, almost nowhere else. So far, in my PhD, so I would definitely recommend it to it’s really been “if you can think it, you Larisa Labzin: ­every student who’s interested. It was a can do it”. That’s an incredibly valuable One of the important things that great way of to getting input on my re- opportunity but it’s also incredibly rare. ­researchers have realized is that not all search from perspectives outside of my Sometimes, I think the opportunities are HDL is alike. There have been lots of ­immediate field. almost daunting, but, then again, really, I trials with HDL-raising drugs, which so wouldn’t have it any other way. far have been unsuccessful in ­treating ­cardiovascular disease. Probably a lot of ImmunoSensation: this is because when it comes to HDL - It’s a bit off topic, but speaking of interviewed by Dr. Eva Bartok its ‚quality versus ­quantity‘ - so you need ­drosophila, do they have ATF3? the HDL to be really functional.­ We used a reconstituted form of HDL in our ­studies, Larisa Labzin: which was a gift from CSL-­Behring, and As a matter of fact they do, and the its ­basically ­really hungry HDL - its re- function is conserved! And that’s not ally good at ­removing ­cholesterol from that off-topic. It’s important to keep cells. Its been shown to beneficial in the ­evolutionary background of these animal models of ­sepsis, ­vascular inflam- ­pathways in mind, and Michael Hoch is mation and even ­rheumatoid arthritis, one of my thesis advisors. as well as in animal models of athero- sclerosis. So, potentially, recombinant HDL could be beneficial for treating all ImmunoSensation: sorts of ­inflammatory illnesses, not just And, one last question, as someone who ­atherosclerosis but also autoimmune has come from very far away to do their illnesses like lupus or life-­threatening PhD in a Cluster lab, what would be your

74 75 Interview with Dr. Elmar Endl rapidly for any one individual to keep up my job is in fact communication. The with everything. head of a core facility has to be not only Head of the Flow Cytometry Core Facility an ­excellent communicator but also a Thus, a technical platform is all about ­reasonably good scientist. You have having open access to competitive to know what the researchers on your ­science. Young investigators, in ­particular, campus are up to because you have Technical Platform: would never be able to compete if we to connect them with each other. You Flow Cytometry didn’t provide them with access to bring people together, and you foster ­cutting-edge technology and teach them ­collaborations. how to use it. You also have to connect scientists with Technical Platform: Universities and research institutions have companies. On the one hand, you can also realized that these “platforms” make coordinate purchases with the admin- Flow Cytometry Picture Dr. Elmar Endl plain good sense, economically ­speaking. istration by bundling and ­streamlining © Dr. S. Putz Equipment is used better and more ­orders, and, as I said, this makes it ­efficiently. Platforms can negotiate prices far easier to negotiate prices with with suppliers because they ­represent a ­companies. On the other hand, you also larger user base. It is easier for younger have to know what techniques are on the scientists to obtain grants if they have market and what is in the pipeline, so that an infrastructure supporting them, so you can inform and advise your users. A it means more external funding for the lot of what I also do is put new products ­university. in perspective for scientists here because we know most of the old ones. ImmunoSensation: actually rather recent, isn’t it? Dr. Endl, you are the head of our Flow ImmunoSensation: We also have an important role as ­Cytometry Core Facility and you run Elmar Endl: A sustainable infrastructure with open ­educators and we’re part diplomat, part the ImmunoSensation Flow ­Cytometry In the life sciences, it is relatively new. access sounds quite a bit different than business man, part psychologist… ­Platform. First of all, what is a “core However, my background is in physics. just a shared collection of expensive ­facility”? And what is a “technical If you look at a field such as particle ­machines. ­platform”? ­physics, scientists have always had ImmunoSensation: to share equipment since, well, time Elmar Endl: Part psychologist? Elmar Endl: ­immemorial. A particle accelerator is Absolutely. I can’t stress enough that a A core facility and a technical platform phenomenally expensive and needs platform is not just the machines in it! Elmar Endl: are basically two ways of ­expressing a lot of know-how if it’s to be used The most valuable asset of a “technical Indeed. Our job isn’t only to tell people the same thing. They are a type of ­properly. CERN is a fantastic example of ­platform” is the knowledge that comes what works but also to tell them what ­research infrastructure that is the combi- ­sustainable scientific infrastructure. with it, what is around the machines. You doesn’t. The latter part is actually far nation of technical facilities, the ­current need an excellent staff both to maintain more important because negative re- staff ­working there and the years of Outside of physics, these platforms have the machines and to make sure that sults are not what usually get published. ­knowledge and experience the ­platform developed rather recently. In fact, they are users benefit from their full potential. One of the most important functions of a has ­accrued. Research infrastructures part of a paradigm shift. The life sciences ­Machines are expensive. However, my core facility is as a repository of negative provide all ­researchers access to state- are in the process of a major transition staff is invaluable. data. You don’t see that many papers of-the-art ­instrumentation and ensure between science driven by ­individuals, called “Technique X is overrated hype” this access can be acquired in a ­simple as practiced by the ­stereotypical mad or “­Technique Y cost me two frustrating and ­structured way like any good ­scientist alone in his garage, and ImmunoSensation: years of my life”… ­infrastructure, such a platform should team-oriented science, where ­resources And what about the head of a core be built to last and to serve generations and knowledge are pooled. With ­facility? Jokes aside, it’s essential to warn users of machines and scientists. It should be the ­development of more and more about pitfalls, potential artifacts and even sustainable. ­advanced technology, machines are Elmar Endl: how their data could be misinterpreted. ­getting so ­expensive and so complicated My technicians are excellent, so I don’t Sometimes you have to explain to the that ­almost no one has the money and have to spend that much time with user that the validity of his or her data has ImmunoSensation: the know-how to operate them alone. ­technical problems with equipment to be questioned. If it’s at the ­beginning But the idea of a “technical platform” is ­Scientific knowledge is expanding too and such. The most important part of of someone’s project, then good enough,

76 77 but if someone’s been working on some- so to speak. A fast-food restaurant may I know that means a lot of work for our ImmunoSensation: thing for a long time, and you’re the provide quick and reliable service, but you facility. However, the quality of the Cluster What are your plans for the Office and the bearer of the bad news that they’ve been would never go to the staff for cooking will also be measured by the quality of the Cluster in the coming years? doing it all wrong… That’s the hard part lessons. My approach is more of a “Jamie scientists we train. of the job. Oliver or Tim Mälzer” style. It’s to provide Elmar Endl: my users with the tricks of the trade, so Within the “Office of Shared ­Resources”, that they have learned something for ImmunoSensation: we would like to coordinate and stream- ImmunoSensation: life. Small tips can often make a huge I completely agree with you. But could line the use of the technical platforms. It’s That brings me to another point. When ­difference. In addition, the real challenge you maybe briefly explain to our readers important that the heads of the technical should people come to you for advice? is trying to figure out what could help my what the “Office of Shared Resources” is? platforms are in close contact, not just users before they even realize that they for technical matters, but also so that we Elmar Endl: need it. But that’s also a really fun part of Elmar Endl: can have a coordinated uniform approach Well, there are two answers depending the job. The idea comes from the US, to education and young investigator on your perspective: “whenever they where ­federal funding is provided to ­support. want” and “as soon as possible”. A core ­establish such a central facility for the facility should be available to any user, ImmunoSensation: ­communication and organization of However, my ultimate goal is something Technical Platform: anywhere, anytime,so to speak. We are That brings us back to education. ­scientific research at a particular site or that no one really has the blueprints for happy to help users at all stages of their university. It’s an official point of ­contact yet. We would like to collect detailed Flow Cytometry project whether it’s the planning, the Elmar Endl: and exchange. The office keeps tabs on ­information on which researchers have execution or the interpretation of data Education is one of the central missions what resources available, for ­example, established which techniques, so that ­afterwards. However, it is usually easier of a core facility. It is also very ­important within the Cluster, and ­communicates their colleagues can contact them for for users if they get advice early on in their in the context of ImmunoSensation. this to researchers. I don’t just mean help or advice. We would also like to projects so that they can plan things as As you know, we are working on an ­instrumentation but also ­established have a reagent database, not only to efficiently as possible. “­Office of Shared Resources” within ­techniques, reagents and most impor- share things like rare antibodies but also the ­ImmunoSensation Cluster, and this tantly know-how. People sometimes to share information about them, such Technical Platform: In fact, sometimes my advice is not to ­Office will, amongst many other things, ­forget that the most valuable resource of as “Can you use this antibody to detect use flow cytometry at all! FACS ­offers help ­coordinate education for Cluster-­ a university is knlowledge. endogenous protein levels? Or for immu- Flow Cytometry some fantastic techniques but it’s not associated scientists. noprecipitation?” This information is not magic! There are many fascinating only important for the next experiment, it ­scientific questions that are nonetheless The measure of a core facility is not only ImmunoSensation: can also help us to negotiate prices with better answered with other techniques. the know-how of the staff that is there but That must be invaluable for new a supplier because it allows us to know also how qualified your former users have ­researchers. which products really work. We also want I’m also more than happy to hear what become. to use social media or whatever else my colleagues are doing even if they have Elmar Endl: ­people are using to exchange information no initial intention of using my facility for Within the “Office of Shared Resources”, This Office is here to help scientists that and ideas. their project. Sometimes I realize that we meaning collaboratively between the are new to the Cluster, in particular. We’re have a technique that could help them, technical platforms, one of our central still at the beginning of things, but we We will need a knowledge base and but, all in all, it’s simply my job to know goals is to standardize the education are working on an information packet a user base. This is going to be the what people are working on and what we give to young scientists. We would for new arrivals, whether they are PhD real challenge. We are in the process questions interest them. I have to keep like to give our PhD students a ­minimum students or professors, detailing what of ­creating a central database, where informed and up to date if I want to make standard of knowledge in standard platforms the Cluster offers, what facilities ­scientists can schedule the use of a relevant contribution to my colleagues’ ­techniques before we send them off into are available, and more importantly whom ­equipment and share information, a research. the world. they should contact. The Office itself is in kind of central organization of ­innately fact the ­default contact point if scientists ­decentralized things. This may just Of course, I love teaching advanced don’t know who to ask. Researchers can sound like a nice theory. However, it is in ImmunoSensation: courses, but, ultimately, I would like always start collecting information at the fact a practical approach to saving our Do you think your approach to your users for all of our PhD students to at least Office of Shared Resources, and we can ­researchers time, money and frustration is typical for the head of a “core facility”? have one introductory course from our direct to specific facilities or laboratories so that they can do better science. ­facility ­before they graduate –even if their from there. Elmar Endl: ­everyday life in the lab has nothing to do There are definitely different approaches with flow cytometry. It’s a basic skill in interviewed by Dr. Eva Bartok out there. There’s the “fast-food model” life-science research.

78 79 Cluster Coordination Family Support & Gender Equality Reports Women are clearly ­underrepresented in doctoral researchers. Moreover, each Family Support & academic science. Although the ­number ­further step in the career ladder also sees of female professors has ­increased sig- a further widening of the gender gap.3 Gender Equality nificantly in the last few years, from 8 to This underrepresentation of women has Family Support & Gender Equality 19 percent since 19951, in ­engineering, lead to a great loss of talent and expertise mathematics and the natural ­sciences that is not only detrimental to women but Young Investigator Support (“MINT-Fächer”), women still only to all of academia. Clearly, realizing the comprise only 9-12% of academic potential of our female researchers is key Public Relations ­chairholders. to realizing our greater scientific potential, Importantly, this gender disparity is which is why the ImmunoSensation Clus- ­neither due to a lack of interest nor ter of Excellence is committed to sup- a lack of ­talent. In Germany, women porting female scientists, their career ad- ­comprise 44% of PhD students and even vancement and their scientific progress. 48.5% of what the German National ­Academic ­Foundation (Studienstiftung Gender Distribution: ImmunoSensation des Deutschen Volkes) considers “­highly in Numbers talented” PhD students2. However, most of these talented young ­women do not Currently, women make up approxi- Endnotes go on to pursue successful ­academic mately 20% of Cluster members (A) and 1 Source: Federal Ministry ­careers. It is striking that the gender 47% of Cluster-associated scientists in of Education and Research, www.bfbm.de ­disparity begins immediately after ­women general (B). Since (B) includes all of scien- 2 Source: German ­National complete their doctorates: female tists within the research groups of Cluster Academic Foundation, ­academics only comprise 25% of post- members, the difference between (A) and www.studienstiftung.de 3 Ibid (1)

81 (B) is largely due to the high percentage was exceptionally successful in 2013 with the University of Bonn. In 2013, we were tion, our goal is to significantly increase of female PhD students, 54% (C), and two publications in the prestigious journal able to reserve and fund positions for the percentage of female members of female postdocs 48%, (D). At the pro- Nature. Dr Ablasser’s research accom- eight female students in MeTra in 2014. the Cluster with the active recruitment of fessorial level, the proportion of women plishments are highlighted in the chapter ­outstanding women in science. drops to 12% (E). “DNA Sensing” of this report (p. 17). Childcare for Women in Science As the numbers indicate, the percentage Support for Scientists on Parental of female professors in the Cluster cur- Establishment of ImmunoSensation Reconciling family and career obligations Leave rently corresponds to the national average Office of Gender Support is particularly important for women in sci- in mathematics and the natural sciences. ence. The Office of Gender Support in- Great value is placed in a continuous Family Support & However, ImmunoSensation is actively In order to coordinate programs and vested considerable resources in 2013 to relationship between the Cluster and its Gender Equality seeking to recruit women to professorial initiatives for women within the Cluster, explore the available possibilities for child- scientists even when an individual is on positions, and we hope to have more ImmunoSensation established an Office care support for Cluster scientists. In April parental leave. In order to assist scien- women in leadership roles in the future. of Gender Support in 2013. This office is 2013, a survey was conducted among tists who cannot continue their laboratory In addition, we see our relatively high pro- coordinated by Nicole Dahms and serves parents in the Cluster to better ascertain work due to parental obligations, special portion of female postdoctoral fellows in as a central contact point for female sci- their childcare needs, and, on the basis of funding will be made available to hire stu- a very positive light. We hope that many entists. Here, women can find out about this input, the Cluster will offer two core dent assistants. (“studentische/wissen- of these women will become the profes- resources for them within the Cluster but services for parental support in 2014. schaftliche Hilfskraft”). This program will sors of tomorrow, and one central priority also on a larger university-wide, national enable researchers to continue their work of ImmunoSensation’s gender support or even international level. In addition, the - The Cluster helps to fund regular child- from home and facilitate their return to the is helping these young women scientists Office regularly reaches out to women care at the nursery “Max and Mary” laboratory after parental leave. fulfill their career potential. in the ImmunoSensation Cluster to find (Venusberg). This childcare center is out about their specific concerns in or- conveniently located at the Venusberg Children and the Future of Science der to better tailor the Cluster’s offers to between the LIMES and the University Gender Support: Our accom- the needs of its female scientists. On the Hospital Bonn. In order to inspire the female scientists of plishments in 2012-2013 basis of this valuable input from female the future, the Cluster is also committed Cluster scientists, the office arranged its - For urgent or emergency childcare, to promoting for children interested in Ex-ante appointment of a Female W3 first “gender communication” ­seminar, the Cluster cooperates with the “pme science. Prof. Micheal Heneka, a member Professor which took place in January 2014. ­Familienservice” in Bonn. Using this of the IS Steering Committee, will take ­Further seminars are planned for 2014. ­service, it will be possible to provide part in the Children’s University Program Family Support & Irmgard Förster was recruited as the childcare for emergencies and out-of- (“Kinderuni”) in January 2014. Immuno- first ImmunoSensation Cluster ­Professor Cooperation with the University of town conferences. In addition, there is Sensation will also participate in the Girls’ Gender Equality in 2012. Prof. Förster has the W3 chair Bonn also the possibility of participating in Day 2014. “­Immunology and Environment” at LIMES. childcare programs during school holi- Moreover, ImmunoSensation is also plan- Within ImmunoSensation, Prof. Förster The University of Bonn already has sev- days (“Ferienbetreuungsangebote”). ning its own programs for outreach in is both a member of the central ­steering eral facilities and programs in place to schools. In 2014, we are also planning an committee of ImmunoSensation and support women in academia. The Cluster Immunology Kindergarten for children one of the leaders of the research area closely cooperates with the gender equal- Outlook for 2014 and Beyond from 3 to 6 as well as other courses for B, “­Local Immune Regulation”. Prof. ity office of the University of Bonn (Ursula older schoolchildren. ­Förster’s research accomplishments in Mättig) and the gender equality office We hope to continue and to continually 2013 are highlighted in the chapter “­Local of the University Hospital Bonn (Sabine improve our programs for female scien- Continuous Improvement of Our Immune Regulation in Tissues” in this Zander). One result of this cooperation tists in 2014 with a specific focus on the ­Current Programs ­report (p. 81). is a seminar series that will start in 2014 following goals: with general and specific information on A sustainable improvement in the Appointment of Three Independent Fe- gender-related topics that are relevant to Further Recruitment of Talented ­representation of women in ­science male Junior Research Group Leaders scientists, especially young scientists and ­Women Scientists to the Cluster is not achievable overnight. At students. ­ImmunoSensation, we are committed Andrea Ablasser, Susanne Buch and In addition, the Cluster will fund the par- Here, the focus is on leadership ­positions. to the long-term support of our female Annett Halle have all established in- ticipation of female scientists in the MeTra In particular, ImmunoSensation aims to scientists. We plan to carefully evaluate dependent research groups within the program, a mentoring and networking recruit one additional female W3 pro- our progress and stay in close communi- ­ImmunoSensation Cluster and have been program for young women in academia. fessor and one additional female W2 cation with the women within the Cluster able to establish productive laboratories This program is part of a collaboration professor and one additional female in order to better adapt our programs to in Bonn. In particular, Dr. Ablasser’s group with the Maria-von-Linden program from ­junior research group leader. In addi- their changing needs.

82 83

Young Investigator Support

Young Immunology is a rapidly expanding field. and 87 young postdocs (< 2 years In order to get to know two of our young ­Science Day 2013 is the first of what Investigator For young immunologists, this means since PhD) from more than 20 countries scientists more personally, we would will be an annual meeting for young both an enormous variety of new ­career of the world. These young ­scientists ­encourage you to read our ­interviews with ­scientists to present their work. In 2013, Support opportunities as well as a daunting have ­research focuses as varied as the PhD student Larisa Labzin from Australia over 70 young scientists in the Cluster amount of new information and new field of immunology itself. Within the (p. 72) and young postdoc Dr. Katharina ­submitted their abstracts, and 22 of techniques which they are expected to 52 groups lead by Cluster members, Hochheiser (p. 68) from Germany. Here, them were ­selected to present their work acquire. In order to aid young scientists in our young ­researchers are active such they also describe their experiences with to an ­audience of 200 other scientists this challenging field,­ImmunoSensation fields as innate and ­adaptive immunity, the YIS program. at a ­one-day meeting. The event was a has established a Young Investigator ­neuroimmunology, genetics, bioinformat- resounding success and has been ex- Support (YIS) program for young immu- ics and applied mathematics. tended to three days in 2014. (For more nologists associated with the Cluster of 2013: Our First Year details on ­Science Day, please see also Excellence. The diverse backgrounds of our young p. 102). scientists poses unique challenges but is In August 2013, Dr. Astrid Draffehn and also an innate strength to the program, Dr. Eva Bartok became jointly ­responsible During and after Science Day, at the end Young Our Students and Young Postdocs as it fosters interdisciplinary research and for the YIS program. Dr. Draffehn is a of October, YIS hosted 5 Israeli students Investigator allows young scientists to meet a variety scientist with bioinformatic background and their advisor Prof. Hermona Soreq All of the PhD students and young of colleagues with a variety of academic at the LIMES Institute of the University as part of our scientific exchange with Support postdocs associated with any of and professional backgrounds. Since this of Bonn. Dr. Bartok is a physician at the Edmond and Lily Safra Center of Brain the 52 groups belonging to the diversity reflects the diversity of scientific University Hospital with a background Sciences at the Hebrew University in ­ImmunoSensation Cluster members are research itself, it is excellent preparation in basic immunological research. By Jerusalem. The students presented their eligible to participate in the YIS program. for their further careers. representing two different faculties and research at Science Day as well as in ­Currently, there are 170 PhD students ­professional and educational back- ­internal laboratory meetings from member grounds, Dr. Draffehn and Dr Bartok hope groups. This exchange will be continued to better support the diversity of young in the future as a part of the YIS program. investigators within the Cluster. In November 2013 the Cluster ­began its Figure Our young In September and October 2013, the YIS Meet-the-Expert series for young scien- scientists come from all conducted a large-scale survey among tists. The first professor to­participate over the world: Native young scientists (app. 80 participants) was Prof. Irina Udalova, ­Kennedy Institute countries of current YIS to find out which techniques, programs of Rheumatology, ­University of Oxford, participants shown in orange. and career support would help them who held a ­breakfast meeting with young most. Our young researchers reported ­investigators on ­November 20. that they were most interested in general courses such as statistics, data ­analysis and visualization, scientific writing and Our Plans for 2014 oral presentations. In addition, they were also particularly interested in soft skills In keeping with the needs and wishes to address conflict management in re- expressed by young scientists in the search and research groups. In terms of YIS, the following programs have been career support, students showed par- planned for 2014: ticular ­interest in visiting non-academic ­institutions and biotech companies. We - Scientific Writing with Prof. Wild; MPI for have incorporated all of these wishes into Molecular Biomedicine/ Münster our YIS program for 2014. - R Courses for data analysis & data The first event organized by YIS was ­visualization conducted by Science the Science Day 2013 on October 22. Craft/ Berlin

86 87 Young Investigator Support

Picture In front of - Presentation skills workshop with year ­experimental research ­project Young the envihab, German ­Science Craft/ Berlin in one of the member groups of the Investigator ­Aerospace Center ­ImmunoSensation Cluster. (Deutsches Zentrum für Support - Conflict Management with Dr. Roos Luft- und Raumfahrt/ from ICCON/ Aachen DLR) (f.l.t.r.) back row: Özkan - General and need-suited FACS ­courses Is, Hanna Nievendick, with Dr. Endl from the Institute of Anna Göbel, Fabian ­Molecular Medicine/ Bonn Gondorf, Sven Büttner, Katharina Meyer, Kathy Stein - Proteomics workshop with Dr. Sylvester, front row: Christina Institute for Biochemistry and Molecular Mertens, Janina Küpper, Biology/ Bonn Michaela Wittlich, Lora Heffele, Meike Welz, Karl - Excursions to: envihab, the new Komander ­research facility of the German ­Aerospace Center (Deutsches Zentrum für Luft- und Raumfahrt/ DLR), and to BAYER Pharma AG Wuppertal

- Continuation of the „meet-the-expert“ series

The International Immunology Training Program Bonn (IITB)

Picture: (f.l.t.r.) In the summer of 2014, ImmunoSensation will begin its graduate program the IITB, back row: Sander Tuit, Peeyush Sahu, Kevin the International Immunology Training Baßler, Wolfgang Krebs, Program Bonn, which is affiliated with Thomas Ulas YIS. All young scientists associated with front row: Kathrin Klee, ImmunoSensation will have the possibility Dr. Astrid Draffehn, Jil to apply for the IITB, which will provide Sander graduate students and young postdocs with a structured program on ­immunology and methodology. Throughout the ­program, IITB participants will be ­guided by their supervisor and an additional mentor.

Beside these students who are already integrated in one the Cluster research groups, new IITB students funded by the ImmunoSensation Cluster’s ­fellowships will be recruited in ­summer 2014. The students will perform a three-

88 89 Public Relations the ­Cluster started a Facebook page Public and a Twitter account. These ­platforms provide an opportunity for interactive Relations ­communication for all kinds of ­people ­interested in science. In terms of Communicating Science to the ­contributions we have made to the field of ­spreading news and getting a reaction ­Public… immunology in the last year. We encour- to a posted content, social media plat- age you to do so. forms have become a common way of Public ..is always a challenge. On the one hand, ­interaction. the subject matter is specialized. Even However, we would like to go further Relations ideas and innovations that can bring by offering a website, podcasts and a ­fundamental change to society may ­presence on social media that explain Print Material ­require a lot of background information and promote our scientific successes before they can be understood. On the to the public. We would like to inspire Last but not least, the Cluster provides other hand, scientists ­themselves may young people to go into our field, whether printed materials, e.g. folders, flyers, and not have the time, interest or ­didactic it is recruiting excellent young research- this annual report, about the Cluster’s know-how to communicate their discov- ers or reaching out to school pupils. performance and achievements. The eries to a larger public. Furthermore, we would like to promote ­member’s group is presented, so every Cluster uses a combined approach with “­ImmunoSensation” as a brand that is interested person can comprehend what online and print communication. In order However, the public should not just be connected with successful science and is kind of research is done in that group. to connect with scientists all over the interested in science for their own sake. a fitting environment for young, ambitious world, most communication material is They also have a right to know how their and outstanding scientists. ­Ultimately, Our podcasts about immunological in English and translated from German if tax money is being spent. Thus, as Kaite a modern and open image will help ­research provide an entertaining way for necessary. Pratt wrote on the Soapbox Science ­scientists, from students to professors, the public to come into contact with our ­Editor, a community guest blog from decide to become a part of our excellent research. The ImmunoSensation Cluster of ­nature.com: “Science has a PR problem.” research community. ­Excellence has been internationally visible for scientists from the beginning – now, we are working on being visible for the So, how do we solve it? What have we done so far? greater public, as well.

The ImmunoSensation Cluster of Our most important “public relations tool” ­Excellence would like to reach out to is the website: www.immunosensation.de the public. The field of immunology has seen many breakthroughs in the last Here it is possible to get the latest decades that we feel are important to ­information about Cluster publications, society at large. We now know that the ­scientific talks, seminars and news with immune system plays a central role in public outreach. Furthermore, students such ­widespread diseases as cancer, have the opportunity to get information ­diabetes, atherosclerosis and Alzheimer’s. about our programs and download the In ­addition, we have also made import- application form for the Cluster Graduate ant progress in our understanding of the Program (IITB). underlying mechanisms of autoimmune diseases such as systemic lupus ery- thematodes and glomerulonephritis. We Podcasts believe that our research is relevant for society, and we would like to share our On immunosensation.de, there are enthusiasm. ­pictures of Cluster events and podcasts about publications and topics of broader One central way of reaching out is the interest. These podcasts focus on com- Social Media ­report you are now reading. If you read municating highly complex research ideas our Scientific Reports (p. 17-59) from to non-scientists. In some podcasts, To announce news and podcasts, we 2013, you can see what important the basic research topic of a Cluster use social media. In October 2013,

90 91 Events First Retreat of the ImmunoSensation Cluster

In May 2013, the ImmunoSensation On the second day, Prof. Ola Winqvist Cluster of Excellence organized its opened the session with an inspiring first scientific retreat in St. Goar (Rhine ­presentation on “Tailored leukapheresis, ­valley), Germany. More than 45 Cluster a new approach for treating immune First Retreat of the ImmunoSensation Cluster ­members from the University of Bonn, ­mediated diseases”. Prof. Winqvist LIMES, ­caesar, the University Hospital ­presented a new clinical ­methodology, ImmunoSensation Cluster Seminars Bonn, and DZNE attended the meeting. in which the active immune system A ­particular highlight was the chance to is balanced by the removal of the International Cooperation of the Cluster‘s Graduate attend talks given by three outstanding ­proinflammatory cells which are direct- Program ITTB national and international guest speakers: Prof. ­Hermann Wagner (Technical Univer- Retreat sity Munich, Germany), Prof. Ola Winqvist (Karolinska Institute Stockholm, ­Sweden), May 2013, and Prof. Hermona Soreq (Hebrew St. Goar ­University of Jerusalem, Israel).

The retreat started with an informal hiking tour in the beautiful Rhine valley, giving the scientists the possibility to exchange ideas and discuss opportunities for new collaborations in an informal manner. In the evening the official opening by the Cluster speaker Prof. Gunther ­Hartmann ed against chronically damaged ­tissues, such as those found patients with ­autoimmune disease. For this work, he was recently awarded with the ­Athena prize, a highly prestigious award for ­clinical research.

The session was then continued with ­scientific talks given by several­Cluster members. They presented exciting

Prof. Hermann Wagner

was followed by the fascinating ­lecture of Prof. Hermann Wagner entitled “­Immune-sensing of nucleotides: Why to abdicate TLR13?“. As a pioneering expert in Toll-like receptor signalling, he shared his personal perspective on the ­development in the field and presented new data from his work.

93 Retreat new data covering the different Cluster ImmunoSensation Cluster Seminars ­research topics ranging from the basic May 2013, molecular and structural mechanisms St. Goar of nucleic acid recognition by the innate immune system to the immunopathol- ogy of Alzheimer disease and lupus July 1, 2013 ImmunoSensation ­erythematosus. Cluster Seminars Prof. Hans-Joachim Anders, MD Medizinische Klinik und Poliklinik IV Ludwig-Maximilians-University Munich

„NLRP3 and ASC in lupus-like systemic autoimmunity“ The NLRP3 inflammasome is a ­critical danger signalling platform in innate im- munity. Little data is available on its role in adaptive immunity. We found that lack of NLRP3 and ASC aggravates ­systemic Prof. Hermona Soreq autoimmunity in a mouse model of ­lupus. This effect seems independent of canoni- cal inflammasome signalling as lack of IL- In the second session, Prof. ­Hermona 1R or IL-18 did not share this phenotype. Soreq presented intriguing insights into Potential explanations were discussed. the crosstalk between the ­nervous ­system and the immune system in her ­lecture entitled “­MicroRNAs in the inter- August 21, 2013 face between anxiety and ­inflammation”. The session was ­continued with talks by Prof. Jens Titze, MD Cluster ­members from on ­research area Vanderbilt University Medical Center B: “Local ­Context ­Sensing”. The last part Nashville, TN, USA of scientific talks was specifically dedicat- ed to the ­development of new analytical „Electrolyte homeostasis: ­immunology techniques and technological platforms beyond innate and adaptive used within the Cluster framework. ­stereotypes“

Altogether, the retreat gave an ­overview of the excellent scientific progress September 13, 2013 and ­development of the technological ­platforms in the Cluster. The positive Prof. Matthew Sweet, PhD feedback by the participants showed that University of Queensland the retreat fostered the communication Australia among the Cluster members and initiated new interdisciplinary collaborations. „Mapping TLR-inducible ­inflammatory and antimicrobial pathways in The open atmosphere and the lively ­macrophages“ ­scientific discussions made this first ­retreat of the ImmunoSensation Cluster As key innate immune cells, ­macro- of Excellence a great success, combining phages use distinct families of ­pattern science with the inspiring atmosphere of recognition receptors to respond to the UNESCO world heritage Rhine Valley ­danger signals. This enables these cells in St. Goar. to initiate effective host defence, but can also lead to inappropriate inflammatory

94 95 ImmunoSensation responses during acute and chronic in- The talk was about the interactions be- ImmunoSensation Cluster Seminars flammatory diseases. This talk focused on tween innate and adaptive lymphocytes; Cluster Seminars species differences in cellular responses specifically, Prof. Gasteiger discussed initiated by the Toll-like Receptor (TLR) how regulatory T cells control the function family of pattern recognition receptors, of natural killer cells, and how an „ILC- the role of TLR-inducible zinc trafficking like“ population of NK cells expands in in human macrophage responses against response to IL-2 in the absence of reg- bacterial pathogens, and the roles of his- ulatory T cells, as well as in response to tone deacetylases in regulating TLR-me- tumors and chronic viral infection. diated inflammatory responses. The find- ings from this work help us to understand October 29, 2013 how some bacterial pathogens overcome macrophage-mediated antimicrobial re- Dr. Shamith Smarajiwa sponses, and may provide opportunities Computational Biology Group for manipulating TLR signalling for thera- peutic benefit. CRUK Cambridge Institute, University of Cambridge, UK September 16, 2013 „Integrative computational approaches Dr. Dirk Baumjohann, PhD for systems immunology and regulatory University of California, San Francisco genomics“ (UCSF), USA In order to understand complex biology „MicroRNA Regulation of T Helper Cell associated with immunity, inflammation Differentiation and Plasticity“ and cancer we have developed integra- tive systems biology approaches. This MicroRNAs are potent regulators of T includes constructing computational helper (Th) cell differentiation. Here we resources to integrate, data-mine and show that global microRNA expression in understand pathways, networks and T cells is required for the ­differentiation of underlying regulatory relationships within naive CD4 T cells into T follicular helper these systems as well as modelling these (Tfh) cells, the prototypic Th cell subset systems. We presented examples of such that provides help to B cells for the pro- computational resources for innate im- duction of high-affinity antibodies. Fur- munity and inflammation (interferome: the thermore, we show that the microRNA database of interferon regulated genes, cluster miR-17-92 regulates Tfh cells by tollome and interferonscape: systems promoting Tfh cell differentiation and by models of TLR and IFN systems) and in repressing subset-inappropriate gene ex- cancer (models of p53 target gene net- pression. works, generated by integrating transcrip- tion factor binding and gene expression in phenotypes associated with p53 activity). September 16, 2013 Dr. Georg Gasteiger, MD October 16, 2013 Immunology Program, Memorial Sloan-Kettering Cancer Center and Prof. Owen Sansom, PhD ­Howard Hughes Medical Institute, New University of Glasgow, Beatson Institute York, USA for Cancer Research, Scotland, UK

„Help and Regulation: Cooperations „Investigating key pathways important at the Interface of Adaptive and Innate for tumour initiation, progression and ­Immunity“ dedifferentiation in vivo“

96 97 left Picture: (f.l.t.r.) International cooperation of the Cluster’s Prof. Michael Heneka, graduate program IITB Prof. Hermona Soreq

Internationality and interdisciplinarity The program will include: Cooperation of are important key factors for creating right Picture: (f.l.t.r.) ­experienced and creative networks. To - Elective courses. Courses of the ELSC the Prof. Hermona Soreq, enable our young Cluster ­scientists to will cover topics like cognitive process- International Prof. Gunther Hartmann build up those networks and to ­broaden es, methods in neurobiology, advanced Immunology their knowledge beyond their own physiology, neural networks, and com- Training ­research focus, the Excellence ­Cluster puting statistics whilst courses of the Program Bonn ImmunoSensation has established a ImmunoSensation Cluster will focus on ­cooperation /an exchange with the basic immunology, methods in immunol- (IITB) ­Edmond and Lily Safra Brain Center, ogy, medical immunology, and medical ­Jerusalem, Israel (ELSC). The ELSC was microbiology. established within the Hebrew ­University of Jerusalem and aims to explore the - Practical courses in technologies. of both collaboration partners will work Science Day on October 22, 2013. At ­relationships between gene function, Three-week courses in high-end re- together on a joint project using the that event, Geula Hanin and Nir ­Waiskopf brain neuronal circuits, and behavior. search techniques will be set up to ­excellent resources of both the ELSC (both from ELSC) gave talks on their share expertise and enable researchers and the Cluster. ­current research. (For more detailed In June 2013, the Dean of the Medical to efficiently benefit from the provided ­information about the Science Day 2013, Faculty of the University of Bonn, Prof. technical platforms. - Scientific meetings and retreats. please see page 102). Max P. Baur together with Prof. Gunther The young scientists of the Hartmann and other professors of the - Exchange program. ­ImmunoSensation Cluster as well as Our collaboration with the ELSC gives Excellence Cluster visited the ELSC. In PhD students can participate in the of the ELSC can participate at the us the unique opportunity to study a joint effort, the Bonn scientists defined graduate program of the partner univer- ­scientific meetings and retreats of the the ­relationship between cognitive together with their Israeli colleagues the sity and benefit from the expertise of the other respective institution. ­neuroscience and immunology. Although cornerstones of their shared international two institutions. such an approach may seem unorthodox, program for student exchange. In a first exchange, Prof. Hermona Soreq we see great research potential in the - Collaborative research projects. (ELSC) and five of her Israeli students intersection of these fields, and we are PhD students as well as group leaders visited member groups at the University looking forward to future exchanges and of Bonn and participated in the Cluster collaborations with the ELSC.

Picture: (f.l.t.r.) Picture: (f.l.t.r.) Prof. Max Baur, Prof. Andreas Zimmer, Prof. Michael Heneka Prof. Michael Heneka, Prof. Gunther Hartmann

98 99

Cluster Science Day 2013 Cluster Science Day Joint Meeting of Young Cluster Scientists October 22, 2013

Cluster On October 22, 2013 ImmunoSensation nological vantage point, including applied Science Day held its first „Science Day“, a meeting mathematics, biophysics, bioinformatics, dedicated to the young scientists of the genetics, dermatology, electrophysiology, Geula Hanin: “Competing targets of October 22, ImmunoSensation Cluster. All students neurology and developmental biology. ­microRNA-608 modulate risks of hyper- 2013 and young postdocs (< 2 years since Thus, the research of our young scien- tension and anxiety” PhD) working in Cluster member groups tists also reflects the broad spectrum of were invited to submit abstracts. We topics and the interdisciplinary of the re- received 71 entries, all of which were search in the Cluster. In addition to the 22 for scientific exchange. Many scientists excepted for publication in the confer- ­students selected for oral presentations, also saw the conference as an opportu- ence book (available online at www. 120 young scientists attended the con- nity to get up to date on research within immunosensation.de). Twenty-two young ference. ­Although this made for a large the Cluster in general. We hope that this scientists were also chosen to give oral ­conference, even more attendees are ex- contact has also formed a basis for future presentations on October 22 at caesar pected in 2014. scientific collaborations between Cluster (center of advanced european studies scientists. and research) and competed for a total The Conference Nir Waiskopf: “Semiconductor Nanopar- of 5000€ in prize money. (Please view Altoghether over 170 Cluster-associated International Guests ticles for Biological Applications: The our profiles of the “Prizewinners” on page scientists attended Science Day. Thus, We were very please to welcome Prof. Promise and Challenges”. 105) our young scientists were able to present Hermona Soreq from the Edmond and their research to a full auditorium. During Lily Safra Institute in Jerusalem. Prof. In honor of our Israeli guests, everyone Student Participation the question-and answer session after Soreq was also accompanied by five of was invited to stay for beer and snacks All submitted abstracts themselves each talk, presenters had the opportu- her Israeli students, Bettina Nadorp, Geu- after the conference in the foyer of cae- were of impressive quality, and much nity to field questions from both young la Hanin, Nadav Yayon, Shani Shenhar- sar. Even though the scientific discussion of the research has been subsequently colleagues and renowned experts alike. Tsarfaty, and Nir Waiskopf. Two of Prof. continued, the atmosphere was relaxed, published. The scope of the abstracts This lively scientific discussion continued Soreq’s group members were chosen to and many of the guests stayed well into covered not only “classical immunology” well into the coffee breaks, giving scien- give talks on Science Day. the evening to chat with our guests. but also other disciplines from an immu- tists “young and old” an excellent forum

Picture Lecture Hall Picture (f.l.t.r.) at ­center of advanced Prof. Gunther ­european studies and Hartmann, Dr. Shani ­research (caesar) Shenhar-Tsarfaty, Geula Hanin, Prof. Hermona Soreq

102 103 Cluster Science Day 2013 First Prize Sebastian is a PhD student in Prof. Cluster ­Michael Pankratz’s laboratory (p. 164) Science Day Prizewinners ­Sebastian presented his work on patho- gen avoidance in Drosophila, a topic 2013 that is at the intersection of behavioral October 22, biology, electrophysiology and immunol- 2013 ogy. Sebastian was able to show that Cluster Science Day 2014 oral intake of food could be inhibited via Prizewinners Science Day a neural circuit under the control of neu- The popularity and success of this rons expressing the Hugin neuropeptide. October 22, year’s Science Day encouraged us to Activating these neurons resulted in an 2013 ­extend that event from one to three increase in expression of the anti-microbi- days in 2014 and to include not only oral al peptide Drosomycin, which is normally ­presentations but also poster sessions. Marion Goldeck upregulated in response to fungal infec- The next “­Science Days” will take place Marion is a PhD student under the tion. Interestingly, Hugin has a mamma- in ­November and additionally host the ­supervision of Prof. Gunther Hartmann lian homologue, NeuromedinU, which is ­scientific advisory board (SAB) of the (p. 147) and Dr. Janos Ludwig. On also involved in inflammatory processes. ImmunoSensation Cluster. The Cluster’s ­Science Day, she presented her work Sebastian and his colleagues have since SAB includes: on the chemical analysis, synthesis and published a selection of these results in bioactivity of STING ligands. Specifically, PloS Biology.w (PMID: 24960360, “Selec- Anthony Cerami (CEO Araim in collaboration with Dr. Andrea Ablasser tion of motor programs for suppressing ­Pharmaceuticals, Ossining, USA) (p.141) and Prof. Veit Hornung (p.152), food intake and inducing locomotion in We are looking forward to ­Immuno- the researchers were able to determine the Drosophila brain”, PloS Biology 2014) Steve Cohen (Department of Cellular Sensation’s Science Days 2014 and the precise endogenous ligand of STING More information on this publication will and Molecular Medicine, Copenhagen, would encourage you to attend. downstream of the cytosolic DNA-sens- be included in the Annual Report 2014. ­Denmark) ing protein cGAS. This molecule, cyclic [G(2’,5’)pA(3’,5’)p], is the first example Charles Dinarello (Division of Infectious Science Day: the Prizewinners in of a combined 2’-5’ / 3’-5’ phosphodi- Diseases, Aurora, USA) ­Profile ester linkage in a natural nucleic acid. ­Marion, Dr. Andrea Ablasser and Prof. Douglas T. Golenbock (Universi- All of the Science Day presentations Veit ­Hornung have published these results ty of Massachusetts Medical School, on October 22 were excellent, and the in Nature. (PMID: 23722158, “cGAS pro- ­Worcester, MA, USA) ImmunoSensation Steering Committee duces a 2’-5’-linked cyclic dinucleotide had quite a difficult time choosing the second messenger that activates STING”, Herbert Jäckle (Max Planck Institute prizewinners. Ultimately, 10 participants Nature 2013). For more information on for Biophysical Chemistry, Göttingen, were chosen for the “first” and “second” this publication, please see the chapter ­Germany) prizes with 6 “second prizes” (350€) and “DNA Sensing” of this report (p. 17) four “first prizes” (700€) being awarded. Luke O’Neill (Trinity College Dublin, We would like to extend our sincerest ­Dublin, Ireland) congratulations to the winners, and we Sarah Kim encourage you to read the profiles of Sarah is a medical resident in Human Hidde Ploegh (Whitehead Institute for our prizewinners and their outstanding Genetics and performs research on the Biomedical Research, Cambridge, USA) ­research! intersection between genetics and innate immunology under the joint supervision Brigitta Stockinger (MRC National of Dr. Johannes Schumacher and Prof. ­Institute for Medical Research, London, Veit Hornung (p.152) Sarah’s work ex- UK) amines genetic variants that influence gene expression under LPS stimulation Hermann Wagner (Technische (so called immune response expression ­Universität München, Munich, Germany) quantitative trait loci (iQTLs)). In her study, she examined monocytes isolated from Tony Wyss-Coray (Stanford, CA, USA) Sebastian Hückesfeld

104 105 Cluster Science Day 2013 neurin/nuclear factor of activated T cells Cluster pathway. Calcineurin and NFAT are Science Day Prizewinners well-known mediators of inflammatory responses and are the targets of the 2013 immunosuppressive drugs Ciclosporin October 22, A and Tacrolimus. In addition, Elvira and 2013 Cluster 136 human volunteers and was able to Second Prize her colleagues were able to show that map several novel iQTLs, which are active Creld1 deficiency leads to defective car- Prizewinners Science Day after TLR-4 stimulation. In particular, she diac valve development and embryonic 2013 identified iQTLs that confer risk to primary lethality in knockout mice, which most October 22, bililary cirrhosis (PBC), inflammatory bow- likely accounts for the known association 2013 el disease (IBD) and celiac disease. These between Creld1 mutations and atrioven- findings could bring novel insights into the Felix Eppler tricular septal defects in human patients. Prizewinners pathophysiology of these disorders. Felix is a PhD student under the supervi- Thus, Elvira’s work is at the intersection of sion of Prof Waldemar Kolanus (p. 157). immunology and developmental biology. Felix presented his research about T-cell These results have since been published adhesion mediated by the small GTPase in Developmental Cell. (PMID: 24697899 RAP-1 and the large GTPase Dynamin “Murine Creld1 Controls ­Cardiac Devel- 2. RAP-1 is known to be an important opment through Activation of Calcineurin/ regulator of integrin activity and cell polar- NFATc1 Signaling”, ­Developmental Cell Tobias Bald ization in leukocytes. However, Felix was 2014) More information on this publica- Tobias is a PhD student under the super- the first to investigate the role of Dynamin tion will be included in the Annual Report vision of Prof. Thomas Tüting (p. 166). 2 as a mediator of RAP-1 activation. 2014. He presented his research on the effect Chemical inhibition as well as siRNA-me- of UV-induced inflammation on mela- diated knockdown of Dynamin 2 resulted noma metastasis. In collaboration with in deficient cell adhesion which could be Prof. Waldemar Kolanus (p. 157) and Dr. rescued by RAP-1 overexpression. Thus, Larisa Labzin Thomas Quast, Tobias and his colleagues Felix was able to identify Dynamin 2 as Larisa is a PhD student under the super- were able to show that a UV-induced a completely novel mediator of integrin vision of Prof. Eicke Latz (p. 159). Her neutrophilic inflammatory response pro- dynamics and has elucidated a new layer research has focused on the anti-inflam- motes tumor cell migration along blood of regulation in the complex process of matory role of HDL in normocholester- vessel surfaces and is associated with leukocyte adhesion and migration. olemic individuals. In collaboration with a higher number of metastases. These Prof. Joachim L. Schultze (p. 165), Larisa results have recently been published in and her colleagues were able to show Nature. (PMID: 24572365 “Ultraviolet-ra- that HDL activates the transcriptional diation-induced inflammation promotes repressor ATF3 in macrophages leading angiotropism and metastasis in mela- Jonathan Schmid-Burgk to a downregulation in the production of noma”, Nature 2014.) More information Jonathan is a PhD student under the su- inflammatory cytokines. These results on this publication will be included in the pervision of Prof. Veit Hornung (p. 152). have since been published in Nature Im- Annual Report. Jonathan and his colleagues have devel- munology. (PMID: 24317040 “High-densi- oped a semi-automated high-throughput ty lipoprotein mediates anti-inflammatory assembly platform for TALE nuclease reprogramming of macrophages via the genes and CRISPR gRNA plasmids. transcriptional regulator ATF3”, Nature ­Using a ligation-independent cloning Immunology 2014.) For more information method developed by Jonathan, the re- on this publication, please see the chap- Elvira Mass searchers are currently working on the ter on „Sterile Inflammation“ in this report Elvira completed her PhD in molecular production of genome-wide libraries (p. 42). In addition, Larisa was also kind biomedicine at the end of 2013 under with the goal of pursuing genome-wide enough to allow us to interview on her the supervision of Prof. Michael Hoch (p. ­CRISPR screenings. Jonathan and his studies and research in Bonn (p. 72). 149). In collaboration with Dr. ­Dagmar colleague have already published this Wachten, Elvira was able to identify the cloning approach for TALE nuclease gene Creld1 as key regulator of the calci- genes in ­Nature ­Biotechnology. (PMID:

106 107 Cluster Science Day 2013 Prizewinners

23242165 “A ­ligation-independent clon- Picture (f.l.t.r.) ing technique for high-throughput assem- Tobias Bald, Julia Vorac, bly of transcription activator–like effector Jonathan Schmid-Burgk, genes”, Nature Biotechnology 2013). Sarah Kim, Marion Goldeck, Andrea Stutz, ­Sebastian Hückesfeld, Larisa Labzin, Felix Eppler Cluster Science Day 2013 October 22, Julia Vorac 2013 Julia is a PhD student under the super- Cluster vision of Prof. Irmgard Förster (p. 145). Prizewinners Julia presented her research on the Aryl Science Day Hydrocarbon Receptor Repressor(AhRR) 2013 and its role in the immune response to October 22, LPS. AhRR negatively regulates Aryl Andrea Stutz Hydrocarbon Receptor(AhR) activity by 2013 Andrea Stutz is a PhD student under the competing for their common binding supervision of Prof. Eicke Latz (p 159). partner ARNT. The expression of AhR is Prizewinners Andrea presented her work on the regula- known to be induced by LPS-mediated tion of NLRP3, a protein which is involved NF-KB signaling. After generating an eG- in the secretion of pro-inflammatory cyto- FP-reporter mouse for AhRR, Julia was kines in response to bacterial toxins and able to demonstrate that many immune endogenous danger signals. It is already cells of barrier organs, such as the skin known that NLRP3 is regulated on at or the intestinal epithelium, constitutively the transcriptional and translational level. express AhRR. Using eGFP-expressing However, Andrea was also able to discov- AhRR-deficient mice, Julia could show er that NLRP3 may require dephosphor- that AhRR deficiency improved­survival ylation of a critical serine residue in order after LPS challenge and Citrobacter ro- to activate downstream signaling. Since dentium infection with lower systemic NLRP3 has been implicated in many pro-inflammatory cytokine levels. Interest- widespread diseases including diabetes ingly, the reduction of pro-inflammatory mellitus, Alzheimer disease and athero- cytokines in the liver could be directly sclerosis, a better understanding of en- attributed to the smaller number of dogenous NLRP3-regulation could allow Kupffer cells (liver macrophages) found for novel therapeutic approaches. in AhRR-deficient mice. These results suggest that there is important ­crosstalk between the AhR/AhRR system and microbe sensing by the innate immune system.

108 109 Publications ImmunoSensation Publication List 2013

Abdullah Z, Schlee M, Roth S, Mraheil Commun Signal. 2013 Dec 20;11:98. MA, Barchet W, Böttcher J, Hain T, ­Geiger S, Hayakawa Y, Fritz JH, Civril Al-Amoudi A, Frangakis AS. Three-di- F, Hopfner KP, Kurts C, Ruland J, mensional visualization of the molecular Hartmann­ G, Chakraborty T, Knolle PA. architecture of cell-cell junctions in situ by RIG-I detects infection with live Listeria by cryo-electron tomography of vitreous sec- sensing secreted bacterial nucleic acids. tions. Methods Mol Biol. 2013;961:97- EMBO J. 2012 Nov 5;31(21):4153-64. 117.

Ablasser A, Goldeck M, Cavlar T, Alvarez L, Friedrich BM, Gompper ­Deimling T, Witte G, Röhl I, Hopfner KP, G, Kaupp UB. The computation- Ludwig J, Hornung V. cGAS produces al sperm cell. Trends Cell Biol. 2014 a 2‘-5‘-linked cyclic dinucleotide second Mar;24(3):198-207. Epub Dec 2013. messenger that activates STING. Nature. 2013a Jun 20;498(7454):380-4. Amanzada A, Kopp W, Spengler U, ­Ramadori G, Mihm S. Interferon-λ4 Ablasser A, Hornung V. DNA sens- (IFNL4) Transcript Expression in Human ing unchained. Cell Res. 2013 Liver Tissue Samples. PLoS One. 2013 May;23(5):585-7. Dec 20;8(12):e84026.

Ablasser A, Hertrich C, Waßermann R, Arbel Y, Shenhar-Tsarfaty S, Waiskopf N, Hornung V. Nucleic acid driven ­sterile Finkelstein A, Halkin A, Revivo M, Berliner inflammation.Clin Immunol. 2013 S, Herz I, Shapira I, Keren G, Soreq H, Jun;147(3):207-15. Banai S. Decline in Serum Cholinesterase Activities Predicts 2 Year Major Adverse Ablasser A, Schmid-Burgk JL, Cardiac Events. Mol Med. 2014 Feb ­Hemmerling I, Horvath GL, Schmidt T, 12;20:38-45. Epub Dec 2013. Latz E, Hornung V. Cell intrinsic immunity spreads to bystander cells via the inter- Bader R, Sarraf-Zadeh L, Peters M, cellular transfer of cGAMP. Nature. 2013b ­Moderau N, Stocker H, Köhler K, Nov 28;503(7477):530-4. Pankratz­ MJ, Hafen E. The IGFBP7 homolog Imp-L2 promotes insulin signal- Aburizaiza AS, Mattes FM, Azhar EI, ing in distinct neurons of the Drosophila Hassan AM, Memish ZA, Muth D, ­Meyer brain. J Cell Sci. 2013 Jun 15;126(Pt B, Lattwein E, Müller M, Drosten C. In- 12):2571-6. vestigation of anti-MERS-Coronavirus antibodies in blood donors and abbatoir Barth A, Bilkei-Gorzo A, Drews E, Otte workers in Jeddah and Makkah, Kingdom DM, Diaz-Lacava A, Varadarajulu J, Turck of Saudi Arabia, fall 2012. J Infect Dis. CW, Wienker TF, Zimmer A. Analysis of 2014 Jan 15;209(2):243-6. Epub 2013 quantitative trait loci in mice suggests Nov 11. a role of Enoph1 in stress reactivity. J ­Neurochem. 2014 Mar;128(6):807-17. Adrian A, Schoppmann K, ­Sromicki J, Epub Nov 2013. Brungs S, von der Wiesche M, Hock B, Kolanus W, Hemmersbach R, Bartok E, Bauernfeind F, Khaminets ­Ullrich O. The oxidative burst reaction in MG, Jakobs C, Monks B, Fitzgerald KA, ­mammalian cells depends on gravity. Cell Latz E, Hornung V. iGLuc: a lucifer-

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ase-based inflammasome and protease 2013;960:379-88. tegration for Biomarker Signature Discov- Ellinghaus D, Baurecht H, Esparza-­ activity reporter. Nat Methods. 2013 ery via Network Smoothed T-Statistics. Gordillo J, Rodríguez E, Matanovic A, Feb;10(2):147-54. Choinitzki V, Zwink N, Bartels E, ­Baudisch PLoS One. 2013 Sep 3;8(9):e73074. Marenholz I, Hübner N, Schaarschmidt F, Boemers TM, Hölscher A, Turial S, H, Novak N, Michel S, Maintz L, Werfel Bauerfeind F, Hornung V. Of inflamma- Bachour H, ­Heydweiller A, Kurz R, De Nardo D, Labzin LI, Kono H, Seki R, T, Meyer-Hoffert U, Hotze M, Prokisch somes and pathogens--sensing of ­Bartmann P, Pauly M, ­Brokmeier U, Schmidt SV, Beyer M, Xu D, ­Zimmer S, H, Heim K, Herder C, Hirota T, Tamari ­microbes by the inflammasome.EMBO Leutner A, Nöthen MM, ­Schumacher Lahrmann C, Schildberg FA, ­Vogelhuber M, Kubo M, Takahashi A, Nakamura Y, Mol Med. 2013 Jun;5(6):814-26. J, Jenetzky E, Reutter H. Second J, Kraut M, Ulas T, Kerksiek A, Krebs W, Tsoi LC, Stuart P, Elder JT, Sun L, Zuo X, study on the recurrence risk of ­isolated Bode N, Grebe A, Fitzgerald ML, Yang S, Zhang X, Hoffmann P, Nöthen Beutner C, Linnartz-Gerlach B, ­esophageal atresia with or without ­Hernandez NJ, Williams BR, Knolle P, MM, Fölster-Holst R, Winkelmann J, Schmidt SV, Beyer M, Mallmann MR, ­trachea-esophageal fistula among Kneilling M, Röcken M, Lütjohann D, ­Illig T, Boehm BO, Duerr RH, Büning Staratschek-Jox­ A, Schultze JL, first-degree­relatives: No evidence for Wright SD, Schultze JL, Latz E. High- C, Brand S, Glas J, McAleer MA, Fahy Neumann H. Unique transcriptome sig- increased risk of ­recurrence of EA/ density lipoprotein mediates anti-inflam- CM, Kabesch M, Brown S, McLean WH, nature of mouse microglia. Glia. 2013 TEF or for ­malformations of the VATER/ matory reprogramming of macrophages ­Irvine AD, Schreiber S, Lee YA, Franke Sep;61(9):1429-42. VACTERL association spectrum. Birth via the transcriptional regulator ATF3. Nat A, Weidinger S. High-density genotyping Defects Res A Clin Mol ­Teratol. 2013 Immunol. 2014 Feb;15(2):152-60. Epub study identifies four new susceptibility loci Bossaller L, Rathinam VA, Bonegio R, Dec;97(12):786-91. 2013 Dec 8. for atopic dermatitis. Nat Genet. 2013 Chiang PI, Busto P, Wespiser AR, Caffrey Jul;45(7):808-12. DR, Li QZ, Mohan C, Fitzgerald KA, Latz Civril F, Deimling T, de Oliveira Mann CC, Debald M, Schildberg FA, Linke A, E, Marshak-Rothstein A. Overexpression Ablasser A, Moldt M, Witte G, Hornung ­Walgenbach K, Kuhn W, Hartmann G, Erk S, Meyer-Lindenberg A, ­Schmierer of membrane-bound fas ligand (CD95L) V, Hopfner KP. Structural mechanism of Walgenbach-Brünagel G. Specific P, Mohnke S, Grimm O, Garbusow exacerbates autoimmune disease and cytosolic DNA sensing by cGAS. Nature. ­expression of k63-linked ubiquitination of M, Haddad L, Poehland L, Mühleisen renal pathology in pristane-induced lupus. 2013 Jun 20;498(7454):332-7. calmodulin-like protein 5 in breast cancer TW, Witt SH, Tost H, Kirsch P, J Immunol. 2013 Sep 1;191(5):2104-14. of premenopausal patients. J Cancer ­Romanczuk-Seiferth N, Schott BH, Claude J, Linnartz-Gerlach B, Kudin Res Clin Oncol. 2013 Dec;139(12):2125- ­Cichon S, Nöthen MM, Rietschel M, Böttcher JP, Schanz O, ­Wohlleber AP, Kunz WS, Neumann H. Microglial 32. Heinz A, Walter H. Hippocampal and D, ­Abdullah Z, Debey-Pascher S, CD33-Related Siglec-E Inhibits Neurotox- Frontolimbic Function as Intermediate Staratschek-Jox­ A, Höchst B, icity by Preventing the Phagocytosis-As- Dimmeler S, Nicotera P. MicroRNAs in Phenotype for Psychosis: Evidence from ­Hegenbarth S, Grell J, Limmer A, Atreya sociated Oxidative Burst. J Neurosci. age-related diseases. EMBO Mol Med. Healthy Relatives and a Common Risk I, Neurath MF, Busch DH, Schmitt E, van 2013 Nov 13;33(46):18270-6. 2013 Feb;5(2):180-90. Variant in CACNA1C. Biol Psychiatry. Endert P, Kolanus­ W, Kurts C, ­Schultze 2013 Dec 8;15;76(6):466-75. JL, Diehl L, Knolle PA. Liver-primed Coch C, Lück C, Schwickart A, Putschli Eckerle I, Müller MA, Kallies S, Gotthardt memory T cells generated under nonin- B, Renn M, Höller T, Barchet W, DN, Drosten C. In-vitro renal epithelial Fathy A, Chen SJ, Novak N, Schuppe flammatory conditions provide anti-in- Hartmann­ G, Schlee M. A human in vitro cell infection reveals a viral kidney tropism HC, Haidl G, Allam JP. Differential leu- fectious immunity. Cell Rep. 2013 Mar whole blood assay to predict the system- as a potential mechanism for acute renal cocyte detection by flow cytometry 28;3(3):779-95. ic cytokine response to therapeutic oligo- failure during Middle East Respiratory improves the diagnosis of genital tract nucleotides including siRNA PLoS One. 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Isolation of a specialized, antigen-­ Sep;45(9):984-94. TGF-β1 silencing with RIG-I activation in MM, Rietschel M, Ophoff RA, Hofman loaded early endosomal subpopulation pancreatic cancer. Cancer Res. 2013 A, Uitterlinden AG, Werge T, Cichon S, by flow cytometry.Methods Mol Biol. Cun Y, Fröhlich H. Network and Data In- Mar 15;73(6):1709-20. Espeseth T, Andreassen OA, Steen VM,

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Le Hellard S. A genetic deconstruction of Confers Resistance to Cytosolic Nucle- Receptors RIG-I and MDA5 Effectively Jakobs T, Keller M, Klempnauer J, Kolligs neurocognitive traits in schizophrenia and ase TREX1 Degradation and Potentiates Counteracts Cancer Cell ­Heterogeneity F, Körber J, Lang H, Lehner F, ­Lordick bipolar disorder. PLoS One. 2013 Dec STING-Dependent Immune Sensing. in Glioblastoma. Stem Cells. 2013 F, Lubienski A, Manns MP, Mahnken 12;8(12):e81052. Immunity.­ 2013 Sep 19;39(3):482-95. Jun;31(6):1064-74. A, Möhler M, Mönch C, Neuhaus P, ­Niederau C, Ocker M, Otto G, Pereira P, Forstner AJ, Degenhardt F, Schratt G, Geißler KJ, Jung MJ, Riecken LB, Sperka Globisch T, Steiner N, Fülle L, Lukacs- Pott G, Riemer J, Ringe K, Ritterbusch Nöthen MM. MicroRNAs as the cause T, Cui Y, Schacke S, Merkel U, ­Markwart Kornek V, Degrandi D, Dresing P, Alferink U, Rummeny E, Schirmacher P, Schlitt of schizophrenia in 22q11.2 deletion car- R, Rubio I, Than ME, Breithaupt C, J, Lang R, Pfeffer K, Beyer M, Weighardt HJ, Schlottmann K, Schmitz V, Schuler A, riers, and possible implications for idio- ­Peuker S, Seifert R, Kaupp UB, ­Herrlich H, Kurts C, Ulas T, Schultze JL, Förster Schulze-Bergkamen H, von Schweinitz pathic disease: a mini-review. Front Mol P, Morrison H. Regulation of Son of sev- I. Cytokine-dependent regulation of D, Seehofer D, Sitter H, Straßburg CP, Neurosci. 2013 Dec 5;6:47. enless by the membrane-actin linker denditic cell differentiation in the splenic Stroszczynski C, Strobel D, Tannapfel protein ezrin. Proc Natl Acad Sci U S A. microenvironment. Eur J Immunol. 2014 A, Trojan J, van Thiel I, Vogel A, Wacker Franken L, Kurts C, Burgdorf S. 2013 Dec 17;110(51):20587-92. Feb;44(2):500-10. Epub Dec 2013. F, Wedemeyer H, Wege H, Weinmann Monitoring the intracellular routing of A, Wittekind C, Wörmann B, Zech CJ. internalized antigens by immunofluores- Gennequin B, Otte DM, Zimmer A. CRIS- Goll Y, Bekenstein U, Barbash S, Diagnosis of and therapy for hepatocel- cence microscopy. Methods Mol Biol. PR/Cas-induced double-strand breaks ­Greenberg DS, Zangen R, Shoham S, lular carcinoma. Z Gastroenterol. 2013 2013;960:371-7. boost the frequency of gene replace- Soreq H. Sustained Alzheimer‘s Amy- Nov;51(11):1269-326. ments for humanizing the mouse Cnr2 loid Pathology in Myeloid Differentiation Gaffal E, Cron M, Glodde N, Bald T, gene. Biochem Biophys Res Commun. Protein-88-Deficient APPswe/PS1 Mice. Hagmann CA, Herzner AM, Abdullah Z, Kuner R, Zimmer A, Lutz B, Tüting T. 2013 Nov 29;441(4):815-9. Neurodegener Dis. 2014;13(2-3):58-60. Zillinger T, Jakobs C, Schuberth C, Coch Cannabinoid 1 receptors in keratinocytes Epub Oct 2013. C, Higgins PG, Wisplinghoff H, Barchet modulate proinflammatory chemokine Gerloff K, Pereira DI, Faria N, Boots AW, W, Hornung V, Hartmann G, Schlee M. secretion and attenuate contact allergic Kolling J, Förster I, Albrecht C, Powell JJ, Goller T, Seibold UK, Kremmer E, Voos RIG-I detects triphosphorylated RNA of inflammation.J Immunol. 2013 May Schins RP. Influence of simulated gastro- W, Kolanus W. Atad3 function is es- Listeria monocytogenes during infection 15;190(10):4929-36. intestinal conditions on particle-induced sential for early post-implantation de- in non-immune cells. PLoS One. 2013 cytotoxicity and interleukin-8 regulation velopment in the mouse. PLoS One. Apr 30;8(4):e62872. Gao P, Ascano M, Wu Y, Barchet W, in differentiated and undifferentiated 2013;8(1):e54799. Gaffney BL, Zillinger T, Serganov AA, Caco-2 cells. Nanotoxicology. 2013 Hammerschmidt T, Kummer MP, ­Terwel Liu Y, Jones RA, Hartmann G, Tuschl T, Jun;7(4):353-66. Gottschalk C, Damuzzo V, Gotot J, D, Martinez A, Gorji A, Pape HC, Patel DJ. Cyclic [G(2‘,5‘)pA(3‘,5‘)p] Is the Kroczek RA, Yagita H, Murphy KM, ­Rommelfanger KS, Schroeder JP, Stoll Metazoan Second Messenger Produced Gewies A, Ferch U, Jährling N, ­Heinrich Knolle PA, Ludwig-Portugall I, Kurts C. M, Schultze J, Weinshenker D, Heneka by DNA-Activated Cyclic GMP-AMP Syn- K, Hoeckendorf U, Przemeck GK, Batf3-dependent dendritic cells in the re- MT. Selective loss of noradrenaline exac- thase. Cell. 2013a May 23;153(5):1094- ­Munding M, Groß O, Schroeder T, Horsch nal lymph node induce tolerance against erbates early cognitive dysfunction and 107. M, Karran EL, Majid A, Antonowicz S, circulating antigens. J Am Soc Nephrol. synaptic deficits in APP/PS1 mice.Biol Beckers J, Hrabé de Angelis M, Dodt HU, 2013 Mar;24(4):543-9. Psychiatry. 2013 Mar 1;73(5):454-63. Gao P, Ascano M, Zillinger T, Wang W, Peschel C, Förster I, Dyer MJ, Ruland J. Dai P, Serganov AA, Gaffney BL, ­Shuman Prdm6 is essential for cardiovascular de- Grebe A, Latz E Cholesterol crystals and Harriff MJ, Burgdorf S, Kurts C, ­Wiertz S, Jones RA, Deng L, Hartmann G, velopment in vivo. PLoS One. 2013 Nov inflammation.Curr Rheumatol Rep. EJ, Lewinsohn DA, Lewinsohn DM. Barchet W, Tuschl T, Patel DJ. Struc- 21;8(11):e81833. 2013 Mar;15(3):313. TAP Mediates Import of Mycobacteri- ture-Function Analysis of STING Activa- um tuberculosis-Derived Peptides into tion by c[G(2‘,5‘)pA(3‘,5‘)p] and Targeting Glas M, Coch C, Trageser D, Daßler J, Greten TF, Malek NP, Schmidt S, Arends Phagosomes and Facilitates Loading by Antiviral DMXAA. Cell. 2013b Aug Simon M, Koch P, Mertens J, Quandel T, J, Bartenstein P, Bechstein W, ­Bernatik onto HLA-I. PLoS One. 2013 Nov 15;154(4):748-62. Gorris R, Reinartz R, Wieland A, von Lehe T, Bitzer M, Chavan A, Dollinger M, 11;8(11):e79571. M, Pusch A, Roy K, Schlee M, Neumann­ Domagk D, Drognitz O, Düx M, Farkas S, Gehrke N, Mertens C, Zillinger T, Wenzel H, Fimmers R, Herrlinger U, Brüstle O, ­Folprecht G, Galle P, Geißler M, Gerken Heilmann S, Kiefer AK, Fricker N, J, Bald T, Zahn S, Tüting T, Hartmann G, Hartmann G, Besch R, Scheffler B. G, Habermehl D, Helmberger T, Herfarth Drichel D, Hillmer AM, Herold C, Tung Barchet W. Oxidative Damage of DNA Targeting the Cytosolic Innate Immune K, Hoffmann RT, Holtmann M, Huppert P, JY, ­Eriksson N, Redler S, Betz RC,

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Li R, Kárason A, Nyholt DR, Song K, glomerulonephritis progression. J Clin NA-126 Promotes Vascular Endothelial Beckhove P. Low-Dose Irradiation Pro- ­Vermeulen SH, Kanoni S, Dedoussis ­Invest. 2013 Oct 1;123(10):4242-54. Cell Repair via SPRED1 and is Abro- grams Macrophage Differentiation to an G, Martin NG, Kiemeney LA, Mooser V, gated in Glucose-Damaged Endothelial iNOS+/M1 Phenotype that Orchestrates Stefansson K, Richards JB, Becker T, Hölzel M, Bovier A, Tüting T. Plasticity Microparticles. Circulation. 2013 Oct Effective T Cell Immunotherapy. Cancer Brockschmidt FF, Hinds DA, Nöthen of tumour and immune cells: a source 29;128(18):2026-38. Cell. 2013 Nov 11;24(5):589-602. MM. Androgenetic alopecia: identifica- of heterogeneity and a cause for thera- tion of four genetic risk loci and evidence py resistance? Nat Rev Cancer. 2013 Jüngst C, Lammert F, Strassburg CP. Kopatz J, Beutner C, Welle K, Bodea LG, for the contribution of WNT signaling to May;13(5):365-76. 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Schunkert H, Brockmeier K, Hescheler Held SA, Duchardt KM, Tenzer S, Cardiol. 2014 Jan;66:126-32. Epub J, Reppel M. A new model to perform ­Rückrich T, von Schwarzenberg K, 2013. Kastenmüller W, Brandes M, Wang Z, electrophysiological studies in the early ­Bringmann A, Kurts C, Schild H, Herz J, Egen JG, Germain RN. Peripheral embryonic mouse heart. Cell Physiol ­Driessen C, Brossart P, Heine A. Imatinib Huang LR, Wohlleber D, Reisinger prepositioning and local CXCL9 chemo- Biochem. 2013;32(1):1-10. mesylate and nilotinib affect MHC-class F, Jenne CN, Cheng RL, Abdullah Z, kine-mediated guidance orchestrate I presentation by modulating the protea- ­Schildberg FA, Odenthal M, Dienes HP, rapid memory CD8+ T cell responses in Körschen HG, Yildiz Y, Raju DN, somal processing of antigenic peptides. van Rooijen N, Schmitt E, Garbi N, the lymph node. Immunity. 2013 Mar Schonauer S, Bönigk W, Jansen V, Cancer Immunol Immunother. 2013 Croft M, Kurts C, Kubes P, Protzer U, 21;38(3):502-13. 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Kurts C, Panzer U, Anders HJ, Rees AJ. Cheng AT, Hodgkinson C, Yuan Q, palate in a mesoamerican population. Risk Variant in ZNF804A on The Theory of The immune system and kidney disease: Kane JM, Lee AT, Pisanté A, Gregersen Birth Defects Res A Clin Mol Teratol. Mind Network. Neuropsychopharmacol- basic concepts and clinical implications. PK, Pe‘er I, Malhotra AK, Goldman D, 2014 Jan;100(1):43-7. ogy. 2014 Apr;39(5):1196-205. Nat Rev Immunol. 2013 Oct;13(10):738- ­Darvasi A. Genome-wide association 53. study ­implicates NDST3 in ­schizophrenia Lutz SM, Vansteelandt S, Lange C. Test- Molinuevo JL, Gispert JD, Dubois B, and bipolar disorder. Nat Commun. ing for direct genetic effects using a Heneka MT, Lleo A, Engelborghs S, ­Pujol Kurts C. Molecular and cell-biological 2013;4:2739. screening step in family-based associ- J, de Souza LC, Alcolea D, Jessen F, mechanisms of antigen cross-presenta- ation studies Front Genet. 2013 Nov Sarazin M, Lamari F, Balasa M, Antonell tion. 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Arch Dermatol Res. 2013 Zielecki F, Horvath G, Suliman T, ­Barchet Melanomas resist T-cell therapy through P, Andrié R, Schrickel JW, Chkourko H, Apr;305(3):249-53. W, Weber F, Drosten C, Müller MA. inflammation-induced reversible de- Bukauskas FF, Kim JS, Frank M, Malan Middle East respiratory syndrome coro- differentiation. Nature. 2012 Oct D, Zhang J, Wirth A, Dobrowolski R, Malhotra A, Younesi E, Gündel M, Müller navirus accessory protein 4a is a type 18;490(7420):412-6. Mohler PJ, Offermanns S, Fleischmann B, Heneka MT, Hofmann-Apitius M. I interferon antagonist. J Virol. 2013 BK, Delmar M, Willecke K. Deletion of the ADO: A disease ontology representing the Nov;87(22):12489-95. Langhans B, Krämer B, Louis M, last five C-terminal amino acid residues domain knowledge specific to ­Alzheimer‘s ­Nischalke HD, Hüneburg R, ­Staratschek- of connexin43 leads to lethal ventricu- disease. 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Nokhbehsaim M, Eick S, Nogueira AV, Hum Genet. 2013 Jan 10;92(1):81-7. Rabionet M, Bayerle A, Marsching J. Treatment options in patients with chy- Hoffmann P, Herms S, Fröhlich H, C, Jennemann R, Gröne HJ, Yildiz Y, lothorax. Dtsch Arztebl Int. 2013 Nov Jepsen S, Jäger A, Cirelli JA, Deschner Peng WM, Maintz L, Allam JP, Raap Wachten­ D, Shaw W, Shayman JA, 29;110(48):819-26. J Stimulation of MMP-1 and CCL2 U, Gütgemann I, Kirfel J, Wardelmann Sandhoff R. 1-O-acylceramides are by NAMPT in PDL Cells. Mediators E, Perner S, Zhao W, Fimmers R, natural components of human and Schmid-Burgk JL, Schmidt T, ­Kaiser V, ­Inflamm. 2013;2013:437123. ­Walgenbach K, Oldenburg J, Schwartz mouse epidermis. J Lipid Res. 2013 Höning K, Hornung V. A ligation-inde- LB, Novak N. 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Epub ­Levels in an IL-18-Dependent Manner in P, Dobson K, Böhmer AC, Becker J, Nov 2013. Nuwaihyd R, Redler S, Heilmann S, Caspase-1-Deficient Mice Infected with ­Giehl KA, Tazi-Ahnini R, Kruse R, Wolff Drichel D, Wolf S, Birch P, Dobson K, Francisella novicida. J Immunol. 2013 H, Miesel A, Fischer T, Böhm M, Nuway- Simon D, Bieber T. Systemic ­therapy Lutz G, Giehl KA, Kruse R, Tazi-­Ahnini R, Oct 1;191(7):3847-57. hid R, Garcia Bartels N, Lutz G, Becker­ for atopic dermatitis. Allergy. 2014 Hanneken S, Böhm M, Miesel A, Fischer T, Blume-Peytavi U, Nöthen MM, Jan;69(1):46-55. Epub Dec 2013. T, Wolff H, Becker T, Garcia-­Bartels N, Pontén A, Walsh S, Malan D, Xian X, ­Messenger AG, Betz RC. The oestrogen Blume-Peytavi U, Nöthen MM, Messen- Schéele S, Tarnawski L, Fleischmann receptor 2 (ESR2) gene in female pattern Sirois CM, Jin T, Miller AL, Bertheloot D, ger AG, Betz RC. Investigation of four BK, Jovinge S. FACS-Based Isolation, hair loss: Replication of association with Nakamura H, Horvath GL, Mian A, Jiang novel male androgenetic alopecia sus- Propagation and Characterization of rs10137185 in German patients. Br J J, Schrum J, Bossaller L, Pelka K, Garbi ceptibility loci: no association with female Mouse Embryonic Cardiomyocytes Based Dermatol. 2014 Apr;170(4):982-5. N, Brewah Y, Tian J, Chang C, Chowd- pattern hair loss. Arch Dermatol Res. on VCAM-1 Surface Marker Expression. hury PS, Sims GP, Kolbeck R, Coyle AJ, 2014 May;306(4):413-8. Epub Dec 2013. PLoS One. 2013 Dec 30;8(12):e82403. Riedel JH, Paust HJ, Turner JE, Tittel Humbles AA, Xiao TS, Latz E. RAGE is AP, Krebs C, Disteldorf E, Wegscheid C, a nucleic acid receptor that promotes Oldenburg J, Müller CR, Rost S, Watzka Praveen P, Fröhlich H. Boosting prob- Tiegs G, Velden J, Mittrücker HW, Garbi inflammatory responses to DNA.J Exp M, Bevans CG. 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Vilz TO, Wehner S, Pantelis D, Kalff JC. netic variation in the lymphotoxin-α (LTA)/ Immunomodulatory Aspects in the De- tumour necrosis factor-α (TNFα) locus as Tang J, van Panhuys N, Kastenmüller velopment, Prophylaxis and Therapy for a risk factor for idiopathic achalasia. Gut. W, Germain RN. The future of immunoim- Postoperative Ileus. Zentralbl Chir. 2014 2014 Sep;63(9):1401-9. Epub Nov 2013. aging--deeper, bigger, more precise, and Aug;139(4):434-44. doi: 10.1055/s-0033- definitively more colorful.Eur J Immunol. 1350678. Epub 2013 Dec 10. Yassin AA, Elwaseef AM, Elnashar MM, 2013 Jun;43(6):1407-12. Oldenburg J, Mayer G, Pötzsch B, von Websky MW, Liermann U, Buchholz Müller J. Protamine-adsorbed magnetic Tigges J, Weighardt H, Wolff S, Götz C, BM, Kitamura K, Pascher A, Lamprecht nanoparticles for efficient isolation and Förster I, Kohne Z, Huebenthal U, Merk G, Fimmers R, Kalff JC, Schäfer N. 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122 123 List of Seminars Seminars and Meetings 2013 and Meetings SFB 704: Epigenetic silencing of ATG5 in melanoma April 10, 2013 Prof. Dr. Dr. Hans-Uwe Simon, Institute of Pharmacology, University of Bern

SFB 645: Role of Ceramides in Metabolic Diseases April 25, 2013 Prof. Scott Summers, PhD Duke-NUS Graduate Medical School, Singapore

Bonn Lecture Series in Neuroscience: Brain networks underlying episodic memory retrieval May 14, 2013 Prof. Michael D. Rugg, PhD Distinguished Chair in Behavioral and Brain Sciences Co-Director of the Center for Vital Longevity, University of Texas Institute of Physiology, University of Leipzig

SFB 704: Visualizing Type I Interferon producing cells – a matter of commitment? June 11, 2013 Prof. Dr. rer. nat. Stefanie Scheu, Institute for Medical Microbiology and Hospital ­Hygiene, University Hospital Duesseldorf

SFB/TRR 57 CMM-lecture: Homodimers of the NF-kappB p50 subunit function as tumour suppressors in ageing- and carcinogen-associated liver disease June 26, 2013 Prof. Dr. Derek Mann, Institute of Cellular Medicine, Newcastle University

Bonn Lecture Series in Neuroscience: Autonomous and non-autonomous ­regulation of axon integrity June 27, 2013 Dr. Bogdan Beirowski, MD, PhD, Washington School of Medicine, Department of ­Genetics, St Louis, Missouri

SFB 704: Studying Epstein-Barr Virus pathologies and immunosurveillance by reconstructing EBV infection in mice June 28, 2013 Prof. Dr. rer. nat. Klaus Rajewsky, Max Delbrück Center for Molecular Medicine, Berlin

ImmunoSensation Seminar: NLRP3 and ASC in lupus-like systemic autoimmunity July 01, 2013 Prof. Dr. med. Hans-Joachim Anders, Medizinische Klinik und Poliklinik IV Ludwig-Maximilians-University Munich

125 Seminars 2013 Seminars 2013

SFB 704: CD4 T cells amplify innate immune response by dendritic cells for SFB 704: Antibodies modulate immune highways and dendritic cell trafficking ­optimal anti-viral CTL immunity November 05, 2013 July 09, 2013 Dr. Menna Clatworthy, Department of Medicine, Laboratory of Molecular Biology Dr. Sammy Bedoui, University of Melbourne University of Cambridge, UK

ImmunoSensation Seminar: Electrolyte homeostasis: immunology beyond innate SFB 704: Mechanisms of Gene Regulation in Immune Cells and adaptive stereotypes November 11, 2013 August 21, 2013 Dr. Elke Glasmacher, Institute for Diabetes and Obesity Prof. Dr. Jens Titze, Vanderbilt University Medical Center, Nashville, TN, USA Helmholtz Zentrum, München

ImmunoSensation Seminar: Mapping TLR-inducible inflammatory and SFB 704: Ab initio characterization of the immune system using massively ­antimicrobial pathways in macrophages ­parallel single cell RNA-Seq September 13, 2013 November 14, 2013 Prof. Matt Sweet, PhD, Department of Pediatric Haematology & Oncology, Prof. Dr. Ido Amit, Laboratory for Immuno-Genomics, Weizmann Institute of Science, University of Queensland, Australia Rehovot, Israel

ImmunoSensation Seminar: MicroRNA Regulation of T Helper Cell Differentiation SFB 704: IRF5 expressing macrophages: regulation of inflammatory gene and Plasticity ­programme September 16, 2013 November 19, 2013 Dr. Dirk Baumjohann, University of California, San Francisco (UCSF), USA Prof. Irina Udalova, PhD Kennedy Institute of Rheumatology, University of Oxford, UK

ImmunoSensation Seminar: Help and Regulations: Cooperations at the Interface Bonn Lecture Series on Systems Biology - Kick-off Seminar: Regulatory RNAs of Adaptive and Innate Immunity December 05, 2013 September 16, 2013 Prof. Dr. Nikolaus Rajewsky, Max-Delbrück-Center for Molecular Medicine, Berlin Dr. Georg Gasteiger, Immunology Program, Memorial Sloan-Kettering Cancer Center and Howard Hughes Medical Institute, New York, USA

SFB 704: The growing family of NKT cells meet the growing family of lipid ­antigens Meetings 2013 September 18, 2013 Prof. Dr. Dale Godfrey, University of Melbourne, Australia

SFB 704: Vaccination against chronic diseases September 24, 2013 SFB 704 Symposium: Immuno Regulation Prof. Dr. Martin Bachmann, The Jenner Institute, University of Oxford, UK April 22, 2013 - April 23, 2013 Speaker Prof. Tom Freeman, Division of Genetics & Genomics, University of Edinburg ImmunoSensation Seminar: Investigating key pathways important for tumour Speaker Prof. Hans-Uwe Simon, Institute of Pharmacology, University of Bern initiation, progression and dedifferentiation in vivo October 16, 2013 Retreat ImmunoSensation Cluster of Excellence Prof. Owen Sansom, PhD, Beatson Institute for Cancer Research, May 26-27, 2013, Schlosshotel Rheinfels, St. Goar University of Glasgow, Scotland Cluster Science Day ImmunoSensation Seminar: Investigating key pathways important for tumour October 22, 2013, research center caesar, Bonn initiation, progression and dedifferentiation in vivo October 29, 2013 Roche Workshop 2013 for Young Scientists of the ImmunoSensation Cluster of Dr. Shamith Samarajiwa, University of Cambridge, UK Excellence November 19-20, 2013, Life & Brain, University Hospital Bonn

126 127 Prizes and Distinctions awarded within the Prizes & Distinctions ImmunoSensation Cluster 2013

June 29, 2013 University of Bonn awarded Prof. Hermann Wagner an honorary doctorate Prof. Hermann Wagner from the Institute of Medical Microbiology at the Technical ­University Munich received an honorary doctorate from the Medical Faculty of the ­University of Bonn for his achievements in immunology.

July 01, 2013 ImmunOligo received third prize at Science4Life business plan competition The GO-Bio funded project „RNA Therapeutics“ and its partner company ImmunOligo won third prize at the Science4Life annual business plan competition. The business plan was presented by Prof. Gunther Hartmann, Dr. Annegret de Baey-Diepolder, Dr. Christine Schuberth, Dr. Marcel Renn, Anna Schwickart.

August 05, 2013 Prof. Anton Bovier became a Fellow of the Institute of ­Mathematical Statistics (IMS) Anton Bovier, Professor in Applied Mathematics at Rheinische Friedrich-Wilhelms-­ Universität Bonn, has been named a Fellow of the Institute of Mathematical Statistics (IMS). An induction ceremony took place at the Joint Statistics Meetings in Montreal, Quebec, Canada. Prof. A. Bovier received the award for his research into the theory of random media.

October 07, 2013 Dr. Andrea Ablasser and Prof. Veit Hornung received ­Pettenkofer Prize Dr. Ablasser and Prof. Hornung from the Institute for Molecular Medicine, ­University Hospital Bonn won the prize granted by the Pettenkofer Foundation in Munich in ­recognition of their work on the activation of STING by the cGAS produced second messenger (see: Ablasser A. et. al. Nature 2013 June 0;498(7454):380-4).

October 24, 2013 Dr. Andrea Ablasser received Jürgen Wehland Prize The Jürgen Wehland Prize is for junior scientists. Dr. Ablasser from the Institute of ­Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn was awarded the Jürgen Wehland Prize for her outstanding research on mechanisms of pathogen recognition by the innate immune system.

October 24, 2013 Prof. Michael T. Heneka received the Alzheimer Research Award The Hans und Ilse Breuer Foundation awarded Prof. Dieter Edbauer (DZNE-Munich) und ImmunoSensation cluster member Prof. Michael T.Heneka (University of Bonn and DZNE-Bonn) with the Alzheimer Research Award. Prof. Michael T. Heneka was ­awarded in recognition of his research on neuroinflammatory diseases.

2013 Prof. Hermona Soreq from The Edmond and Lily Safra Center for Brain ­Sciences (Hebrew University of Jerusalem) became an Advanced ERC

129 Prizes and Distinctions awarded within the Prizes and Distinctions awarded within the Cluster 2013 Cluster 2013

2013 Prof. Gunther Hartmann from the Institute of Clinical Chemistry and ­Clinical was awarded for his research on the Toll-like-rezeptor 3 in arteriogenesis, which he Pharmacology, University Hospital Bonn became an elected member of the ­presented during the BONFOR-Symposium in Bonn. Dr. Zimmer’s group is a part of the ­German National Academy of Sciences, Leopoldina Medical Clinic II under the supervision of Prof. G. Nickenig.

2013 Prof. Frank Bradke form the German Center for Neurodegenerative December 05, 2013 Dr. med Laura Maintz received the second prize from ­Diseases (DZNE) became an elected EMBO member The European Molecular ­BONFOR for junior research group leaders ­Biology Organization elects members based on their outstanding achievements over Dr. Maintz from the Department of Dermatology and Allergy, University Hospital of the course of their scientific careers. Bonn, was awarded for her research on “Neuropeptide and Neurotrophin levels and the increased expression of their receptors in skin of patients with mastocytosis”, which December 05, 2013 Carola Hertrich received the first prize from BONFOR for she presented during the BONFOR-Symposium in Bonn. Dr. Maintz’s group is a part of SciMed- scholars Clinic of Dermatology and Allergology under the supervision of Prof. N. Novak. Carola Hertrich is from the Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn. She was awarded for her work on “ iFi203-An Important componen of cyclic dinucelotide sensing”. Her advisors are Dr. A. Ablasser and Prof. V. Hornung.

December, 05 2013 Barbara Heinemann received the second prize from BONFOR for SciMed-scholars Barbara Heinemann is from the Institute for Human Genetics, University Hospital Bonn, was awarded for her work on the “Analysis of genetic risk factors on KCTD13, a ­candidate gene for schizophrenia”. Her work was done in the Institute of Human ­Genetics, which is under the supervision of Prof. M. Nöthen.

December 05, 2013 Maren Schmalenströr received the third prize from BONFOR for SciMed-scholars Maren Schmalenströr from the Institute of Clinical Chemistry and Clinical ­Pharmacology (University Hospital Bonn), was awarded for her work on “Antitumoral CD8+ T cell ­response after therapeutic vaccination with whole-cell vaccines in syngeneic mouse models of ovarian cancer”. Her advisors are the Cluster members Dr. W. Barchet and Prof. G. Hartmann.

December 05, 2013 Dr. Judith Kohlmeyer received the first prize from BONFOR for Gerok-scholars Dr. Kohlmeyer from the Institute of Dermatology and Allergy, University Hospital Bonn, was awarded for her work on “ TNF-alpha reversibly impairs recognition of melanomas by antigen specific T cells”. Her advisor is Prof. T. Tüting.

December 05, 2013 Dr. Isabel Spier received the second prize from BONFOR for Gerok-scholars Dr. Spier from the Institute of Human Genetics, University Hospital Bonn, was awarded for her work on the “Identification of candidate genes in intestinal polyposis”. Dr. Spier is a physician in the Institute of Human Genetics under the supervision of Prof. M. Nöthen.

December 05, 2013 Dr. Sebastian Zimmer received the first prize from BONFOR for junior research group leaders Dr. Zimmer from the Department of Medicine/Cardiology, University Hospital Bonn,

130 131 Annual Report 2013 Members ImmunoSensation Member List

Andrea Ablasser Institute of Clinical Chemistry & Clinical Pharmacology Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

Al-Amoudi, Ashraf German Centre for Neurodegenerative Diseases (DZNE) [email protected]

Bano, Daniele German Centre for Neurodegenerative Diseases (DZNE) [email protected]

Barchet, Winfried Institute of Clinical Chemistry & Clinical Pharmacology Medical Faculty, University of Bonn, University Hospital of Bonn [email protected]

Becker, Tim German Centre for Neurodegenerative Diseases (DZNE) [email protected]

Betz, Regina Institute of Human Genetics Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

Bieber, Thomas Department of Dermatology & Allergology Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

Bovier, Anton Probability Theory and Stochastic Analysis Institute for Applied Mathematics, University Bonn [email protected]

Bradke, Frank German Centre for Neurodegenerative Diseases (DZNE) [email protected]

Brossart, Peter Medical Clinic III for Haematology and Oncology Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

133 Annual Report 2013 Annual Report 2013 ImmunoSensation Member List ImmunoSensation Member List

Buch, Susanne Gerzer, Rupert Life & Medical Sciences Institute (LIMES) Institute of Aerospace Medicine University of Bonn German Aerospace Center (DLR), Cologne [email protected] [email protected]

Burgdorf, Sven Gieselmann, Volkmar Life & Medical Sciences Institute (LIMES) Institute of Biochemistry & Molecular Biology University of Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Dilloo, Dagmar Halle, Annett Department of Pediatric Haematology & Oncology center of advanced european studies and research (caesar) Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected] Hartmann, Gunther Drosten, Christian Institute of Clinical Chemistry & Clinical Pharmacology Institute of Virology Medical Faculty, University of Bonn, University Hospital Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected] Heneka, Michael Fava, Eugenio Institute of Neurology German Center for Neurodegenerative Diseases (DZNE) Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Fleischmann, Bernd K. Hoch, Michael Institute of Physiology 1 Life & Medical Sciences Institute (LIMES) Medical Faculty, University of Bonn, University Hospital of Bonn University of Bonn [email protected] [email protected]

Förster, Irmgard Hölzel, Michael Life & Medical Sciences Institute (LIMES) Institute of Clinical Chemistry & Clinical Pharmacology University of Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Fröhlich, Holger Hörauf, Achim Algorithmic Bioinformatics at the B-IT Medical Microbiology, Immunology and Parasitology University of Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Garbi, Natalio Hornung, Veit Institutes of Molecular Medicine and Experimental Immunology (IMMEI) Institute of Molecular Medicine Medical Faculty, University of Bonn, University Hospital Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

134 135 Annual Report 2013 Annual Report 2013 ImmunoSensation Member List ImmunoSensation Member List

Kalff, Jörg Nickenig, Georg Department of Surgery Medical Clinic II for Cardiology, Angiology and Pneumology Medical Faculty, University of Bonn, University Hospital Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Kastenmüller, Wolfgang Nicotera, Pierluigi Institutes of Molecular Medicine and Experimental Immunology (IMMEI) German Centre for Neurodegenerative Diseases (DZNE) Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected] Nöthen, Markus M. Kaupp, U. Benjamin Institute of Human Genetics center of advanced european studies and research (caesar) Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Knolle, Percy Novak, Natalija Institutes of Molecular Medicine and Experimental Immunology (IMMEI) Department of Dermatology Medical Faculty, University of Bonn, University Hospital Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Kolanus, Waldemar Oldenburg, Johannes Life & Medical Sciences Institute (LIMES) Experimental Haematology and Transfusion Medicine University of Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Kurts, Christian Pankratz, Michael J. Institutes of Molecular Medicine and Experimental Immunology (IMMEI) Life & Medical Sciences Institute (LIMES) Medical Faculty, University of Bonn, University Hospital Bonn University of Bonn [email protected] [email protected]

Lange, Christoph Sahl, Hans-Georg Institute of Genomic Mathematics Medical Microbiology, Immunology and Parasitology Medical Faculty, University of Bonn, University Hospital Bonn Medical Faculty, University of Bonn, University Hospital Bonn [email protected] [email protected]

Latz, Eicke Schultze, Joachim L. Institute of Innate Immunity Life & Medical Sciences Institute (LIMES) Medical Faculty, University of Bonn, University Hospital Bonn University of Bonn [email protected] [email protected]

Neumann, Harald Soreq, Hermona Institute of Reconstructive Neurobiology Department of Biological Chemistry Medical Faculty, University of Bonn, University Hospital Bonn Hebrew University, Jerusalem [email protected] [email protected]

136 137 Annual Report 2013 ImmunoSensation Member List

Spengler, Ulrich Medical Clinic I - General Internal Medicine Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

Staratschek-Jox, Andrea Life & Medical Sciences Institute (LIMES) University of Bonn [email protected]

Strassburg, Christian Medical Clinic I - General Internal Medicine Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

Thiele, Christoph Life & Medical Sciences Institute (LIMES) University of Bonn [email protected]

Tüting, Thomas Department of Dermatology Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

Wachten, Dagmar center of advanced european studies and research (caesar) [email protected]

Zimmer, Andreas Institute of Molecular Psychiatry (IMP) Medical Faculty, University of Bonn, University Hospital Bonn [email protected]

138 139 2010 Dissertation Price of the University of ­Munich (Münchener Dr. Andrea Ablasser, MD Universitätsgesellschaft) Institute of Clinical Chemistry and Clinical Pharmacology Biosketches 2009 Fellow of the program “BONFOR“, ­Medical Faculty, ­University of Bonn 2007 Cluster Application Members Fellow of the Munich-Harvard-Alliance Fellow of the German Academic Exchange Service (DAAD) 2006 Graduate School 1202 “Oligonucleotides in cell biology an therapy“, German Research Foundation (DFG) 2005 Fellow of the German National Merit Foundation ­(Studienstiftung des Deutschen Volkes)

10 Most Relevant Publications for Dr. Andrea Ablasser 1. Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Rheinische Friedrich-Wilhelms-Universität Bonn Roers A, Hornung V. TREX1-deficiency triggers cell-autono- Institute of Clinical Chemistry and Clinical mous immunity in a cGAS-dependent manner. ­Pharmacology Journal of Immunology. 2014, in press 2. Ablasser A, Schmid-Burgk JL , Hemmerling I, Horvath G, E-Mail: [email protected] Schmidt T, Latz E, Hornung V. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Research Expertise Nature 2013 Sep 29. doi: 10.1038/nature12640 Dr. Ablasser’s main research focus is the immunorecogni- 3. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, tion of nucleic acids. Her work has contributed to identifying­ Röhl I, Hopfner K-P, Ludwig J, Hornung V. cGAS produces intracellular DNA sensors and to elucidating DNA-triggered a 2´-5´-linked cyclic dinucleotide second messenger that antiviral signaling mechanisms. activates STING. Nature 2013 Jun 20;498(7454):380-4. doi: 10.1038/nature12306. Education / Training 4. Civril F, Deimling T, de Oliveira Mann C. C, Ablasser A, Moldt M, Witte G, Hornung V, Hopfner K-P. Structural mecha- University of Munich, Germany, Medicine, M.D., thesis, nism of cytosolic DNA sensing by cGAS. 2010 Nature 2013 Jun 20; 498 (7454):332-7. doi: 10.1038/na- University of Munich, Germany, Medicine, M.D., state ture12305. examination, 2008 5. Cavlar T, Deimling T, Ablasser A, Hopfner KP, Hornung V. Species-specific detection of the antiviral small-molecule Appointments / Positions Held compound CMA by STING. EMBO J. 2013 May; 15;32 (10): Since 2014 1440-50. Assistant Professor, Global Health Institute, École 6. Kim S, Bauernfeind F, Ablasser A, Harmann G, Fitzgerald KA, Hornung V. Listeria monocytogenes is sensed by the ­Polytechnique Féderale de Lausanne, Switzerland NLRP3 and AIM2 inflammasome. European Journal of Immu- 2011 - 2014 nology. 2010 Jun; 40 (6):1545-51. Junior Group Leader, Institute of Clinical Chemistry and 7. Ablasser A, Bauernfeind F, Hartmann G, Latz E, ­Fitzgerald Clinical Pharmacology, University of Bonn, Germany KA, Hornung V. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed 2008 - 2011 RNA intermediate. Nature Immunology. 2009; 10 (10):1065-72. Postdoctoral Research Fellow, Department of Clinical 8. Ablasser A, Poeck H, Anz D, Berger M, Schlee M, Kim S, Chemistry and ­Clinical Pharmacology, University of Bonn, Bourquin C, Goutagny N, Jiang Z, Fitzgerald KA, Rothenfusser ­Germany S, Endres S, Hartmann G, Hornung V. Selection of molecular structure and delivery of RNA oligonucleotides to activate 2008 TLR7 versus TLR8 and to induce high amounts of IL-12p70 in Visiting scientist, Division of Infectious Diseases and primary human monocytes. Journal of Immunology. 2009 Jun ­Immunology, University of Massachusetts, Worcester, USA 1;182 (11): 6824-33. 9. Berger M, Ablasser A, Kim S, Bekeredjian-Ding I, Giese Honors / Awards T, Endres S, Hornung V, Hartmann G. TLR8 driven IL-12-de- 2014 pendent reciprocal and synergistic activation of NK cells and Paul Ehrlich- und Ludwig Darmstaedter Prize for Young monocytes by immunostimulatory RNA. Journal of Immuno- Researchers therapy. 2009 Apr; 32 (3): 262-71. 2013 10. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA. AIM2 recognizes Max von Pettenkofer Prize cytosolic dsDNA and forms a caspase-1-activating inflam- 2013 masome with ASC. Jürgen Wehland Prize Nature. 2009 Mar 26; 458 (7237): 514-8.

141 2005 hair growth and treatment of hair loss.” (together with Prof. Prize of excellence for young researchers for the PhD work, Nöthen, S. Pasternack Dipl.-biol., and Dr. Al Aboud) Dr. Ashraf Al-Amoudi, PhD Faculty of Biology and Medicine, University of ­Lausanne, Prof. Regina Betz, MD 2008 Lecture Prize at the Annual Meeting of the European Hair German Centre for Neurodegenerative Diseases (DZNE) and Lausanne, Switzerland Research Society in Genoa, Italy center of advanced european studies and research (caesar) Institute of Human Genetics 2006 Gottron-Just-Scientific Prize of the University and City of 10 Most Relevant Publications for Dr. Ashraf Al- Ulm, Germany ­Amoudi 2002 - 2004 Flemish Research Council Postdoctoral ­Fellowship 1. Al-Amoudi A, Frangakis AS. 2013. Three-dimension- 2000 - 2002 DFG Postdoctoral Fellowship al visualization of the molecular architecture of cell-cell junctions in situ by cryo-electron tomography of vitreous sections. Methods Mol Biol 961: 97-117. 10 Most Relevant Publications for Prof. Regina Betz 2. Al-Amoudi A, Castaño-Diez D, Devos DP, Russell RB, 1. Basmanav FB*, Oprisoreanu AM*, Pasternack SM*, Thiele Johnson GT, Frangakis AS. The three-dimensional molec- H, Fritz G, Wenzel J, Größer L, Wehner M, Wolf S, Fagerberg C, Bygum A, Altmüller J, Rütten A, Parmentier L, El Shabrawi-Caelen ular structure of the desmosomal plaque. Proc. Natl. Acad. L, Hafner C, Nürnberg P, Kruse R, Schoch S, Hanneken S, Betz Sci. 2011,108, 6480-5. RC. 2014. Mutations in POGLUT1, encoding protein O-glucosyl- 3. Al-Amoudi A, Diez DC, Betts MJ, Frangakis AS. 2007. transferase 1, cause autosomal dominant Dowling-Degos disease. The molecular architecture of cadherins in native epidermal Am J Hum Genet 94:135-143. desmosomes. Nature 450: 832-7. 2. Pasternack SM, Refke M, Paknia E, Hennies HC, Franz T, 4. Castano-Diez D, Al-Amoudi A, Glynn AM, Seybert A, Schäfer N, Fryer A, van Steensel M, Sweeney E, Just M, Grimm Frangakis AS. 2007. Fiducial-less alignment of cryo-sec- C, Kruse R, Ferrándiz C, Nöthen MM, Fischer U, Betz RC. 2013. tions. J Struct Biol 159: 413-23. Mutations in SNRPE, encoding a core protein of the spliceosome, German Centre for Neurodegenerative Diseases (DZNE) Rheinische Friedrich-Wilhelms-Universität Bonn cause autosomal-dominant hypotrichosis simplex. Am J Hum 5. , Studer D, Dubochet J. 2005. Cutting and center of advanced european studies and research Al-Amoudi A Institute of Human Genetics Genet 92:81-87. artefacts and cutting process in vitreous sections for (caesar) E-Mail: [email protected] 3. Jagielska D, Redler S, Brockschmidt FF, Herold C, Garcia cryo-electron microscopy. J Struct Biol 150: 109-21. E-Mail: [email protected] Bartels N, Hanneken S, Eigelshoven S, Refke M, Barth S, Giehl 6. Al-Amoudi A, Dubochet J, Norlen L. 2005. Nanostruc- Research Expertise KA, Kruse R, Lutz G, Wolff H, Blaumeiser B, Böhm M, Blume-Pey- ture of the epidermal extracellular space as observed by tavi U, Becker T, Nöthen MM, Betz RC. 2012. A follow-up study of Research Expertise The aim of our research is the identification and functional cryo-electron microscopy of vitreous sections of human characterization of genes for monogenic and genetically com- a genome-wide association scan in alopecia areata: replication of previously identified loci and identification of IL13 and KIAA0350 as Structural biology, cryo-electron tomography, ­intercellular skin. J Invest Dermatol 124: 764-77. plex hair loss disorders with a major focus on the autoimmune adhesion unctions, synapses, neurodegenerative ­diseases. 7. Norlen L, Al-Amoudi A. 2004. Stratum corneum keratin new susceptibility loci supported with genome-wide significance. J disorder alopecia areata (AA). We have the largest sample Invest Dermatol 132:2192-2197. structure, function, and formation: the cubic rod-packing of AA patients available worldwide, which includes a current 4. Wen Y, Liu Y, Xu Y, Zhao Y, Hua R, Wang K, Sun M, Li Y, Yang Education / Training and membrane templating model. J Invest Dermatol 123: total of more than 2.200 individuals of middle European origin. S, Zhang XJ, Kruse R, Cichon S, Betz RC, Nothen MM, van University of Lausanne, Switzerland, Life science/EM 715-32. We have been able to demonstrate the contribution of the Steensel MA, van Geel M, Steijlen PM, Hohl D, Huber M, Dunnill ­Structural, Biology, PhD, 2004 8. Al-Amoudi A, Chang JJ, Leforestier A, McDowall A, HLA-complex and the genes PTPN22, TRAF1/C5 , CTLA4, GS, Kennedy C, Messenger A, Munro CS, Terrinoni A, Hovnanian University of Lausanne, Switzerland, Physics, Science Salamin LM, Norlen LP, Richter K, Blanc NS, Studer D, IL13 and KIAA0350 to the disease risk using candidate gene A, Bodemer C, de Prost Y, Paller AS, Irvine AD, Sinclair R, Green diploma, 1999 Dubochet J. 2004. Cryo-electron microscopy of vitreous studies. By the use of genome-wide association studies, meta- J, Shang D, Liu Q, Luo Y, Jiang L, Chen HD, Lo WH, McLean WH, analyses, immunochips and further functional studies, we are He CD, Zhang X. 2009. Loss-of-function mutations of an inhibitory Birzeit University, West Bank, Palestine, Physics, B.Sc, sections. EMBO J 23: 3583-8. 9. Norlen L, Al-Amoudi A, Dubochet J. 2003. A cryotrans- currently aiming to identify new causative genes for AA and will upstream ORF in the human hairless transcript cause Marie Unna 1997 hereditary hypotrichosis. Nat Genet 41: 228-33. mission electron microscopy study of skin barrier formation. thus contribute to a comprehensive understanding of AA. 5. Pasternack SM, von Kugelgen I, Aboud KA, Lee YA, Rus- Appointments / Positions Held J Invest Dermatol 120: 555-60. Education / Training chendorf F, Voss K, Hillmer AM, Molderings GJ, Franz T, Ramirez 10. Al-Amoudi A, Norlen LP, Dubochet J. 2004. Cryo-elec- Jan 2010 - present University of Bonn, Germany Human Genetics, A, Nurnberg P, Nothen MM, Betz RC. 2008. G protein-coupled tron microscopy of vitreous sections of native biological receptor P2Y5 and its ligand LPA are involved in maintenance of Group leader, Cryo-Electron Microscopy and ­Tomography Habilitation, 2009 cells and tissues. J Struct Biol 148: 131-5. University of Bonn, Germany, Human Genetics, Medical human hair growth. Nat Genet 40: 329-34. in neurodegenerative diseases, German Centre for Specialist, 2007 6. Hillmer AM, Brockschmidt FF, Hanneken S, Eigelshoven S, ­Neurodegenerative Disease (DZNE) and Center of Karolinska Institute, Stockholm, Sweden University of Saarland Steffens M, Flaquer A, Herms S, Becker T, Kortum AK, Nyholt DR, ­Advanced European Studies and Research (caesar), Bonn Clinical Medicine, Medical license, 1999 Zhao ZZ, Montgomery GW, Martin NG, Muhleisen TW, Alblas MA, 2005 - 2009 University of Saarland, Germany, Medicine, MD thesis, 1998 Moebus S, Jockel KH, Brocker-Preuss M, Erbel R, Reinartz R, Postdoctoral fellow, Structural and Computational ­Biology Betz RC, Cichon S, Propping P, Baur MP, Wienker TF, Kruse R, Unit, European Molecular Biology Laboratory (EMBL), Appointments / Positions Held Nothen MM. 2008. Susceptibility variants for male-pattern bald- ­Heidelberg, Germany 2010 - present Heisenberg Professorship, Institute of Human ness on chromosome 20p11. Nat Genet 40: 1279-81. 7. , Planko L, Eigelshoven S, Hanneken S, Pasternack 2004 - 2005 Genetics, University of Bonn, Germany Betz RC 2009 - 2010 Research Scientist, Institute of Human Genetics, SM, Bussow H, Van Den Bogaert K, Wenzel J, Braun-Falco M, Postdoctoral, Laboratory of Ultrastructure Analysis Rutten A, Rogers MA, Ruzicka T, Nothen MM, Magin TM, Kruse University of Lausanne, Switzerland University of Bonn, Germany 2004 - 2009 Independent Head of a Junior Research Group, R. 2006. Loss-of-function mutations in the keratin 5 gene lead to ­Institute of Human Genetics, University of Bonn, Germany Dowling-Degos disease. Am J Hum Genet 78: 510-9. 8. Levy-Nissenbaum E, Betz RC, Frydman M, Simon M, Lahat Honors / Awards 2002 - 2004 Postdoctoral fellow, Department of Medical 2014 – 2017 H, Bakhan T, Goldman B, Bygum A, Pierick M, Hillmer AM, Jonca Genetics, University of Antwerp, Belgium N, Toribio J, Kruse R, Dewald G, Cichon S, Kubisch C, Guerrin M, SFB, Transregio Collaborative Research, TRR83 2000 - 2002 Postdoctoral fellow, Institute of Human Genetics, Serre G, Nothen MM, Pras E. 2003. Hypotrichosis simplex of the 2012 – 2017 University of Bonn, Germany scalp is associated with nonsense mutations in CDSN encoding Cluster of Excellence, ImmunoSensation, DFG 1999 - 2000 Research Scientist, Institute of Human Genetics, corneodesmosin. Nat Genet 34: 151-3. 2010 - 2014 University of Bonn, Germany 9. Betz RC, Schoser BG, Kasper D, Ricker K, Ramirez A, Stein V, Wellcome Trust and MRC Career Development Awards - Torbergsen T, Lee YA, Nöthen MM, Wienker TF, Malin JP, Propping Honors / Awards declined P, Reis A, Mortier W, Jentsch TJ, Vorgerd M, Kubisch C. 2001. 2010 Heisenberg-Professorship from the DFG Mutations in CAV3 cause mechanical hyperirritability of skeletal 2007 - 2009 2004 - 2009 Emmy Noether Independent Junior Research Marie Curie Intra-European Fellowship muscle in rippling muscle disease. Nat Genet 28: 218-9. Group (DFG) 10. Betz RC, Lee Y-A, Bygum A, Brandrup F, Bernal AI, Toribio 2006 - 2007 2008 PRO-SCIENTIA-Sponsorship Award of the Eckhart-­ J, Alvarez JI, Kukuk GM, Ibsen HHW, Rasmussen HB, Wienker EMBO Fellowship Buddecke-Foundation for the advancement of basic medical TF, Reis A, Propping P, Kruse R, Cichon S, Nöthen MM. 2000. A research gene for hypotrichosis simplex of the scalp maps to chromosome 2008 EP-Patent application 07 01 8871.9: “Maintenance of 6p21.3. Am J Hum Genet 66:1979-1983.

142 143 University of Bonn, Germany 1988 -1990 1986 - 1988 Research Fellow, Institute for Genetics, University of Prof. Anton Bovier, PhD Visiting Assistant Professor, Mathematics Department Prof. Irmgard Förster, PhD ­Cologne Institute for Applied Mathematics University of California, Irvine, CA, USA Life and Medical Sciences Institute (LIMES) 1982 - 1986 Honors / Awards Assistant 1994 Institute for Theoretical Physics Bennigsen Foerder Prize, Ministry of Science and ­Research ETH-Zurich of North Rhine-Westphalia 1991 - 1992 Honors / Awards Research grant from the DFG 2013 1985 - 1988 Elected Fellow, Institute of Mathematical Statistics Research Scholarship from the Fritz Thyssen Stiftung 2012 1988 Kloosterman Chair, University Leiden, NL Awarded Summa cum laude for thesis titled „Studies on 2010 the characterization of Ly1-B-cell population“ Lady Davies Visiting Professor, Technion, Haifa, IL 2010 10 Most Relevant Publications for Prof. Irmgard ­Förster Plenary Speaker, Annual Meeting of the German 1. Globisch, T., Steiner, N.*, Fülle, L.*, Lukacs-Kornek, V., ­Mathematical Association Degrandi, D., Dresing, P., Alferink, J., Lang, R., Pfeffer, K., 2009 Beyer, M., Weighardt, H., Kurts, C., Ulas, T., Schultze J.L and Förster, I. 2014. Cytokine-dependent regulation of denditic cell Rheinische Friedrich-Wilhelms-Universität Bonn EURANDOM Chair, EURANDOM; Eindhoven, NL Rheinische Friedrich-Wilhelms-Universität Bonn differentiation in the splenic microenvironment. Eur. J. Immunol. Institute for Applied Mathematics 2008 Life and Medical Sciences Institute (LIMES), Member of the Selection Committee of the Minerva 44, 500-510. E-Mail: [email protected] Immunology and Environment, Director ­Foundation 2. Köhler, T., Reizis, B., Johnson, R.S., Weighardt, H. and E-Mail: [email protected] 2008 Förster, I. 2012. Influence of hypoxia inducible factor 1a on dendritic cell differentiation and migration. Eur. J. Immunol. 42, Research Expertise Member of the Review Board for Mathematics of the 1226-1236. The main focus of my work concerns the analysis of ­German Research Council Research Expertise 3. Stutte S, Quast T, Gerbitzki N, Savinko T, Novak N, Reifen- interacting stochastic systems of many components. This 2006 Prof. Förster has special expertise in the functional includes a special focus on models from statistical mechan- ­characterization of macrophages and dendritic cells using berger J, Homey B, Kolanus W, Alenius H and Förster I. 2010. Invited Speaker at the International Congress of Requirement of CCL17 for CCR7- and CXCR4-dependent ics with an emphasis on disordered models, in particular ­Mathematicians, Madrid conditional gene targeting techniques. She is interested spin glasses. Apart from classical aspects of equilibrium in cell migration and immune regulation in barrier organs, migration of cutaneous dendritic cells. Proc. Natl. Acad. Sci. Gibbs measures I am particularly interested in aspects of and has profound experience with mouse models of atopic USA 107: 8736-41. 10 Most Relevant Publications for Prof. Anton Bovier 4. Semmling V, Lukacs-Kornek V, Thaiss C, Quast T, Hochhe- long term dynamics such as metastability and aging. More dermatitis, inflammatory bowel disease and 1. Mayer, H., Bovier, A. 2014. Stochastic models of T-cell iser K, Panzer U, Rossjohn J, Perlmutter P, Cao J, Godfrey D, recently I am also interested in ­application of methods from bacterial infection. activation. J. Math. Biology: Online first. Savage P, Knolle P, Kolanus W, Förster I* and Kurts C* 2010. these areas in models of population ­genetics, ecology, and 2. Arguin, L.-P., Bovier, A., Kistler, N. 2013. The extremal pro- Education / Training Alternative cross-priming through CCL17/CCR4-mediated neurodegenerative diseases. cess of branching Brownian motion. Prob. Theor. Rel. Fields: University of Cologne, Germany CTL attraction towards NKT cell-licensed dendritic cells. Nat. 157, 535-574. Genetics, PhD, 1988 Immunol. 11: 313-20. Education / Training 3. Hölzel, M., Bovier, A., Tüting, T. 2013. Plasticity of tumor University of Marburg, Germany 5. Gross O, Gewies A, Finger K, Schäfer M, Sparwasser T, Technical University of Berlin, Germany and immune cells: a source of heterogeneity and a cause for Human Biology, Diploma, 1985 Peschel C, Förster I and Ruland J. 2006. Card9 controls a Mathematics, Habilitation 1995 therapy resistance? Nature Reviews Cancer: 13, 365—376. novel non-TLR signaling pathway for innate anti-fungal immuni- The Swiss Federal Institute of Technology 4. Bovier A., den Hollander F, Spitoni C. 2010. Homogeneous Appointments / Positions Held ty. Nature. 442, 651-656. (ETH), Zurich nucleation for Glauber and Kawasaki dynamics in large vol- 2012 - present 6. Buch T, Polic B, Clausen BE, Weiss S, Akilli Ö, Chang CH, Physics, Dr. sc. nat., 1986 umes and low temperature. Ann Probab 38: 661–713. W3 Professor of Immunology and Environment Life and Flavell R, Schulz A, Jonjic S, Waisman A and Förster I. 2006. University of Bonn, Germany 5. Ben Arous G, Bovier A., Cerný J. 2008. Universality of the Medical Sciences (LIMES) Institute, MHC class II expression through a hitherto unknown pathway REM for dynamics of mean field spin glasses. Commun Math Physics, Diploma, 1981 University of Bonn supports T helper cell dependent immune responses: implica- Phys 282: 663–695. 2005 - 2012 tions for MHC class II deficiency. Blood. 107, 1434-1444. 6. Bovier A. 2006. Statistical mechanics of disordered sys- 7. Alferink J*, Lieberam I*, Reindl W, Behrens A, Weiß S, Appointments / Positions Held Laboratory Head of Molecular Immunology tems. A mathematical perspective”, 312 + xiv pp, Cambridge Hüser N, Gerauer K, Ross R, Reske-Kunz A, Ahmad-Nejad P, 2008 - present IUF - Leibniz Institute for Environmental Medicine at the Series in Statistical and Probabilistic Mathematics Cambridge Wagner H and Förster I. 2003. Compartmentalized production Full Professor, Institute for Applied Mathematics University Press Vol. 18. University of Düsseldorf, Germany of CCL17 in vivo: strong inducibility in peripheral dendritic cells University of Bonn, Germany 7. Bovier A, Gayrard V, Klein M. 2005. Metastability in re- 2004 - 2012 contrasts selective absence from the spleen. J. Exp. Med. 2003 - 2008 versible diffusion processes II. precise asymptotics for small C3 Professor of Molecular Immunology 197, 585-599. Full Professor, Mathematics eigenvalues. J Europ Math Soc 7:69–99. Heinrich-Heine-University Düsseldorf 8. Lieberam I and Förster I. 1999. The murine beta-chemokine Technical University, Berlin, Germany 8. Baake E, Baake M, Bovier A, Klein M. 2005. An asymptotic 1998 - 2004 TARC is expressed by subsets of dendritic cells and attracts 1994 - 2008 maximum principle for essentially linear evolution models. J Head of the Volkswagen Foundation Research Group primed CD4+ T cells. Eur. J. Immunol. 29: 2684-2694. Laboratory Head, and 2nd Deputy Director Math Biology 50: 83-114. ­Institute for Medical Microbiology, Immunology and ­Hygiene 9. Clausen BE, Burkhardt C, Reith W, Renkawitz R and Först- Weierstrass-Institute for Applied Analysis and Stochastics 9. Ben Arous G, Bovier A, Gayrard V. 2003. Glauber dynam- and the second Medical Clinic, Technical ­University of er I. 1999. Conditional gene targeting in macrophages and (WIAS), Berlin ics of the random energy model. 2. Aging below the critical Munich granulocytes using LysMcre mice. Transg. Res. 8: 265-277. 1992 - 1995 temperature. Commun Math Phys 236: 1-54. 1997 - 1998 10. Takeda K*, Clausen BE*, Kaisho T, Tsujimura T, Terada 10. Bovier A, Eckhoff M, Gayrard V, Klein M. 2002. Metastabil- Deputy Laboratory Head Assistant Professor, Institute for Genetics, University of N, Förster I* and Akira S* 1999. Enhanced Th1 activity and ity and low-lying spectra in reversible Markov chains. Commun WIAS, Berlin Cologne development of chronic enterocolitis in mice devoid of Stat3 in Math Phys 228: 219-255. macrophages and neutrophils. Immunity. 10: 39-49. 1991 - 1992 1993 - 1997 Postdoctoral Research Fellow, Institute for Genetics, Research Associate, Mathematics Department *These authors contributed equally Bochum University, Germany ­University of Cologne 1988 - 1991 1990 - 1993 Research Associate, Physics Department Postdoctoral Research Fellow, University of California, San Francisco, USA

144 145 2005 - 2007 Honors / Awards Postdoctoral Fellowship, German Academic Exchange 2013 - present Elected Member of the German Academy of Dr. Annett Halle, MD Foundation (DAAD) Prof. Gunther Hartmann, MD ­Sciences Leopoldina 2006 2012 Gottfried-Wilhelm Leibniz-Preis center of advanced european studies and research (caesar) Institute of Clinical Chemistry and Clinical Pharmacology 2011 - 2012 Elected President of the Oligonucleotide ­Therapeutics Young Scientist Award, Science Foundation Berlin, Society (OTS) ­Germany 2011 Dr.-Friedrich-Sasse-Preis, Berliner Medizinische ­Gesellschaft/ 2006 GoBio-Award of the Federal Ministry for Education and Research Award for the best medical dissertation of 2005, Berlin (BMBF) Society for Psychiatry and Neurology 2010 Elected Vice Speaker of the SFB 670 2005 2009 Elected member of the committee Krebstherapie-Studien of Humboldt Prize (Prize for best dissertation of the year, the German Cancer Aid (Deutsche Krebshilfe) Humboldt University Berlin) 2007 Wilhelm-Vaillant-Award for Medical Sciences 2004 Ludwig-Heilmeyer-Award (Ludwig-Heilmeyer Society, Internal Medicine, Germany) / Biofuture Award, of the Federal Ministry for 10 Most Relevant Publications for Dr. Annett Halle Education and Research (BMBF) / Georg-Heberer Award, Chiles 1. Schnaars M, Beckert H, Halle A. Assessing β-amyloid-in- Foundation, Portland duced NLRP3 inflammasome activation in primary microglia. 2000 Paul-Martini-Award / Award “Young Master” of the German Methods Mol Biol. 2013;1040:1-8. Society for Hematology and Oncology“ 2. Krabbe, G.*, Halle, A.*, Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Ket- 10 Most Relevant Publications for Prof. Gunther Hartmann 1. Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, Tüting tenmann, H. and Heppner, F. L., Functional impairment of T, Hartmann G, Barchet W. Oxidative damage of DNA confers microglia coincides with Beta-amyloid deposition in mice with center of advanced european studies and Rheinische Friedrich-Wilhelms-Universität Bonn resistance to cytosolic nuclease TREX1 degradation and poten- Alzheimer-like pathology. PLoS One 2013. 8: e60921. ­research (caesar), Max Planck Research Group Institute of Clinical Chemistry and Clinical ­Pharmacology, tiates STING-dependent immune sensing. Immunity 2013 Sep 3. Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., „­Neuroimmunology“ Director 19;39(3):482-95. Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, 2. Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, E-Mail: [email protected] A., Tzeng, T. C., Gelpi, E., Halle, A., Korte, M., Latz, E. and E-Mail: [email protected] ­Serganov AA, Liu Y, Jones RA, Hartmann G, Tuschl T, Patel DJ. Golenbock, D. T., NLRP3 is activated in Alzheimer‘s disease Research Expertise Cyclic [G(2‘,5‘)pA(3“,5”)p] Is the Metazoan Second Messenger Pro- Research Expertise and contributes to pathology in APP/PS1 mice. Nature 2013. The focus of research is the immunorecognition of nucleic acids, and duced by DNA-Activated Cyclic GMP-AMP Synthase. Cell 2013 May Dr. Halle’s group studies innate immune mechanisms and 493: 674-678. its intersection with RNA interference. The group contributed to the 23;153:1094-107. 4. Stewart, C. R., Stuart, L. M., Wilkinson, K., van Gils, J. 3. Dann A, Poeck H, Croxford A, Pfeifer D, Maihoefer C, Endres S, microglial function in Alzheimer’s disease using cell culture immunobiology of TLR9 and CpG DNA, specifically the function of M., Deng, J., Halle, A., Rayner, K. J., Boyer, L., Zhong, R., TLR9 in the human immune system. Furthermore, the group found Kalinke U, Knust M, Knobeloch KP, Akira S, Waisman A, Hartmann techniques and mouse models of Alzheimer’s disease. Frazier, W. A., Lacy-Hulbert, A., El Khoury, J., Golenbock, D. T. that short interfering RNA molecules (siRNA) activate TLR7, and G, Prinz M. Systemic activation of RIG-I-like helicases limits Th1/ and Moore, K. J., CD36 ligands promote sterile inflammation worked on the structural requirements for the detection of RNA by Th17-mediated autoimmunity in the CNS. Nature Neuroscience Education / Training through assembly of a Toll-like receptor 4 and 6 heterodimer. TLR7 and TLR8. The group identified the RNA ligand for RIG-I, and 2011;15:98-106. Charité – University Medicine Berlin, Nat Immunol 2010. 11: 155-161. analyzed the signaling pathways of RIG-I, and resolved the crystal 4. Wang Y, Ludwig J, Schuberth C, Goldeck M, Schlee M, Li H, Juranek S, Sheng G, Micura R, Tuschl T*, Hartmann G*, Patel DJ*. Medical Neuroscience, MD thesis, 2005 5. Siednienko, J., Halle, A., Nagpal, K., Golenbock, D. T. structure or RIG-I bound to its ligand 5´-triphosphate RNA. The group 2010. Structural and functional insights into 5‘-ppp RNA pattern and Miggin, S. M., TLR3-mediated IFN-beta gene induction is identified cyclic [G(2‘,5‘)pA(3“,5”)p] as the metazoan second messen- Free University Berlin, Humboldt University Berlin, recognition by the innate immune receptor RIG-I. Nat Struct Mol Biol negatively regulated by the TLR adaptor MyD88 adaptor-like. ger in the cGAS-STING pathway. The group applies immunostimula- Clinical Medicine, MD, 2003 tory nucleic acids and siRNA for immunotherapy of cancer and viral 17:781-7. Eur J Immunol 2010. 40: 3150-3160. infection. 5. Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, Appointments / Positions Held 6. Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Hannesschlager N, Schlee M, Rothenfusser S, Barchet W, Kato H, Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, Education / Training Akira S, Inoue S, Endres S, Peschel C, Hartmann G*, Hornung V*, 2011 - present K. J. and Golenbock, D. T., The NALP3 inflammasome is University of Munich, Germany, Experimental Pharmacology and Ruland J*. 2010. Recognition of RNA virus by RIG-I results in acti- Max-Planck Research Group leader involved in the innate immune response to amyloid-beta. Nat Toxicology Degree, 2006 vation of CARD9 and inflammasome signaling for interleukin 1 beta Center of Advanced European Studies and Research Immunol 2008. 9: 857-865. University of Munich, Germany, Clinical Pharmacology, Degree, 2003 production. Nat Immunol 11: 63-9. ­(caesar), Bonn, Germany 7. Halle, A.*, Zhou, S*., Kurt-Jones, E. A., Cerny, A. M., University of Munich, Germany, Clinical Pharmacology, Habilitation, 6. Schlee M, Roth A, Hornung V, Hagmann CA, Wimmenauer V, 2009 - 2011 Porpiglia, E., Rogers, M., Golenbock, D. T. and Finberg, R. W., 2001 Barchet W, Coch C, Janke M, Mihailovic A, Wardle G, Juranek S, Research fellow and resident in Neuropathology Lymphocytic choriomeningitis virus (LCMV) infection of CNS University of Ulm, Germany, Clinical Genetics, MD thesis, 1994 Kato H, Kawai T, Poeck H, Fitzgerald KA, Takeuchi O, Akira S, Tuschl University of Ulm, Germany, Clinical Medicine, MD, 1993 Department of Neuropathology, Charité – University glial cells results in TLR2-MyD88/Mal-dependent inflammatory T, Latz E, Ludwig J, Hartmann G. 2009. Recognition of 5‘ triphos- ­Medicine Berlin, Germany responses. J Neuroimmunol 2008. 194: 70-82. Appointments / Positions Held phate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 31: 25-34. 2005 - 2008 8. Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., 2012 - present Speaker of the DFG-Excellence Cluster ImmunoSensation, University of Bonn, Germany 7. Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Postdoctoral fellow and instructor in Internal ­Medicine, Kono, H., Rock, K. L., Fitzgerald, K. A. and Latz, E., Silica crystals and aluminum salts activate the NALP3 inflammasome 2008 - present Head of Research Committee BONFOR, University Hornung V. 2009. RIG-I-dependent sensing of poly(dA:dT) through Department of Infectious Diseases, University of the induction of an RNA polymerase III-transcribed RNA intermedi- through phagosomal destabilization. Nat Immunol 2008. 9: of Bonn, Germany ­Massachusetts, Worcester, USA 2007 - present Full Professor and Chair, Institute of Clinical Chem- ate. Nat Immunol 10: 1065-72. 847-856. 2003 - 2005 istry and Clinical Pharmacology with the Central Laboratory of the 8. Poeck H, Besch R, Maihoefer C, Renn M, Tormo D, Morskaya SS, 9. Jain, V., Halle, A., Halmen, K. A., Lien, E., Charrel-Dennis, Medical dissertation and resident in Neurology, ­Department University Hospital, University of Bonn, Germany Kirschnek S, Gaffal E, Landsberg J, Hellmuth J, Schmidt A, Anz D, M., Ram, S., Golenbock, D. T. and Visintin, A., Phagocytosis of Experimental Neurology, Charité – ­University Medicine 2006 - present Member oft the Steering committee, Bscheider M, Schwerd T, Berking C, Bourquin C, Kalinke U, Kremmer and intracellular killing of MD-2 opsonized gram-negative bac- Berlin, Germany Comprehensive Cancer Center Köln-Bonn (CIO), University of Bonn, E, Kato H, Akira S, Meyers R, Hacker G, Neuenhahn M, Busch D, teria depend on TLR4 signaling. Blood 2008. 111: 4637-4645. Ruland J, Rothenfusser S, Prinz M, Hornung V, Endres S, Tuting T, 2000 2005 Full Professor and Head, Division of Clinical Pharmacology, 10. Halle, A.*, Bermpohl, D.*, Freyer, D., Dagand, E., Braun, J. Hartmann G. 2008. 5‘-Triphosphate-siRNA: turning gene silencing Research internship, Department of Cell Biology, Harvard University of Bonn, Germany S., Bechmann, I., Schroder, N. W. and Weber, J. R., Bacterial 2002 Assistant Professor, Division of Clinical Pharmacology, Univer- and Rig-I activation against melanoma. Nat Med 14: 1256-63. University, Boston, USA programmed cell death of cerebral endothelial cells involves sity of Munich, Germany 9. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck dual death pathways. J Clin Invest 2005. 115: 1607-1615. 1999 - present Research group: Therapeutic Oligonucleotides, H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G. Honors / Awards University of Munich, Germany 2006. 5‘-Triphosphate RNA is the ligand for RIG-I. Science 314: 2010 *These authors contributed equally 1998 - 1999 Postdoctoral Fellow, Department of Internal Medicine, 994-7. 10. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee Ernst Jung-Career Award for Medical Research ­University of Iowa, USA 1995 Research Fellow, Division of Clinical Pharmacology, University M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, 2008 of Munich, Germany Endres S, Hartmann G. 2005. Sequence-specific potent induction Lydia Rabinowitsch Fellowship for young scientists, Charité 1994 Research Fellow, Department of Internal Medicine, University of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells Berlin of ­Munich, Germany through TLR7. Nat Med 11: 263-70. * These authors contributed equallly

146 147 2008 1992 - 1994 Editorial board, Journal of Chemical Neuroanatomy Post-doc Fellow, Dept. Mol. Developmental Biology (Head: Prof. Michael Heneka, MD 1998 Prof. Michael Hoch, PhD Prof. H. Jäckle), Max Planck Institute for Biophysical ­Chemistry, Clinical Neurosciences Unit Attempto Award - best Thesis of the University of Bonn Life and Medical Sciences Institute (LIMES) Göttingen, Germany

10 Most Relevant Publications for Prof. Michael Honors / Awards ­Heneka 2014 1. Heneka MT, Klockgether T, Feinstein DL. Peroxisome Member of the Academic Senate of the University of Bonn proliferator-activated receptor-gamma ligands reduce 2013 - present neuronal inducible nitric oxide synthase expression and cell Member of the PhD fellowship selection committee of the German National Academic Foundation (Studienstiftung des death in vivo. J Neurosci 2000;20:6862-6867. deutschen Volkes) 2. , Galea E, Gavriluyk V, Dumitrescu-Ozimek Heneka MT 2012 - present L, Daeschner J, O´Banion MK, Klockgether T, Feinstein DL. Member of the Steering Committee of the Bonn Excellence Noradrenergic depletion potentiates beta-amyloid induced Cluster ImmunoSensation (German Research foundation DFG) cortical inflammation: Implications for Alzheimer’s disease. 2009 - present J Neurosci 2002;22:2434-2442. Member of the Minerva Fellowship Committee of the Max 3. Heneka MT, Dewachter I, Sastre M, Dumitrescu-Ozimek Planck Society, Munich L, Cuiperi K, a gonist pioglitazone and ibuprofen reduces 2006 - 2009 inflammation and βA 1-42 levels in APP V717I transgenic Founding Head of the Section Molecular Biomedicine of the mice. Brain 2005;128:1442-1453. Faculty for Mathematics & Natural Science, University of Bonn Rheinische Friedrich-Wilhelms-Universität Bonn 4. Schütz B, Reimann J, Dumitrescu-Ozimek L, Kappes- Rheinische Friedrich-Wilhelms-Universität Bonn 2005 - present Clinical Neurosciences Unit, Director Horn K, Landreth GE, Schürmann B, Zimmer A, Hene- Life and Medical Sciences Institute (LIMES), ­Managing Speaker of the Collaborative Research Centre SFB 645 ­(German Research Foundation) ka MT. The oral antidiabetic pioglitazone protects from Director, Genetics, Developmental Biology & ­Molecular E-Mail: [email protected] 2003 - 2004 neurodegeneration and ALS-like symptoms in SOD1-G93A Physiology, Director transgenic mice. J Neurosci 2005;25:7805-7812. Head of the Section Biology of the Faculty for Mathematics & E-Mail: [email protected] Research Expertise 5. Sastre M, Dewachter I, Rossner S, Bogdanovic N, Ros- Natural Science, University of Bonn Prof. Heneka is involved in basic science and translational 2002 - 2004 en E, Borghraef P, Evert BO, Dumitrescu-Ozimek D, Thal research with focus on neurodegeneration and neuroinflam- Chairman of the Bonner Forum Biomedizin DR, Landreth GE, Walter J, Klockgether T, Van Leuven F, Research Expertise mation. His major disease of interest and research topics Our aim is to identify new key regulators and genetic 2001 - 2004 Heneka MT (2006) NSAIDs suppress BACE1 gene expres- include Alzheimer disease, amyotrophic lateral sclerosis, ­networks which control metabolism and cell and organ Speaker of the Research Unit FOR 425, funded by the DFG sion by the activation of PPARγ. Proc Natl Acad Sci USA septic encephalopathy and multiple sclerosis. In clinical physiology. In particular, we elucidate the metabolism – 2000 - 2007 2006;103:443-448. neurology, Prof. Heneka holds special expertise in neurode- ­innate immunity – gut microbiome axis, we investigate Member of the reviewer panel for the award of Post ­Graduate 6. Heneka MT, Ramanathan M, Jacobs AH, Dumitres- generative and autoimmune CNS disorders. cellular (sphingo)lipid metabolism and body fat regulation, Fellowships of the DAAD (German Academic Exchange cu-Ozimek L, Debeir T, Sastre M, Bilkei-Gorzo A, Zimmer we study peroxisome and lysosome biogenesis and met- ­Service) A, Galldiks N, Hoehn M, Heiss WD, Klockgether T, Staufen- 1996 Education / Training abolic disorders (e.g. lipid storage diseases or neurode- biel M. Locus ceruleus degeneration promotes Alzhei- Gerhard Hess Young Investigator Award (DFG) generation), and we analyse new regulators of cell-to-cell University of Bonn, Germany, Neurology, Professorial mer pathogenesis in APP transgenic mice. J. Neurosci 1989 - 1992 communication and tissue physiology. We use the fruit fly ­qualification (Habilitation), 2003 2006;26:1343-1354. PhD Fellowship of the Boehringer Ingelheim Fonds (Foundation ­Drosophila, the mouse and zebra fish as genetic model University of Bonn, Germany, Neurology, Specialty 7. Weberpals M, Hermes M, Hermann M, Kummer MP, for Basic Research in Medicine) organisms for our studies. ­qualification, 2002 Terwel D, Semmler A, Berger M, Schäfers M, Heneka MT 1986 - 1989 University of Tübingen, Germany, Medicine, M.D., 1996 (2009) NOS2 gene deficiency protects from sepsis-induced Member of the German National Academic Foundation long-term cognitive deficits, J Neurosci, 29:14177-84. Education / Training ­(Studienstiftung des deutschen Volkes) Appointments / Positions Held 8. Heneka MT, Nadrigny F, Regen T, Dumitrescu-Ozimek University of Munich, Germany, Developmental Biology 2008 - present L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, PhD, 1992 5 Most Relevant Publications for Prof. Michael Hoch Full Professor (W3) for Clinical Neurosciences, Head of the Hanisch U, Kummer MP (2010) Locus ceruleus controls University of Heidelberg, Germany, Biology Undergraduate 1. Mass E, Wachten D, Aschenbrenner AC, Voelzmann A, Clinical Research Group 177 of the DFG, University of Bonn Alzheimer disease pathology by modulating microglial func- (Dipl.), 1989 Hoch M. 2014. Murine Creld1 controls cardiac development 2004 - 2008 tions through norepinephrine. Proc. Natl. Acad. Sci. U.S.A., through activation of calcineurin/NFATc1 signaling. Develop- Full Professor (C3) for Molecular Neurology, University of 107:6058-63. Appointments / Positions Held mental Cell 28, 711-726. DOI: 10.1016/j.devcel.2014.02.012. 2. Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Münster 9. Kummer MP, Hermes M, Delekarte A, Hammerschmidt 2010 Visiting Research Professors, ASMeW Institute, Carrera P, Inhester T, Schultze JL, Hoch M. 2010. FOXO-de- 2004 T, Kumar S, Terwel D, Walter J, Pape HC, König, S, Roeber Waseda University, Japan pendent regulation of innate immune homeostasis. Nature Senior Clinical Fellow in Neurology, University of Bonn S, Jessen F, Klockgether T, Korte M, Heneka MT (2011) 2006 - present 463: 369-73. 1999 - 2003 Nitration of tyrosine 10 critically enhances amyloid β aggre- Resident in Neurology, University of Bonn Managing Director of the LIMES Institute, Chair Molecular 3. Loer B, Bauer R, Bornheim R, Grell J, Kremmer E, Kolanus gation and plaque formation. Neuron 71:833-44. W, Hoch M. 2008. The NHL-domain protein Wech is crucial 1996 - 1999 Developmental Biology, LIMES Institute, University of Bonn, 10. Heneka MT, Kummer MP, Stutz A, Delekate A, for the integrin-cytoskeleton link. Nat Cell Biol 10: 422-8. Resident in Neurology, University of Tübingen Germany Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, 2000 - 2002 4. Behr M, Wingen C, Wolf C, Schuh R, Hoch M. 2007. Wurst 1992 - 1996 Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock Director, Institute of Animal Physiology, University of Bonn, is essential for airway clearance and respiratory-tube size Predoctoral research fellow in the Dept. of Pharmacology, DT (2013) NLRP3 is activated in Alzheimer‘s disease and Germany control. Nat Cell Biol 9: 847-53. University of Cologne contributes to pathology in APP/PS1 mice. Nature. 493: 1999 - present 5. Fuss B, Becker T, Zinke I, Hoch M. 2006. The cytohesin 674-678. Full Professor, Chair of Molecular Developmental Biology Steppke is essential for insulin signalling in Drosophila. Nature Honors / Awards LIMES Institute, University of Bonn, Germany 444: 945-8. 2010 - present 1996 Editorial Board Journal of Neurochemistry Habilitation in Developmental Genetics & Cell Biology 2007 - present Technical University of Braunschweig, Germany Board Member of the Competence Network Degenerative 1994 - 1999 Dementias (CNDD) Group Leader, Dept. Mol. Developmental Biology (Head: Prof. H. Jäckle), Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

148 149 2002 Honors / Awards Prof. Michael Hölzel, MD Scholarship „Harvard-Munich Alliance“ Prof. Achim Hörauf, MD 2012 1999 President of the Paul Ehrlich Society for Chemotherapy e.V. Institute of Clinical Chemistry and Clinical Pharmacology Scholarship “Studienstiftung des deutschen Volkes” Institute of Medical Microbiology, Immunology and Parasitology 2010 Coordinator for the partner BonnCologne, Dt. Zentrum für 10 Most Relevant Publications for Prof. Michael Hölzel Infektionsforschung (DZIF) – German Center for Infectious 1. Bald, T., Landsberg, J., Lopez-Ramos, D., Renn, M., Disease. Glodde, N., Jansen, P., Gaffal, E., Steitz, J., Tolba, R., Kalinke, 2002 U., Limmer, A., Jönsson, G., Hölzel, M., Tüting T (2014). Im- Main annual award, German Society for Hygiene and mune-cell poor melanomas benefit from PD-1 blockade after ­Microbiology (DGHM) targeted type I IFN activation. Cancer Discovery, 2014 Mar 3. 2001 Epub ahead of print. 2. Bald, T., Quast, T., Landsberg, J., Rogava, M., Glodde, Martini-Prize (bi-annual) for best clinical research of the N., Lopez-Ramos, D., Kohlmeyer, J., Riesenberg, S., van den University Clinic, Eppendorf/Hamburg Boorn-Konijnenberg, D., Hömig-Hölzel, C., Reuten, R. Schad- 1999 ow, B., Weighardt, I., Wenzel, D., Helfrich, I., Schadendorf, Main bi-annual award, German Society for Tropical D., Bloch, W.,. Bianchi, M.E., Koch, M., Fleischmann, B.K., ­Medicine (DTG) Förster, I., Kastenmüller, W., Kolanus, W., Hölzel, M.*, Gaffal, 1984 - 1989 G.*, Tüting, T* (*corresponding authors). (2014). Ultraviolet Recipient of the “Bavarian Gifted Scholarship” radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature, 507, 109-13. 10 Most Relevant Publications for Prof. Achim Hörauf Rheinische Friedrich-Wilhelms-Universität Bonn 3. Hölzel, M., Bovier, A., Tüting, T. (2013) Plasticity of tumour Rheinische Friedrich-Wilhelms-Universität Bonn 1. Mand S, Debrah AY, Klarmann U, Batsa L, Marfo-Debrekyei Institute of Clinical Chemistry and Clinical and immune cells: a source of heterogeneity and a cause for Institute of Medical Microbiology, Immunology and Y, Kwarteng A, Specht S, Belda-Domene A, Fimmers R, Taylor ­Pharmacology therapy resistance? Nat Rev Cancer 13, 365-76. Parasitology, Director M, Adjei O, Hoerauf A. 2012. Doxycycline improves filarial 4. Landsberg, J., Kohlmeyer, J., Renn, M., Bald, T., Roga- E-Mail: [email protected] E-Mail: [email protected] lymphedema independent of active filarial infection: a random- va, M., Cron, M., Fatho, M., Lennerz, V., Wölfel, T., Hölzel, ized controlled trial. Clin Infect Dis. 55:621-30. M., Tüting, T. (2012) Melanomas resist T-cell therapy through Research Expertise Research Expertise 2. Specht S, Frank JK, Alferink J, Dubben B, Layland LE, inflammation-induced reversible dedifferentiation. Nature, 490, Denece G, Bain O, Förster I, Kirschning CJ, Martin C, Hoerauf Michael Hölzel has long-standing research expertise in the Prof. Hörauf is internationally renowned for his work in 412–416. A. 2011. CCL17 controls mast cells for the defense against field of tumor biology and functional genomics with a partic- Tropical Medicine, specifically, for pioneering a new drug 5. Huang, S., Hölzel, M., Knijnenburger, T., Schlicker, A., filarial larval entry. J Immunol 186:4845-52. ular focus on neural crest derived tumors such as melano- Roepman, P., McDermott, U., Garnett, M.J., Grernrum, W., treatment for filariasis (a group of neglected tropical diseas- 3. Taylor M, Hoerauf A, Bockarie M. 2010. Lymphatic filariasis ma. Currently his group investigates how the immune sys- Sun, C., Prahallad, A., Groenendijk, F.H., Mittempergher, L., es). The new treatment exploits an endosymbiosis between and onchocerciasis. tem crosstalks with the tumor cells in response to danger Nijkamp, W., Neefjes, J., Salazar, R., Ten Dijke, P., Uramoto, the worms and bacterial endosymbionts called Wolbachia, Lancet 376: 1175-85. and proinflammatory signals released by therapy-induced H., Tanaka, F., Beijersbergen, R.L., Wessels, L.F., Bernards, which are susceptible to some classes of antibiotic. Prof. 4. Hoerauf A. 2009. Mansonella perstans--the importance of tumor tissue injury. A central hypothesis is that this recipro- R. (2012) MED12 controls the response to multiple cancer Hörauf’s group was the first to characterize a TLR2 ligand an endosymbiont. N Engl J Med 361: 1502-4. cal communication drives therapy relapse due to rewiring drugs through regulation of TGFβ receptor signaling. Cell, 151, from Wolbachia, and established that blindness brought 5. Specht S, Hoerauf A. 2007. Does helminth elimination of survival and differentiation pathways in tumor cells. This 937–950. about by filarial antigens as the worm larvae migrate into promote or prevent malaria? knowledge is critically needed for the rational combination 6. Heuckmann JM, Hölzel M., Sos ML, Heynck S, Bal- the eye in onchocerciasis (or “river blindness”) is dependent Lancet 369: 446-7. ke-Want H, Koker M, Peifer M, Weiss J, Lovly CM, Grütter C, of immunotherapies and targeted signal transduction inhib- on Wolbachia, and again mediated by the innate immune 6. Taylor MJ, Makunde WH, McGarry HF, Turner JD, Mand S, Rauh D, Pao W, Thomas RK. (2011) ALK mutations conferring itors in the clinic. system. Prof. Hörauf’s second focus is in the field of Hoerauf A. 2005. differential resistance to structurally diverse ALK inhibitors. Clin Macrofilaricidal activity after doxycycline treatment of Wuchere- Cancer Res., 17, 7394-401. infection immunity, where his group were the first to detect Education / Training regulatory T cells in humans in an infection. ria bancrofti: a double- blind, randomised placebo-controlled 7. Hölzel, M.*, Huang, S.*, Koster, J., Ora, I., Lakeman, A., trial. Lancet 365: 2116-21. University of Munich, Germany Caron, H., Nijkamp, W., Xie, J., Callens, T., Asgharzadeh, S., Medicine M.D. thesis, 2004 Education / Training 7. Brattig NW, Bazzocchi C, Kirschning CJ, Reiling N, Buttner Seeger, RC., Messiaen, L., Versteeg, R., Bernards, R. NF1 DW, Ceciliani F, Geisinger F, Hochrein H, Ernst M, Wagner Universities of Munich, Germany is a tumor suppressor in neuroblastoma that determines University of Erlangen, Germany, Clinical Immunology H, Bandi C, Hoerauf A. 2004. The major surface protein of Medicine M.D., 2003 retinoic acid response and disease outcome. Cell, 2010; 142, MD, 1989 Wolbachia endosymbionts in filarial nematodes elicits immune 218–229. University of Erlangen, Germany, Duke University, USA and responses through TLR2 and TLR4. J Immunol 173: 437-45. Appointments / Positions Held 8. Burger K, Mühl B, Harasim T, Rohrmoser M, Malamoussi Galaway University, Ireland 8. Saint Andre A, Blackwell NM, Hall LR, Hoerauf A, Brat- 2012 - present A, Orban M, Kellner M, Gruber-Eber A, Kremmer E, Hölzel Clinical Immunology MD, with clinical rotations, 1989 tig NW, Volkmann L, Taylor MJ, Ford L, Hise AG, Lass JH, W2 Professor, Unit for RNA Biology, Institute of Clinical M., Eick D. (2010) Chemotherapeutic drugs inhibit ribosome Diaconu E, Pearlman E. 2002. The role of endosymbiotic Wol- biogenesis at various levels. J Biol Chem., 285, 12416-25. Chemistry and Clinical Pharmacology, University of Bonn, Appointments / Positions Held bachia bacteria in the pathogenesis of river blindness. Science Germany 9. Hölzel M., Orban M, Hochstatter J, Rohrmoser M, Harasim 295: 1892-5. 2003 - present 2007 - 2011 T, Malamoussi A, Kremmer E, Längst G, Eick D. (2010) Defects 9. Hoerauf A, Mand S, Adjei O, Fleischer B, Buttner DW. Full Professor and Director, Institute for Medical Post-Doc, Laboratory of Rene Bernards, The Netherlands in 18 S or 28 S rRNA processing activate the p53 pathway. J 2001. Depletion of wolbachia endobacteria in Onchocerca Biol Chem., 285, 6364-70. Microbiology, Immunology and Parasitology, University Cancer Institute, Amsterdam, The Netherlands volvulus by doxycycline and microfilaridermia after ivermectin 10. Huang S, Laoukili J, Epping MT, Koster J, Hölzel M., Hospital Bonn, Germany 2003 - 2006 treatment. Lancet 357: 1415-6. Westerman BA, Nijkamp W, Hata A, Asgharzadeh S, Seeger 2001 - 2003 Residency Hematology/Oncology, University Hospital 10. Hoerauf A, Volkmann L, Hamelmann C, Adjei O, Autenri- RC, Versteeg R, Beijersbergen RL, Bernards R. (2009) ZNF423 Head, Department of Helminthology, Bernard Nocht ­Munich (LMU), Germany eth IB, Fleischer B, Buttner DW. 2000. Endosymbiotic bacteria is critically required for retinoic acid-induced differentiation ­Institute for Tropical Medicine, Germany in worms as targets for a novel chemotherapy in filariasis. and is a marker of neuroblastoma outcome. Cancer Cell, 15, 1995 - 2001 Lancet 355: 1242-3. Honors / Awards 328-40. Independent Laboratory Head, Bernard Nocht Institute for 2014 Tropical Medicine, Germany Invited junior speaker, DFG cancer symposium *These authors contributed equally 1990 - 1994 “­Hinterzartener Kreis”, Italy Fellow, Institute for Clinical Microbiology, Immunology and 2011 Hygiene, University of Erlangen, Germany Invited junior speaker, DFG cancer symposium “­Hinterzartener Kreis”, Italy

150 151 2007 Honors / Awards Heinz Maier Leibnitz Prize of the German Research 2006 Prof. Veit Hornung, MD ­Foundation Prof. Jörg C. Kalff, MD Fellow of the American College of Surgeons (FACS) Institute of Molecular Medicine 2006 Department of Surgery 2003 Graduate-Scholarship of the Novartis-Foundation for Elected Speaker of the KFO 115 ­Therapeutical Research 2000 2002 Ferdinand Sauerbruch Award, Berlin, Germany Study Scholarship of the Munich-Harvard-Alliance 2000 2000 - 2003 Young Investigator Award, American Motility Society Fellow of the German National Academic Foundation 2000 ­(“Studienstiftung des deutschen Volkes”) BONFOR Young Investigator Research Award

10 Most Relevant Publications for Prof. Veit Hornung 10 Most Relevant Publications for Prof. Jörg C. Kalff 1. Ablasser, A., J. L. Schmid-Burgk, I. Hemmerling, G. L. 1. Pantelis D, Beissel A, Kahl P, Vilz TO, Stoffels B, Wehner S, Horvath, T. Schmidt, E. Latz and V. Hornung. Cell intrinsic im- Kalff JC. 2011. Colonic anastomotic healing in the context of munity spreads to bystander cells via the intercellular transfer altered macrophage function and endotoxemia. Int J Colorect of cGAMP Nature, 2013; Dis 26:737-46. 2. Ablasser, A., M. Goldeck, T. Cavlar, T. Deimling, G. Witte, I. 2. Engel DR, Koscielny A, Wehner S, Maurer J, Schumak B, Rohl, K. P. Hopfner, J. Ludwig and V. Hornung. cGAS produc- Limmer A, Sparwasser T, Hirner A, Knolle P, Kalff JC*, Kurts es a 2‘-5‘-linked cyclic dinucleotide second messenger that C* (*joined corresponding authorship). 2010. T helper type activa- tes STING Nature, 2013; 498: 380-384. 1 memory cells disseminate postoperative ileus over the Rheinische Friedrich-Wilhelms-Universität Bonn 3. Bartok, E., F. Bauernfeind, M. G. Khaminets, C. Jakobs, B. Rheinische Friedrich-Wilhelms-Universität Bonn entire intestinal tract. Nat Med. 16:1407-13. Institute of Molecular Medicine, Director Monks, K. A. Fitzgerald, E. Latz and V. Hornung. iGLuc: a Department of Surgery, Director 3. Wehner S, Buchholz BM, Schuichtrup S, Rocke A, Schaefer E-Mail: [email protected] luciferase-based inflammasome and protease activity reporter E-Mail: [email protected] N, Lysson M, Hirner A, Kalff JC. 2010. Mechanical strain Nat Methods, 2013; 10: 147-154. and TLR4 synergistically induce cell-specific inflammatory Research Expertise 4. Schmid-Burgk, J. L., T. Schmidt, V. Kaiser, K. Honing and Research Expertise gene expression in intestinal smooth muscle cells and Prof. Hornung has expertise in pattern recognition, innate V. Hornung. A ligation-indepen- dent cloning technique for The focus of research are the immunological consequences peritoneal macrophages. Am J Physiol Gastrointest Liver high-throughput assembly of transcription activator-like effector Physiol 299:G1187-97. immunology, macrophages, dendritic cells, RNA biology of operative trauma and their recognition and regulation genes Nat Biotechnol, 2013; 31: 76-81. 4. Pantelis D, Kabba MS, Kirfel J, Kahl P, Wehner S, Buettner and genome engineering technologies. in postoperative dysfunction of the gastrointestinal tract. 5. Duewell, P., H. Kono, K. J. Rayner, C. M. Sirois, G. Vladi- R, Hirner A, Kalff JC. 2010. Transient perioperative pharma- mer, F. G. Bauernfeind, G. S. Abe- la, L. Franchi, G. Nunez, The group described and elucidated the immunological cologic inhibition of muscularis macrophages as a target for Education / Training M. Schnurr, T. Espevik, E. Lien, K. A. Fitzgerald, K. L. Rock, pathomechanism of postoperative ileus. Furthermore, the prophylaxis of postoperative ileus does not affect anastomotic University of Munich, Germany, Clinical Pharmacology MD K. J. Moore, S. D. Wright, V. Hornung* and E. Latz*. NLRP3 group found that the gastrointestinal field effect - a panen- healing in mice. Surgery 148:59-70. thesis, 2004 inflammasomes are required for athe- rogenesis and activated teric inflammation following localized abdominal surgery - is 5. Wehner S, Straesser S, Vilz TO, Pantelis D, Sielecki T, de University of Munich, LMU, including exchange rotations by cholesterol crystals Nature, 2010; 464: 1357-1361. mediated by an immunological response involving resident la Cruz VF, Hirner A, Kalff JC. 2009. Inhibition of p38 mito- at Harvard University, USA, and University of Zürich, 6. Ablasser, A., F. Bauernfeind, G. Hartmann, E. Latz, K. A. intestinal macrophages, mesenteric dendritic cells and gen-activated protein kinase pathway as prophylaxis of post- ­Switzerland, Clinical Medicine, MD, 2003 Fitzgerald and V. Hornung. RIG- I-dependent sensing of poly memory TH1 cells. operative ileus in mice. Gastroenterology 136:619-29. (dA:dT) through the induction of an RNA polymerase III-tran- 6. Wehner S, Behrendt FF, Lyutenski BN, Lysson M, Bauer AJ, Appointments / Positions Held scribed RNA intermediate Nat Immunol, 2009; 10: 1065-1072. Education / Training Hirner A, Kalff JC. 2007. Inhibition of macrophage function Since 2014 7. Hornung, V., A. Ablasser, M. Charrel-Dennis, F. Bauern- University of Bonn, Germany, Surgery, Habilitation, 1999 prevents intestinal inflammation and postoperative ileus in Director (W3) Institute of Molecular Medicine, University feind, G. Horvath, D. R. Caffrey, E. Latz and K. A. Fitzgerald. University of Aachen, Germany, Intensive Care , MD thesis, rodents. Gut 56:176-185. Hospital, University of Bonn AIM2 recognizes cytosolic dsDNA and forms a caspase-1-acti- 1988 7. Wehner S, Schwarz NT, Hundsdörfer R, Hierholzer C, 2008 - 2013 vating inflammasome with ASC Nature, 2009; 458: 514-518. University of Aachen, Germany, Clinical Medicine, MD, Tweardy DJ, Billiar TR, Bauer AJ, Kalff JC. 2005. Induction of Professor of Clinical Biochemistry, Institute for Clinical 8. Hornung, V.*, F. Bauernfeind*, A. Halle, E. O. Samstad, H. 1987 IL-6 within the rodent intestinal muscularis following intestinal Kono, K. L. Rock, K. A. Fitz- gerald and E. Latz. Silica crystals surgical stress. Surgery 137:436-46. Chemistry and Clinical Pharmacology, University of Bonn, and aluminum salts activate the NALP3 inflammasome through 8. Schwarz NT, Kalff JC, Turler A, Speidel N, Grandis JR, Germany phagosomal destabilization Nat Immunol, 2008; 9: 847-856. Appointments / Positions Held Billiar TR, Bauer AJ. 2004. Selective jejunal manipulation 2006 - 2008 9. Hornung, V., J. Ellegast, S. Kim, K. Brzozka, A. Jung, H. 2010 - present causes postoperative pan-enteric inflammation and dysmotility. Postdoctoral research fellow, Division of Infectious ­Diseases Kato, H. Poeck, S. Akira, K. K. Conzelmann, M. Schlee, S. Full Professor and Head, Dept. of Surgery, University of Gastroenterology 126:159-69. and Immunology, University of Massachusetts, USA Endres and G. Hartmann. 5‘-Triphosphate RNA is the ligand Bonn, Germany 9. Kalff JC, Türler A, Schwarz NT, Schraut WH, Lee KKW, 2005 - 2006 for RIG-I Science, 2006; 314: 994-997. 2009 Tweardy DJ, Billiar TR, Simmons RL, Bauer AJ. 2003. Intra-ab- Group leader, Division of Clinical Pharmacology 10. Hornung, V., M. Guenthner-Biller, C. Bourquin, A. Ablasser,­ Head, Division of Transplant Surgery, University of Bonn, dominal activation of a local inflammatory response within University of Munich, Germany M. Schlee, S. Uematsu, A. Noronha, M. Manoharan, S. Akira, Germany the human muscularis externa during laparotomy. Ann Surg 2003 - 2005 A. de Fougerolles, S. Endres and G. Hartmann. Sequen- 2003 237:301-15. Research Fellow, Division of Clinical ce-specific potent induction of IFN-alpha by short interfering Professor of Surgery, University of Bonn, Germany 10. Engel BM, Eskandari M, Kalff JC, Grandis JR, Bauer Pharmacology, University of Munich, Germany RNA in plasmacytoid dendritic cells through TLR7 Nat Med, 1999 - 2001 AJ. 2002. Lipopolysaccharide preconditioning and cross-toler- 2005; 11: 263-270. Visiting Research Professor, Dept. of Medicine, University of ance: the induction of protective mechanisms for rat intestinal Honors / Awards Pittsburgh, USA ileus. Gastroenterology 123:586-98. *These authors contributed equally 2013 1995 - 1998 Pettenkofer Prize of the Max von Pettenkofer Foundation Research Fellow, Department of Surgery, University of 2010 Pittsburgh, USA GlaxoSmithKline Foundation Prize for basic medical 1995 ­research Clinical Fellow, Department of Surgery, University of Bonn, 2010 Germany Paul-Martini-Prize of the Paul-Martini-Foundation 1989 Resident, Department of Surgery, University of Bonn, Germany

152 153 10 Most Relevant Publications for Prof. Wolfgang 1987 Prof. Wolfgang Kastenmüller, PhD Kastenmüller Prof. U. Benjamin Kaupp, PhD Feodor-Lynen-Stipend at the Department of Medical 1. Bald T, Quast T, Landsberg J, Rogava M, Glodde N, ­Chemistry, University of Kyoto, Japan Institute of Molecular Medicine Lopez-Ramos D, Kohlmeyer J, Riesenberg S, van den center of advanced european studies and research (caesar) 1985 - 1988 Boorn-Konijnenberg D, Hömig-Hölzel C, Reuten R, Schadow Assistant Professor of Biophysics, University of Osnabrück B, Weighardt H, Wenzel D, Helfrich I, Schadendorf D, Bloch 1982 - 1985 W, Bianchi ME, Lugassy C, Barnhill RL, Koch M, Fleischmann Hochschulassistent, University of Osnabrück BK, Förster I, Kastenmuller W, Kolanus W, Hölzel M, Gaffal E, 1981 Tüting T. Ultraviolet-radiation-induced inflammation promotes Postdoctoral Fellow, SUNY Stony Brook, USA angiotropism and metastasis in melanoma. Nature. 2014 Mar 6; 507 (7490):109-13. Honors / Awards 2. Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, Meyer-Schwesinger C, Pohl JM, Maurice NJ, Thiebes S, 2013 Member of the North Rhine-Westphalian Academy of Lorenz K, Quast T, Fuhrmann M, Baumgarten G, Lohse MJ, Sciences Opdenakker G, Bernhagen J, Bucala R, Panzer U, Kolanus W, 2005 Member of the “German Academy of Sciences Gröne HJ, Garbi N, Kastenmuller W, Knolle PA, Kurts C, En- ­Leopoldina” gel DR.: Crosstalk between sentinel and helper macrophages 1999 Novartis Lecture, University Regensburg permits neutrophil migration into infected uroepithelium. Cell. 1999 Keynote lecturer on international conferences 2014 Jan 30;156 (3):456-68. 1994 Alcon Research Award 3. Honda T, Egen JG, Lämmermann T, Kastenmuller W, 1987 Feodor-Lynen-Fellowship Torabi-Parizi P, Germain RN.: Tuning of antigen sensitivity by 1978 Member of the Academic Senate Technical ­University Rheinische Friedrich-Wilhelms-Universität Bonn T cell receptor-dependent negative feedback controls T cell center of advanced european studies and research Berlin Institute of Molecular Medicine effector function in inflamed tissues. Immunity. 2014 Feb 20; (caesar), Molecular Sensory Systems, Scientific 40 (2): 235-47. E-Mail: [email protected] ­Director and Head of Department 10 Most Relevant Publications for Prof. U. Benjamin 4. Lämmermann T, Afonso PV, Angermann BR, Wang JM, Kaupp Kastenmuller W, Parent CA, Germain RN.: Neutrophil swarms E-Mail: [email protected] Research Expertise require LTB4 and integrins at sites of cell death in vivo. Nature. 1. Alvarez L, Dai L, Friedrich BM, Kashikar ND, Gregor I, Pascal The scientific focus of his group are cellular interactions and 2013 Jun 20; 498 (7454): 371-5. Research Expertise R, Kaupp UB. (2012) The rate of change in Ca2+ concentra- tion controls sperm chemotaxis J. Cell. Biol. 196, 653-663. cell-cell communication in the context of acute ­infections. 5. Kastenmuller, W, Brandes, M., Wang, Z., Herz, J., Egen Biophysics of sensory systems. Physiology of receptors 2. Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyand Central techniques are live intravital imaging and histocy- YG., Germain, RN.: Peripheral pre-positioning and local and ion channels in cellular signaling. Cell motility and I, Seifert R, Kaupp UB. 2011. The CatSper channel mediates tometry. CXCL9-mediated guidance orchestrate rapid memory CD8+ T chemotaxis. Development of chemical tools for kinetic cell responses in the lymph node. Immunity, 2013, Jan 24. progesterone-induced Ca2+ influx in human sperm. Nature techniques in cell biology. 471: 382-386. Education / Training 6. Kastenmuller, W, Torabi-Parizi, P., Subramanian, S., Lam- mermann, T., Germain, R.N.: A spatially-organized multicellular 3. Kaupp UB. 2010. Olfactory signalling in vertebrates and Education / Training Laboratory of Systems Biology NIH/USA, innate immune response in the lymph node limits the systemic insects: differences and commonalities. Nat. Rev. Neurosci. Ronald N. Germain, 2008 - 2011 spread of tissue-invasive pathogens. Cell, 2012, Sep 14; 150 University of Osnabrück, Biophysics, Habilitation, 1983 11: 188-200. Technical University of Munich, Germany, Specialization, (6):1235-48. Technical University of Berlin, Chemistry, PhD, 1979 4. Schröder-Lang S, Schwärzel M, Seifert R, Strünker T, Infectious Disease 2008 7. Gerner, M.Y., Kastenmuller, W, Ifrim, I., Kabat J., Germain, University of Tübingen and Technical University of Berlin ­Kateriya S, Looser J, Watanabe M, Kaupp UB, Hegemann P, Technical University of Munich, Germany, Medicine, M.D. R.N.: Histo-Cytometry: in situ multiplex cell phenotyping, Chemistry, Diploma, 1974 Nagel G. 2007. Fast manipulation of cellular cAMP level by light thesis, 2003 quantification, and spatial analysis applied to dendritic cell in vivo. Nat. Methods 4: 39-42. 5. Strünker T, Weyand I, Bönigk W, Van Q, Loogen A, Brown Technical University of Munich, Germany, Medicine, subset analysis in lymph nodes. Immunity, 2012 Aug 24; 37(2): Appointments / Positions Held JE, Kashikar ND, Hagen V, Krause E, Kaupp UB. 2006. A 1997 - 2002 364-76. 2010 - 2011 K+-selective cGMP-gated ion channel controls chemosensa- Universities of Regensburg, Germany, Medicine, 8. Kastenmuller W, Gasteiger G, Subramanian N, Sparwasser Director of the Max-Planck-Institute for Neurological tion of sperm. Nat Cell Biol 8: 1149-54. 1995 - 1997 T, Busch DH, Belkaid Y, Drexler I, Germain RN. Regulatory T Cells Selectively Control CD8+ T Cell Effector Pool Size via IL-2 ­Research, University of Cologne, Germany 6. Kaupp UB, Solzin J, Hildebrand E, Brown JE, Helbig Restriction. J Immunol. 2011 Sep 15;187 (6): 3186-97. 2008 - present A, Hagen V, Beyermann M, Pampaloni F, Weyand I. 2003. Appointments / Positions Held 9. Kastenmuller, K., Wille-Reece, U., Lindsay R. W. B., Trager Professor of Molecular Neurobiology, University of Bonn, The signal flow and motor response controling chemotaxis of 2013 L. R., Darrah P. A., Flynn B. J., Becker M. R., Udey M. C., Germany sea urchin sperm. Nat Cell Biol 5: 109-17. Associate Professor, University of Bonn, Germany Clausen B. E., Igyarto B. Z., Kaplan D. H., Kastenmuller W, 2008 - present 7. Stevens DR, Seifert R, Bufe B, Müller F, Kremmer E, Gauss 2008 - 2012 Germain R. N., and Seder R. A. Protective T cell immunity in Scientific Director of caesar and Head of Department R, Meyerhof W, Kaupp UB, Lindemann B. 2001. Hyperpolar- Post-Doc, NIH/Besthesda USA mice following protein-TLR7/8 agonist-conjugate immunization Molecular Sensory Systems (Center of Advanced European ization-activated channels HCN1 and HCN4 mediate respons- 2002 - 2008 requires aggregation, type I IFN, and multiple DC subsets. J Studies and Research) es to sour stimuli. Nature 413: 631-5. Clinical Fellow/Post-Doc, Technical University of Munich, Clin Invest. 2011 May 2; 121 (5): 1782-96. 2007 - present 8. Körschen HG, Beyermann M, Müller F, Heck M, Vantler M, Koch KW, Kellner R, Wolfrum U, Bode C, Hofmann KP, Kaupp Germany 10. Kastenmuller W, Gasteiger G, Subramanian N, Sparwas- Scientific Member of the Max-Planck-Society, UB. 1999. Interaction of glutamic-acid-rich proteins with the ser T, Busch DH, Belkaid Y, Drexler I, Germain RN. Regulatory Max-Planck-Society cGMP signalling pathway in rod photoreceptors. Nature 400: Honors / Awards T cells selectively control CD8+ T cell effector pool size via IL-2 2000 - present restriction. J Immunol. 2011 Sep 15; 187 (6): 3186-97. 761-6. 2012 Whitman Investigator, Marine Biological Laboratory (MBL), 9. Gauss R, Seifert R, Kaupp UB. 1998. Molecular identifi- CIG – Best Paper Award NIH Woods Hole, USA cation of a hyperpolarization- activated channel in sea urchin 2003 1988 - present sperm. Nature 393: 583-7. Dietmar-Zumpf-Promotions Preis Professor of Biophysical Chemistry, University of Cologne, 10. Kaupp UB, Niidome T, Tanabe T, Terada S, Bönigk W, Germany Stühmer W, Cook NJ, Kangawa K, Matsuo H, Hirose T, et al. 2006 - 2009 1989. Primary structure and functional expression from com- Director of the International Helmholtz Research plementary DNA of the rod photoreceptor cyclic GMP-gated School of Biophysics and Soft Matter , Research Centre channel. Nature 342: 762-6. Jülich 1988 - 2007 Director at the Institute of Neuroscience and Biophysics Research Centre Jülich

154 155 1991 - 1997 2007 Physician at the 1st Medical Department, University of Mainz, US Patent 20070287153 - Methods for identification and Prof. Percy Knolle, MD Germany Prof. Waldemar Kolanus, PhD validation of functional intracellular targets with intramers or in Institute of Molecular Immunology 1990 - 1991 Life and Medical Sciences Institute (LIMES) vivo selection Postdoctoral Fellow, BASF Bioresearch, Corporation, 2004 ­Cambridge, USA US Patent 20040170990 - Intracellular nucleic acid inhibitors of small guanine nucleotide exchange factors Honors / Awards US Patent 20040029775 - Methods and compounds for 2001 ­influencing beta3-integrin- dependent intracellular processes Award by the Volkswagen Foundation (1.5 Million €) 2003 10 Most Relevant Publications for Prof. Percy Knolle US Patent 20030138410 - Targeted cytolysis of HIV-infected 1. Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, cells by chimeric CD4 receptor-bearing cells Meyer-Schwesinger C, Pohl JM, Maurice NJ, Thiebes S, 2002 Lorenz K, Quast T, Fuhrmann M, Baumgarten G, Lohse MJ, US Patent 20020176851 - Redirection of cellular immunity Opdenakker G, Bernhagen J, Bucala R, Panzer U, Kolanus W, by protein-tyrosine kinase chimeras Grone HJ, Garbi N, Kastenmuller W, Knolle PA, Kurts C, Engel 1996 DR. Crosstalk between Sentinel and Helper Macrophages US Patent 6573362 - Cytohesin-PH peptides that affect the Permits Neutrophil Migration into Infected Uroepithelium. Cell ability of integrins to adhere 2014, 156(3): 456-468. 1994 2. Knolle PA, Thimme R. Hepatic Immune Regulation and its Munich Gene Center Junior Group Leader 5-year-Award, Involvement in Viral Hepatitis Infection. Gastroenterology 2014, BMBF and University of Munich Technische Universität München (TU) in press. Rheinische Friedrich-Wilhelms-Universität Bonn Institute for Molecular Immunology, Director 3. De Nardo D, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer Life and Medical Sciences Institute (LIMES), Molecular 10 Most Relevant Publications for Prof. Waldemar Rheinische Friedrich-Wilhelms-Universität Bonn M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber Immunology & Cell Biology, Director Kolanus 1. Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ra- Institute of Molecular Medicine, Director (until 2012) J, Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald ML, Hernandez NJ, Williams BR, Knolle P, Kneilling E-Mail: [email protected] mos D, Kohlmeyer J, Riesenberg S, van den Boorn-Konijnenberg E-Mail: [email protected] M, Rocken M, Lutjohann D, Wright SD, Schultze JL, Latz E. D, Hömig-Hölzel C, Reuten R, Schadow B, Weighardt H, Wenzel High-density lipoprotein mediates anti-inflammatory repro- Research Expertise D, Helfrich I, Schadendorf D, Bloch W, Bianchi M.E, Lugassy C, Research Expertise gramming of macrophages via the transcriptional regulator Prof. Kolanus and his group are interested in intracellular Barnhill RL, Koch M, Fleischmann BK, Förster I, Kastenmüller W, Kolanus W, Hölzel M, Gaffal E, Tüting T. 2014.Ultraviolet-radia- The focus of Prof. Knolle’s research group is on the molecular ATF3. Nature immunology 2014, 15(2): 152-160. signal transduction events which control leukocyte adhe- tion-induced inflammation promotes angiotropism and metastasis and cellular mechanisms governing local immune control in 4. Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, sion, migration, and effector functions. The main emphasis in melanoma. Nature. 507,109-13. tissues. In his laboratory the relevance of local antigen presen- Abdullah Z, Schildberg FA, Odenthal M, Dienes HP, van Roo- of their current research activities lies in elucidating the 2. Salt-dependent chemotaxis of macrophages. 2013 tation by organ-resident liver cells was demonstrated for induc- ijen N, Schmitt E, Garbi N, Croft M, Kurts C, Kubes P, Protzer role of integrin adhesion receptors and the cytoskeleton in Müller S, Quast T, Schröder A, Hucke S, Klotz L, Jantsch J, Gerzer tion of immune tolerance in naïve CD4 and CD8 T cells. The U, Heikenwalder M, Knolle PA. Intrahepatic myeloid-cell the functional adaptation of leukocyte motility to specific R, Hemmersbach R, Kolanus W, PLoS One. 16 :e73439. development of novel cell separation techniques allowed to aggregates enable local proliferation of CD8(+) T cells and microenvironments, some of which include force- 3. Ulbricht A, Eppler FJ, Tapia VE, van der Ven PF, Hampe N, study the mechanisms and functional relevance of different liver successful immunotherapy against chronic viral liver infection. dependent slow migration of immune cells on and across Hersch N, Vakeel P, Stadel D, Haas A, Saftig P, Behrends C, Fürst cell populations at a new level of resolution and to compare the Nature immunology 2013, 14(6): 574-583. barriers, versus force-independent, fast migration in the DO, Volkmer R, Hoffmann B, Kolanus W, Höhfeld J. immune function of these non-professional antigen presenting 5. Bottcher JP, Schanz O, Wohlleber D, Abdullah Z, De- interstitium. Cellular mechanotransduction relies on tension-induced and chap- cells with myeloid professional antigen presenting cells such bey-Pascher S, Staratschek-Jox A, Hochst B, Hegenbarth S, erone-assisted autophagy., Curr Biol., 2013, 23, 430-435. as dendritic cells or macrophages. His group has discovered Grell J, Limmer A, Atreya I, Neurath MF, Busch DH, Schmitt E, 4. Quast T, Eppler F, Semmling V, Schild C, Homsi Y, Levy S, novel stimulatory pathways that are initiated by unique immune van Endert P, Kolanus W, Kurts C, Schultze JL, Diehl L, Knolle Education / Training Lang T, Kurts C, Kolanus W. CD81 is essential for the forma- sensory mechanisms in liver-resident antigen presenting cells PA. Liver-primed memory T cells generated under noninflam- University of Hannover, Molecular Biology, PhD, 1987 tion of membrane protrusions and regulates Rac1-activation in that trigger local T cell immunity in the liver. The lab has devel- matory conditions provide anti-infectious immunity. Cell reports University of Hannover, Biology, Chemistry, State adhesion-dependent immune cell migration., Blood, 2011, 118, oped an interest in local mechanisms determining regulation of 2013, 3(3): 779-795. ­examination, 1984 1818-1827. CD4 T cell differentiation with particular reference to the impact 6. Abdullah Z, Schlee M, Roth S, Mraheil MA, Barchet W, 5. Loer B, Bauer R, Bornheim R, Grell J, Kremmer E, Kolanus W, Hoch M. 2008. The NHLdomain protein Wech is crucial for the of nuclear receptors that also impact on the metabolic state of Bottcher J, Hain T, Geiger S, Hayakawa Y, Fritz JH, Civril F, Appointments / Positions Held integrin-cytoskeleton link. Nat Cell Biol 10: 422-8. T cells. Hopfner KP, Kurts C, Ruland J, Hartmann G, Chakraborty T, 2002 - present 6. Hafner M, Schmitz A, Grune I, Srivatsan SG, Paul B, Kolanus Full Professorship, Molecular Immunology, Knolle PA. RIG-I detects infection with live Listeria by sensing W, Quast T, Kremmer E, Bauer I, Famulok M. 2006. Inhibition of Education / Training secreted bacterial nucleic acids. The EMBO journal 2012, University of Bonn cytohesins by SecinH3 leads to hepatic insulin resistance. Nature University of Mainz, Germany, Internal Medicine Specialist, 31(21): 4153-4164. 1999 - 2002 444: 941-4. 1997 7. Wohlleber D, Kashkar H, Gartner K, Frings MK, Odenthal M, Associate Professor, Biochemistry, 7. Shamri R, Grabovsky V, Gauguet JM, Feigelson S, Manevich E, German Cancer Research Centre, Heidelberg Applied Hegenbarth S, Borner C, Arnold B, Hammerling G, Nieswandt University of Munich (LMU) Kolanus W, Robinson MK, Staunton DE, von Andrian UH, Alon R. ­Immunology, M.D. thesis, 1990 B, van Rooijen N, Limmer A, Cederbrant K, Heikenwalder M, 1999 2005. Lymphocyte arrest requires instantaneous induction of an Universities of Frankfurt, Paris, Birmingham Pasparakis M, Protzer U, Dienes HP, Kurts C, Kronke M, Knol- Habilitation in Biochemistry, Faculty of Chemistry, University of extended LFA-1 conformation mediated by endothelium- bound (UK), Strasbourg, and Geneva, Medicine, M.D., 1988 le PA. TNF-induced target cell killing by CTL activated through Munich (LMU) chemokines. Nat Immunol 6: 497-506. cross-presentation. Cell reports 2012, 2(3): 478-487. 1994 - 1999 8. Boehm T, Hofer S, Winklehner P, Kellersch B, Geiger C, Trock- Appointments / Positions Held 8. Huang LR, Gabel YA, Graf S, Arzberger S, Kurts C, Heik- Independent Group Leader, Gene Center Munich, University of enbacher A, Neyer S, Fiegl H, Ebner S, Ivarsson L, Schneider R, Kremmer E, Heufler C,Kolanus W. 2003. Attenuation of cell 2013 - present enwalder M, Knolle PA, Protzer U. Transfer of HBV genomes Munich (LMU) using low doses of adenovirus vectors leads to persistent 1990 - 1993 adhesion in lymphocytes is regulated by CYTIP, a protein which Director Institute of Molecular Immunology, TU Munich mediates signal complex sequestration. EMBO J 22: 1014-24. 2006 - 2012, University of Bonn infection in immune competent mice. Gastroenterology 2012, Post-doc Fellow, Molecular Immunology, Harvard Medical 142(7): 1447-1450 e1443. School 9. Geiger C, Nagel W, Boehm T, van Kooyk Y, Figdor CG, Krem- Vice-speaker of the Collaborative Research group 704 mer E, Hogg N, Zeitlmann L, Dierks H, Weber KS, Kolanus W. 9. Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic 1988 - 1990 Post-doc Fellow, Immunology, Hannover Medical 2002 - 2012 2000. Cytohesin-1 regulates beta-2 integrin-mediated adhesion infections. Nature reviews Immunology 2012, 12(3): 201-213. School Director Institutes of Molecular Medicine and Experimental through both ARF-GEF function and interaction with LFA-1. EMBO 10. Kern M, Popov A, Kurts C, Schultze JL, Knolle PA. Taking Immunology, University of Bonn, Germany J 19: 2525-36. 2002 off the brakes: T cell immunity in the liver. Trends in immunolo- Honors / Awards 10. Kolanus W, Nagel W, Schiller B, Zeitlmann L, Godar S, Professor of Molecular Medicine and Immunology, University of gy 2010, 31(8): 311-317. 2009 Stockinger H, Seed B. 1996. Alpha L beta 2 integrin/LFA-1 binding Bonn, Germany US Patent 20090105286, Low molecular inhibitors of to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory mole- 1997 - 2002 ­cyohesin-family guanine nucleotide exchange factors cule. Cell 86: 233-42. Independent Group Leader, Center of Molecular Biology Heidelberg (ZMBH), University of Heidelberg, ­Germany

156 157 1991-1995 Humboldt-University of Berlin Medical Officer and Research Fellow, Hannover Medical 1998 Visiting Scientist, Department of Lipid Biochemistry, Merck Prof. Christian Kurts, MD School, Germany Prof. Eicke Latz, MD PhD Research Laboratories Institute of Experimental Immunology Institute of Innate Immunity Honors / Awards Honors / Awards 2012 2013 ERC Consolidator Grant Gottfried-Wilhelm-Leibniz-Prize of the DFG 2011 GlaxoSmithKline Clinical Science Award 2010 2009 Dana Foundation Award Hans-U.-Zollinger-Award of the German Society for 2004 Federation of Clinical Immunology Societies (FOCIS) Award ­Nephrology 2001 Postdoctoral Training Grant of the German Academic 2000 ­Exchange Program (DAAD) 2001 PhD Thesis awarded “summa cum laude” Heisenberg-Fellowship of the 2000 Scholarship of the Japanese Society for Endoscopy Deutsche Forschungsgemeinschaft 2000 Award of the Japanese Society of Surgery, Tokyo National 1999 Cancer Center Sir Hans Krebs award for basic medical research 1992 Annual award of the German Society of Nephrology for best 10 Most Relevant Publications for Prof. Eicke Latz doctoral thesis 1. De Nardo D*, Labzin LI*, Kono H, Seki R, Schmidt SV, Beyer 1986 -1991 M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber J, Fellowship Studienstiftung des deutschen Volkes (German Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald National Academic Foundation) ML, Hernandez NJ, Williams BR, Knolle P, Kneilling M, Rocken M, Lutjohann D, Wright SD, Schultze JL* and Latz E*. (2014). Rheinische Friedrich-Wilhelms-Universität Bonn Rheinische Friedrich-Wilhelms-Universität Bonn High-density lipoprotein mediates anti-inflammatory reprogram- Institute of Experimental Immunology, Director 10 Most Relevant Publications for Prof. Christian Kurts Institute of Innate Immunity, Director ming of macrophages via the transcriptional regulator ATF3. Nat 1. Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, E-Mail: [email protected] E-Mail: [email protected] Immunol, 15(2), 152-160. Meyer-Schwesinger C, Pohl J, Maurice NJ, Thiebes S, Lorenz K, 2. Heneka MT*, Kummer MP, Stutz A, Delekate A, Schwartz S, Quast T, Fuhrmann M, Baumgarten G, Lohse MJ, Opdenakker G, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Research Expertise Bernhagen J, Bucala R, Panzer U, Kolanus W, Gröne HJ, Garbi Research Expertise Prof. Kurts and his group are interested in the mechanisms Halle A, Korte M, Latz E* and Golenbock DT*. (2013). NLRP3 is N, Kastenmüller W, Knolle PA, Kurts C*, Engel DR*. 2014. Cross- The Latz Lab has a longstanding interest in deciphering the activated in Alzheimer‘s disease and contributes to pathology in governing antigen-presentation and the ensuing immune talk between sentinel and helper macrophages permits neutrophil molecular mechanisms of innate immune receptor activation. In APP/PS1 mice. Nature, 493(7434), 674-678. response in the defense against infections and in immune-me- migration into infected uroepithelium. Cell, 156:456–68; particular, the lab is interested in understanding how innate recep- 3. Bossaller L, Rathinam VA, Bonegio R, Chiang PI, Busto P, diated disease. Their main research projects focus on the (*joint senior authorship) tors interact with their ligands and how this molecular interaction Wespiser AR, Caffrey DR, Li QZ, Mohan C, Fitzgerald KA, Latz mechanisms of antigen cross-presentation to cytotoxic CD8 2. Kurts C, Panzer U, Anders HJ, Rees A. 2013. The immune leads to receptor activation. Recently, we have also focused on the E* and Marshak-Rothstein A*. (2013). Overexpression of mem- T cells, peripheral immune tolerance of T and B lymphocytes system and kidney disease: basic concepts and clinical implica- molecular details of the mechanisms that lead to the activation of brane-bound fas ligand (CD95L) exacerbates autoimmune disease against self antigens, and the role of dendritic cells in diseases, tions. Nat Rev Immunol, 13(10):738-53. the NLRP3 and AIM2 inflammasome. The NLRP3 inflammasome and renal pathology in pristane-induced lupus. Journal of Immunol- especially in kidney disease. 3. Hochheiser K, Heuser, C Krause TA, Teteris S, Ilias A, Weisheit can respond to a broad range of cellular stressors and to sub- ogy, 191(5), 2104-2114. C, Hoss F, Tittel AP, Panzer U, Knolle PA, Engel DR, Tharaux PL, stances that indicate metabolic derangements such as aggregated 4. Bossaller L, Chiang PI, Schmidt-Lauber C, Ganesan S, Kaiser Education / Training Kurts C. 2013. Exclusive CX3CR1-dependence of kidney cortex peptides, crystals of monosodium urate (forming in gout) or crys- WJ, Rathinam VA, Mocarski ES, Subramanian D, Green DR, University of Göttingen, Germany dendritic cells identifies a therapeutic target in glomerulonephritis. tals of cholesterol that are found in atherosclerotic plaques. One ­Silverman N, Fitzgerald KA, Marshak-Rothstein A and Latz E. J Clin Invest, 123(10):4242-54. goal of the research is to translate the molecular understanding of Medicine M.D., 1991 (2012). Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1be- 4. Gottschalk C, Damuzzo V, Gotot J, Kroczek R, Yagita H, Mur- innate immune receptor activation into the generation of molecular ta and IL-18 Maturation via Caspase-8 in an RIP3-Independent phy KM, Knolle PA, Ludwig-Portugall I, Kurts C. 2013. Batf3-de- tools that could lead to the development of specific diagnostics Manner. Journal of Immunology, 189(12), 5508-5512. Appointments / Positions Held pendent renal lymph node DCs maintain immune-homeostasis for inflammatory materials. Another goal is to devise means to 5. Duewell P*, Kono H*, Rayner KJ, Sirois CM, Vladimer G, Bau- 2013 against circulating antigens; J Am Soc Nephrol, 24:543-9. pharmacologically interfere with the activation of innate immune re- ernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik Co-speaker SFB 704 “Molecular Mechanisms and Chemical 5. Gotot J, Gottschalk C, Leopold S, Knolle PA, Yagita H, Kurts ceptors in order to develop novel approaches to treat inflammatory T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung ­Modulation of Local Immune Regulation“ University of Bonn, C*, Ludwig-Portugall I*. 2012. Direct PD-1-mediated suppression diseases such as Alzheimer’s disease or atherosclerosis. V* and Latz E*. (2010). NLRP3 inflammasomes are required ­Germany of autoreactive B cells by regulatory T cells. PNAS 109(26):10468- for atherogenesis and activated by cholesterol crystals. Nature, 2012 7. (*joint senior authorship) Education / Training 464(7293), 1357-1361. Co-speaker SFB TR57 “Organ-Fibrosis”, representing the 6. Tittel AP, Heuser C, Ohliger C, Yona S, Hämmerling GJ, Engel Humbolt University of Berlin, Germany, PhD, 2001 6. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Bonn site, University of Bonn, Germany DR, Garbi N, Kurts C. 2012. Functionally relevant neutrophilia in Free University of Berlin, Germany, Molecular Medicine, Hematology, Horvath G, Caffrey DR, Latz E* and Fitzgerald KA*. (2009). AIM2 CD11c-diphteria toxin receptor transgenic mice. Nat Methods recognizes cytosolic dsDNA and forms a caspase-1- activating 2009 - present M.D., 1998 Director Institute of Experimental Immunology, University of 9(4):385-90. inflammasome with ASC. Nature, 458(7237), 514-518. 7. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald Bonn, Germany 7. Engel DR, Koscielny A, Wehner S, Maurer J, Schiwon M, Appointments / Positions Held 2003 - 2008 Schumak B, Limmer A, Sparwasser T, Hirner A, Knolle PA, Kalff K, Speert D, Fernandes- Alnemri T, Wu J, Monks BG, Fitzgerald 2009 - present Full Professor of Medicine, Founder and Director of KA, Hornung V* and Latz E*. (2009). Cutting edge: NF-kappaB Full Professor of Molecular Immunology University of Bonn, JC, Kurts C. 2010. Th1 memory cells disseminate postoperative ileus over the entire intestinal tract. Nat Med, 16(12): 1407–1413. the Institute of Innate Immunity, University of Bonn, Germany activating pattern recognition and cytokine receptors license ­Germany 8. Semmling V, Lukacs-Kornek V, Thaiss CA, Quast T, Hochheiser 2011- present Leader, Cooperation Unit Innate Immunity in NLRP3 inflammasome activation by regulating NLRP3 expression. 2002 K, Panzer U, Rossjohn J, Perlmutter P, Cao J, Godfrey DI, Savage Neurodegeneration, DZNE, Bonn, Germany J Immunol, 183(2), 787-791. Visiting scientist, Stephen Schoenberger Group PB, Knolle PA, Kolanus W, Forster I, Kurts C. 2010. Alternative 2003 - present Assistant Professor of Medicine UMass Medical 8. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock La Jolla Institute for Allergy and Immunology, CA, USA cross-priming through CCL17-CCR4-mediated attraction of CTLs School KL, Fitzgerald KA* and Latz E*. (2008). Silica crystals and alumi- 2000 - 2003 toward NKT cell-licensed DCs. Nat Immunol 11: 313-20. 2008 Adjunct Professor II, Institute of Cancer Research and num salts activate the NALP3 inflammasome through phagosomal Research group leader, Dept. of Nephrology and Clinical 9. Kurts C, Robinson BW, Knolle PA. 2010. Cross-priming in ­Molecular Medicine, Norwegian University of Science and destabilization. Nat Immunol, 9(8), 847-856. ­Immunology, University of Aachen, Germany health and disease. Nat Rev Immunol 10: 403-14. ­Technology 9. Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC, 1998 - 2000 10. Heymann F, Meyer-Schwesinger C, Hamilton-Williams EE, 2007 Founder and Co-Director of UMassNanoMed, Monks BG, McKnight CJ, Lamphier MS, Duprex WP, Espevik Medical Officer and Research Fellow, Hannover Medical Hammerich L, Panzer U, Kaden S, Quaggin SE, Floege J, Grone ­UMassNanoMed Institute T and Golenbock DT. (2007). Ligand-induced conformation- School, Germany HJ, Kurts C. 2009. Kidney dendritic cell activation is required 2003-2006 Assistant Research Professor, UMass Medical School al changes allosterically activate Toll-like receptor 9. Nat 1997 - 1998 for progression of renal disease in a mouse model of glomerular 2001 - 2003 Postdoctoral Fellow, Division of Infectious Disease ­Immunol, 8(7),772-779. Postdoctoral Research Fellow, Dept of Microbiology, Monash injury. J Clin Invest 119: 1286-97. UMass Medical School 10. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks ­Medical School, Melbourne, Australia 2001 Postdoctoral Fellow, Evans Biomedical Research BG, Knetter CF, Lien E, Nilsen NJ, Espevik T and Golenbock DT. 1995 - 1997 *These authors contributed equally Center, Boston University of Medicine (2004). TLR9 signals after translocating from the ER to CpG DNA 1999 - 2001 Research Fellow, Molecular Sepsis Research Labora- Postdoctoral Research Fellow, Thymus Biology Unit, The in the lysosome. Nat Immunol, 5(2), 190-198. tories, Charité University Hospital, Humboldt-University of Berlin Walter and Eliza Hall Institute for Medical Research (WEHI), 1998 - 2000 Internship and Residency (Intensive Care) Department * These authors contributed equally Melbourne, Australia of Surgery and Surgical Oncology, Charité University Hospital,

158 159 2003 - 2008 Honors / Awards Editorial Board member of ‚Stem Cells‘ 2013 Prof. Harald Neumann, MD 2007 Prof. Pierluigi Nicotera, MD The Chancellor’s Award Lecture in Neuroscience at LSU Institute of Reconstructive Neurobiology DANA-Foundation-Award, Neuroimmunology-Program German Centre for Neurodegenerative Diseases (DZNE) ­Neuroscience Center of Excellence, New Orleans, USA 1996 2012 PCR-Award Boehringer Mannheim Honorary Citizenship and Key to the City of New Orleans 1992 2010 Research scholarship (German science foundation) The Cardano Prize University of Pavia and Rotary Club Pavia 2003 The Chancellor’s Award Lecture in Neuroscience at LSU 10 Most Relevant Publications for Prof. Harald ­Neuroscience Center of Excellence, New Orleans, USA ­Neumann 2002 1. Claude J, Linnartz-Gerlach B, Kudin AP, Kunz WS and “Molecular switches in neuronal cell death” Lecture at the 37th Neumann H. (2013). Microglial CD33-related Siglec-E Nobel Conference on Apoptosis, Stockholm inhibits neurotoxicity by preventing the phagocytosis asso- 1999 ciated oxidative burst. J. Neurosci. 33(46):18270-6. The Jacob Hooisma Honorary Lecture at the 7th Meeting of 2. Zhang B*, Gaiteri C*, Bodea LG*, Wang Z, McElwee J, the International Neurotoxicology Association, Leicester Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Flud- 1995 er E, Clurman B, Melquist S, Narayanan M, Suver C, Shah The EUROTOX Award Lecture, 1st G. Zbinden Memorial Lec- H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb ture Award, Prague JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers 1992 “Nuclear Calcium Signalling” Lecture at the 20th Nobel Rheinische Friedrich-Wilhelms-Universität Bonn AJ, Schadt EE, Neumann H, Zhu J, Emilsson V. (2013). German Centre for Neurodegenrative Diseases (DZNE), ­Conference on Calcium Signalling, Saltsjöbaden, Sweden Institute of Reconstructive Neurobiology, Director Integrated systems approach identifies genetic nodes and Scientific Director networks in late-onset Alzheimer‘s disease. Cell. 2013 Apr 1992 E-Mail: [email protected] E-Mail: [email protected] 25;153(3):707-20. The International Life Science Institute Research Foundation 3. Wang Y, Neumann H. 2010. Alleviation of neurotoxicity U.S.A. (ILSI), award Research Expertise by microglial human Siglec-11. J. Neurosci 30: 3482-8. Research Expertise Neuroinflammation, mechanisms of inflammatory neurode- 4. Beutner C, Roy K, Linnartz B, Nappoli I, Neumann H. Prof. Nicotera’s main research focus is on molecular 10 Most Relevant Publications for Prof. Pierluigi generation, microglia-neuron interaction, stem cell-derived 2010. Generation of microglial cells from mouse embryonic mechanisms of cell death and neurodegeneration. ­Nicotera microglia stem cells. Nature Protocols: 5:1481-94. 1. Ziviani E, Lippi G, Bano D, Munarriz E, Guiducci S, Zoli M, Young KW, Nicotera P. 2011. Ryanodine receptor-2 upregula- 5. Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann Education / Training tion and nicotine-mediated plasticity. EMBO J 30(1): 194-204. Education / Training H. 2007. TREM2-transduced myeloid precursors mediate University of Pavia, Medical School, Italy, Cardiology 2. Regad T, Bellodi C, Nicotera P, Salomoni P. 2009. The Technical University Munich, Germany Neuroimmunology nervous tissue debris clearance and facilitate recovery in an Consultant, 1987 tumor suppressor Pml regulates cell fate in the developing Habilitation, 1998 animal model of multiple sclerosis. PLoS Med 4: e124. Karolinska Institute, Stockholm, Biochemical Toxicology neocortex. Nat Neurosci 12: 132-40. University of Hagen, Germany Business Business 6. Stagi M, Gorlovoy P, Larionov S, Takahashi K, Neumann PhD, 1986 3. Berliocchi L, Fava E, Leist M, Horvat V, Dinsdale D, Read D, ­Administration, 1994 H. 2006. Unloading kinesin transported cargoes from the University of Pavia, Medical School, Italy, Medicine MD, Nicotera P. 2005. Botulinum neurotoxin C initiates two differ- University of Würzburg, and University of Munich (LMU), tubulin track via the inflammatory c-Jun N-terminal kinase 1982 ent programs for neurite degeneration and neuronal apoptosis. Germany, Medicine M.D., Thesis, 1991 pathway. FASEB J 20: 2573-5. J Cell Biol 168: 607-18. 7. Takahashi K, Rochford CD, Neumann H. 2005. Clear- Appointments / Positions Held 4. Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, ance of apoptotic neurons without inflammation by microg- Naldini L, Rizzuto R, Carafoli E, Nicotera P. 2005. Cleavage Appointments / Positions Held April 2009 - present lial triggering receptor expressed on myeloid cells-2. J Exp of the plasma membrane Na+/Ca2+ exchanger in excito- 2004 - present Scientific Director & Chairman of the Executive Board Med 201: 647-57. toxicity. Cell 120: 275-85. Head of the Neural Regeneration Group, University of ­vGerman Centre for Neurodegenerative Diseases (DZNE), 8. Stagi M, Dittrich PS, Frank N, Iliev AI, Schwille P, Neu- 5. Orrenius S, Zhivotovsky B, Nicotera P. 2003. Regulation of Bonn, Germany Bonn, Germany mann H. 2005. Breakdown of axonal synaptic vesicle cell death: the calcium- apoptosis link. Nat Rev Mol Cell Biol 4: 2001 - 2004 2002 - 2009 precursor transport by microglial nitric oxide. J Neurosci 552-6. Head of the Neuroimmunology Group European Director of the British Medical Research Council ­Toxicology 25: 352-62. 6. Schierle GS, Hansson O, Leist M, Nicotera P, Widner H, ­Neuroscience Institute Göttingen, University Göttingen Unit and Honorary Professor of Neuroscience (Dept. of Cell 9. Neumann H, Schweigreiter R, Yamashita T, Rosenk- Brundin P. 1999. Caspase inhibition reduces apoptosis and 1995 - 2001 Physiology & Pharmacology), University of Leicester increases survival of nigral transplants. Nat Med 5: 97-100. ranz K, Wekerle H, Barde YA. 2002. Tumor necrosis factor Group leader, Department of Neuroimmunology 2005 - 2008 7. Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P. inhibits neurite outgrowth and branching of hippocampal Max-Planck-Institute of Neurobiology, Martinsried Teaching Professor of Toxicology, Faculty of Pharmacy 1997. Intracellular adenosine triphosphate (ATP) concentration: neurons by a rho-dependent mechanism. J Neurosci 22: 1992 - 1994 University of Siena, Italy a switch in the decision between apoptosis and necrosis. J 854-62. Research fellow, Department of Neuroimmunology 1996 - 2002 Exp Med 185: 1481-6. 10. Medana I, Martinic MA, Wekerle H, Neumann H. 2001. Max-Planck-Institute of Psychiatry, Martinsried Foreign Adjunct Professor in Toxicology, Karolinska 8. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Transection of major histocompatibility complex class I-in- 1990 - 1992 ­Institute, Stockholm, Sweden 1995. Apoptosis and necrosis: two distinct events induced, duced neurites by cytotoxic T lymphocytes. Am J Medical Internship, Department of Neurology, University 1995 - 2000 respectively, by mild and intense insults with N-methyl-D- as- Pathol 159: 809-15. Ulm, Germany C4 Professor of Molecular Toxicology, University of partate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A 92: 7162-6. ­Konstanz, Germany 9. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Honors / Awards 1989 - 1994 Orrenius S, Lipton SA, Nicotera P. 1995. Glutamate-induced 2010 Senior University Lecturer, Karolinska Institute, Stockholm, PCT-Patent (WO2010/125110) entitled ‚Method for obtain- neuronal death: a succession of necrosis or apoptosis de- Sweden pending on mitochondrial function. Neuron 15: 961-73. ing human microglial precursor cells from pluripotent stem 1992 10. Juntti-Berggren L, Larsson O, Rorsman P, Ammala C, cells’; with the following inventors Neumann, Roy, Brüstle, Docent in Molecular Toxicology, Karolinska Institute, Stock- Bokvist K, Wahlander K, Nicotera P, Dypbukt J, Orrenius Peitz; international publication on 4. Nov 2010. holm, Sweden S, Hallberg A, et al. 1993. Increased activity of L-type Ca2+ 2005 - 2010 1986 - 1989 channels exposed to serum from patients with type I diabetes. Co-coordinator of the EU Integrated Project NeuroproMiSe Research assistant Professor, Department of Karolinska Science 261: 86-90. 2002 - 2009 Institute, Stockholm, Toxicology, Sweden Managing Board member of the Institute of MS Research

160 161 2011 - present: European Society of Human Genetics (Elected 2004 Member of the Board) Karl-Hansen Memorial Award, German Society for Allergology Prof. Markus M. Nöthen, MD 2010 - 2012: Project Committee of the National Genome ­Research Prof. Natalija Novak, MD and Immunology (DGAKI) Institute of Human Genetics Network (Spokesman) Department of Dermatology and Allergy 2003 2010 - present: Scientific Advisory Board of the Medical Research Fujisawa “Young Investigator Achievements Award in Atopic Council (MRC) Centre for Neuropsychiatric Genetics and Genom- Dermatitis Research” ics, Cardiff, UK (Member) Award, Herbert-Reeck-Society 2010 - present: German Academy of Sciences Leopoldina Honourable Mention Diploma Pharmacia Research ­Foundation ­(National Academy of Sciences) Travel Award EAACI Meeting, Davos, Switzerland 2009 - present: Hermann Emminghausen-Prize 2008 - 2013: Project Committee of the National Genome ­Research Erich-Hoffmann Memorial Award Network (Elected member) 2002 2007 - present: Institute of Science and Ethics, Bonn (Member of Herbert-Herxheimer Award, German Society for Allergology the Scientific Advisory Board) and Immunology (DGAKI) National Foundation for Legasthenia and Dyscalculia (Member of 2002 the Medical Advisory Board) BONFOR Award 2006 - present: National Alopecia Areata Foundation (Member of the Medical Advisory Board) Task Force on Genetics, World Feder- 10 Most Relevant Publications for Prof. Natalija Novak ation of Societies of Biological Psychiatry 1. Yu CF, Peng WM, Oldenburg J, Hoch J, Bieber T, Limmer 2005 - present: International Society of Psychiatric Genetics (Elect- A, Hartmann G, Barchet W, Eis-Hubinger AM, Novak N. 2010. ed Member of the Board) Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation. J Immunol 184: 1159-67. 10 Most Relevant Publications for Prof. Markus M. Nöthen 2. Allam JP, Würtzen PA, Reinartz M, Winter J, Vrtala S, Chen KW, Rheinische Friedrich-Wilhelms-Universität Bonn Rheinische Friedrich-Wilhelms-Universität Bonn 1. Mühleisen TW, Leber M, Schulze TG, Strohmaier J, Degen- Valenta R, Wenghoefer M, Appel T, Gros E, Niederhagen B, Bieber Institute of Human Genetics, Director hardt F,…,Forstner AJ, Schumacher J,…, Herms S, Hoffmann Department of Dermatology and Allergy T, Lund K, Novak N. 2010. Phl p 3 resorption in human oral muco- E-Mail: [email protected] P,…,Propping P, Becker T, Rietschel M, Nöthen MM, Cichon S. E-Mail: [email protected] sa leads to dose-dependent and time-dependent allergen binding 2014. Genome-wide association study reveals two new risk loci by oral mucosal Langerhans cells, attenuates their maturation, and Research Expertise enhances their migratory and TGF- 1 and IL-10 producing proper- for bipolar disorder. Nature Communications doi: 10.1038/ncom- Research Expertise β The identification of the genetic causes of inherited diseases, and a ties. J Allergy Clin Immunol 126: 638-45. ms4339. Pathophysiology of atopic dermatitis including genetic special focus on genetically complex and multifactorial phenotypes. 2. Cross-Disorder Group of the Psychiatric Genomics Consortium, 3. Gros E, Bussmann C, Bieber T, Forster I, Novak N. 2009. … , Nöthen MM, … , Wray N. 2013. Genetic relationship between changes, regulation of the surface expression of the high Expression of chemokines and chemokine receptors in lesional and Education / Training five psychiatric disorders estimated from genome-wide SNPs. Nat affinity receptor for IgE on dendritic cells, role of IgE recep- nonlesional upper skin of patients with atopic dermatitis. J Allergy University of Bonn, Germany, Human Genetics, Habilitation, 1996 Genet 45:984-994. tor bearing Langerhans cells and inflammatory dendritic Clin Immunol 124: 753-60 e1. University of Bonn, Germany, Human Genetics, Medical Board 3. Ludwig KU, Mangold E, Herms S, Nowak S, Reutter H,…, epidermal cells, predictive factors for atopy in cord-blood, 4. Esparza-Gordillo J, Weidinger S, Folster-Holst R, Bauerfeind ­Qualification, 1995 Nöthen MM. 2012. Genome-wide meta-analyses of nonsyndrom- A, Ruschendorf F, Patone G, Rohde K, Marenholz I, Schulz F, University of Würzburg, Germany, Internal Medicine, development and characterization of new therapeutic strat- ic cleft lip with or without cleft palate identify six new risk loci. Nat Kerscher T, Hubner N, Wahn U, Schreiber S, Franke A, Vogler R, Medical thesis, 1992, University of Würzburg, Germany, Clinical egies for atopic dermatitis, role of dendritic cells in the oral Genet 44:968-971. Heath S, Baurecht H, Novak N, Rodriguez E, Illig T, Lee-Kirsch ­Medicine, MD, 1989 and nasal mucosa. 4. Cichon S, Mühleisen TW, Degenhardt FA, Mattheisen M,..., MA, Ciechanowicz A, Kurek M, Piskackova T, Macek M, Lee YA, Schumacher J, Maier W, Propping P, Rietschel M, Nöthen MM*. Ruether A. 2009. A common variant on chromosome 11q13 is Appointments / Positions Held Education / Training 2008 - present 2011. Genome-wide association study identifies genetic variation associated with atopic dermatitis. Nat Genet 41: 596-601. Director and Chair, Institute of Human Genetics, University of Bonn, in neurocan as a susceptibility actor for bipolar disorder. Am J Hum University of Bonn, Germany, Medicine, MD., 1998 5. Kwiek B, Peng WM, Allam JP, Langner A, Bieber T, Novak N. Germany Genet 88:372-81. 2008. Tacrolimus and TGF-beta act synergistically on the genera- 2006 - present 5. Stefansson H, Ophoff RA, Steinberg S,..., Nöthen MM, Riet- Appointments / Positions Held tion of Langerhans cells. J Allergy Clin Immunol 122: 126-32, 32 Vice Dean for Research, Medical Faculty, University of Bonn, schel M, Matthews PM, Muglia P, Peltonen L, St Clair D, Goldstein 2008 - present e1. Germany DB, Stefansson K, Collier DA*. 2009. Common variants conferring Full Professor of Dermatology and Allergy, University of 6. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, Klopp N, Wagenpfeil S, Zhao Y, Liao H, Lee SP, 2004 - present risk of schizophrenia. Nature 460: 744-7. Bonn, Germany 6. Birnbaum S, Ludwig KU,..., Nöthen MM, Mangold E*. 2009. Palmer CN, Jenneck C, Maintz L, Hagemann T, Behrendt H, Ring Alfried Krupp von Bohlen und Halbach Professor in Genetic 2009 ­Medicine, University of Bonn, Germany Key susceptibility locus for nonsyndromic cleft lip with or without J, Nothen MM, McLean WH, Novak N. 2006. Loss-of-function Board, Andrology, University of Bonn, Germany 2004 - present cleft palate on chromosome 8q24. Nat Genet 41: 473-7. variations within the filaggrin gene predispose for atopic dermatitis Head, Department of Genomics, Life & Brain Center, University of 7. Stefansson H, Rujescu D, Cichon S,..., Nöthen MM, Peltonen 2006 - 2007 with allergic sensitizations. J Allergy Clin Immunol 118: 214-9. Bonn, Germany L, Collier DA, St Clair D, Stefansson K*. 2008. Large recurrent Visiting scientist, Heisenberg-Fellowship, Swiss Institute of 7. Novak N, Valenta R, Bohle B, Laffer S, Haberstok J, Kraft S, 2001 - 2004 microdeletions associated with schizophrenia. Nature 455: 232-6. Allergy and Asthma Research, Davos, Switzerland Bieber T. 2004. FcepsilonRI engagement of Langerhans cell- Head of Department and Chair of Medical Genetics, University of 8. Pasternack SM, von Kügelgen I, Aboud KA, Lee YA, Rüschen- 2004 like dendritic cells and inflammatory dendritic epidermal cell-like Antwerp, Belgium dorf F, Voss K, Hillmer AM, Molderings GJ, Franz T, Ramirez A, Board, Allergy, University of Bonn, Germany dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J Allergy Clin Immunol 113: 949-57. 1999 - 2001 Nürnberg P, Nöthen MM, Betz RC. 2008. G protein- coupled 2003 receptor P2Y5 and its ligand LPA are involved in maintenance of 8. Novak N, Allam JP, Hagemann T, Jenneck C, Laffer S, Valenta Assistant Medical Director, Institute of Human Genetics Assistant Professor, Dermatology and Allergy, University of University of Bonn, Germany human hair growth. Nat Genet 40: 329-34. R, Kochan J, Bieber T. 2004. Characterization of FcepsilonRI-bear- Bonn, Germany 1996 - 2001 9. Hillmer AM, Brockschmidt FF, Hanneken S, Eigelshoven S, ing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic Assistant Professor, Institute of Human Genetics, University of Steffens M, Flaquer A, Herms S, Becker T, Kortum AK, Nyholt Assistant to Medical Director, Dermatology, University of cells in atopic dermatitis. J Allergy Clin Immunol 114: 364-70. Bonn, Germany DR, Zhao ZZ, Montgomery GW, Martin NG, Mühleisen TW, Alblas Bonn, Germany 9. Novak N, Tepel C, Koch S, Brix K, Bieber T, Kraft S. 2003. Evi- 1991 - 1996 MA, Moebus S, Jöckel KH, Bröcker-Preuss M, Erbel R, Reinartz Board, Dermatology, University of Bonn, Germany dence for a differential expression of the FcepsilonRIgamma chain Postdoctoral Fellow, Institute of Human Genetics, University of R, Betz RC, Cichon S, Propping P, Baur MP, Wienker TF, Kruse R, in dendritic cells of atopic and nonatopic donors. J Clin Invest 111: 1047-56. Bonn, Germany Nöthen MM. 2008. Susceptibility variants for male-pattern bald- Honors / Awards 10. Novak N, Bieber T, Katoh N. 2001. Engagement of Fc epsilon 1990 - 1991 ness on chromosome 20p11. Nat Genet 40: 1279-81. 2008 Phadia International Award on Allergy Research, Phadia 10. Cichon S, Martin L, Hennies HC, Müller F, Van Driessche K, RI on human monocytes induces the production of IL-10 and Internship, Institute of Human Genetics, University of Bonn, 2007 Heisenberg-Professorship, German Research Council ­Germany Karpushova A, Stevens W, Colombo R, Renné T, Drouet C, Bork prevents their differentiation in dendritic cells. J Immunol 167: 797- K, Nöthen MM. 2006. Increased activity of coagulation factor XII 2006 Heisenberg-Fellowship, German Research Council 804. Honors / Awards (Hageman factor) causes hereditary angioedema type III. Am J Travel Award EAACI Vienna, Austria 2013 - present: Scientific Advisory Board of the Leipzig Research Hum Genet 79: 1098-104. 2005 Heinz Maier-Leibnitz Award, German Research Council Center for Civilization Diseases (LIFE) (Member) Research Award Atopische Dermatitis, Dermatologikum Ham- 2013 - present: Scientific Advisory Board of the Dr. Margarete * Publications with more than 10 authors have been shortened burg Fischer-Bosch Institute of Clinical Pharmacology (IKP) and the Young Investigator Travel Award, ISAD Meeting Acachand Robert Bosch Hospital (RBK) (Member) 2012 - present: International Advisory Board of iPSYCH (Lundbeck Foundation) (Chair)

162 163 10 Most Relevant Publications for Prof. Michael Research Foundation ­Pankratz 1999 Translational Research Award of the Leukemia & Prof. Michael J. Pankratz, PhD 1. Schoofs A, Hückesfeld S, Schlegel P, Miroschnikow A, Prof. Joachim L. Schultze, MD ­Lymphoma Society Life and Medical Sciences Institute (LIMES) Peters M, Zeymer M, Spieß R, Chiang AS, Pankratz MJ. Life and Medical Sciences Institute (LIMES) 1998 Special Fellowship Award of the Leukemia & ­Lymphoma 2014. Selection of motor programs for suppressing food intake Society and inducing locomotion in the Drosophila brain. PLoS Biol, in 1997 Fellowship Award of the Lymphoma Research ­Foundation of America press. 1997 Travel Award Annual Meeting of the American Society of 2. Bader R, Sarraf-Zadeh L, Peters M, Moderau N, Stocker H, Hematology Köhler K, Pankratz MJ*, Hafen E. 2013. The IGFBP7 homolog 1997 Leukemia Clinical Research Award (Deutsche Imp-L2 promotes insulin signaling in distinct neurons of the ­Gesellschaft für Hämatologie und Onkologie) Drosophila brain. J Cell Science 126, 2571-2576. 3. Bülow M, Aebersold R, Pankratz MJ*, Jünger M. 2010. 10 Most Relevant Publications for Prof. Joachim L. The Drosophila FoxA Ortholog Fork Head Regulates Growth Schultze and Gene Expression Downstream of Target of Rapamycin. 1. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, PLoS One 5(12): e15171. De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, 4. Min KJ, Yamamoto R, Buch S, Pankratz MJ, Tatar M. Nino-Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer 2008. Drosophila lifespan control by dietary restriction inde- M, Latz E, Freeman TC, Ulas T, Schultze JL. Transcriptome-based pendent of insulin-like signaling. Aging Cell 7: 199-206. network analysis reveals a spectrum model of human macrophage 5. Buch S, Melcher C, Bauer M, Katzenberger J, Pankratz activation. Immunity. 2014 Feb 20;40 (2):274-88. doi: 10.1016/j. MJ. 2008. Opposing effects of dietary protein and sugar reg- immuni.2014.01.006. Epub 2014 Feb 13. ulate a transcriptional target of Drosophila insulin-like peptide 2. Sommer D, Peters A, Wirtz T, Mai M, Ackermann J, Thabet Y, signaling. Cell Metab 7: 321-32. Schmidt J, Weighardt H, Wunderlich FT, Degen J, Schultze JL, Rheinische Friedrich-Wilhelms-Universität Bonn Rheinische Friedrich-Wilhelms-Universität Bonn Beyer M. Efficient genome engineering by targeted homologous 6. Melcher C, Bader R, Pankratz MJ. 2007. Amino acids, Life and Medical Sciences Institute (LIMES), Life and Medical Sciences Institute (LIMES), recombination in mouse embryos using transcription activator-like taste circuits, and feeding behavior in Drosophila: towards effector nucleases. Nat Commun. 2014 Jan 13; 5:3045. doi: Department of Molecular Brain Physiology and understanding the psychology of feeding in flies and man. J Genomics & Immunoregulation, Director ­Behavior, Director 10.1038/ncomms4045. Endocrinol 192: 467-72. E-Mail: [email protected] 3. De Nardo D, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer E-Mail: [email protected] 7. Bader R, Colomb J, Pankratz B, Schrock A, Stocker RF, M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber J, Pankratz MJ. 2007. Genetic dissection of neural circuit anat- Research Expertise Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald Research Expertise omy underlying feeding behavior in Drosophila: distinct classes Prof. Schultze’s current central expertise is at the interphase of ML, Hernandez NJ, Williams BR, Knolle P, Kneilling M, Röcken Prof. Pankratz is an expert on the genetics of nutrient of hugin-expressing neurons. J Comp Neurol 502: 848-56. immunoregulation and genomics, with a focus on transcription- M, Lütjohann D, Wright SD, Schultze JL, Latz E. High-density ­control, feeding behavior, gustation and neuroendocrine 8. Melcher C, Bader R, Walther S, Simakov O, Pankratz MJ. al and epigenetic control of cell activation and immunoregula- lipoprotein mediates anti-inflammatory reprogramming of macro- circuits in drosophila. 2006. Neuromedin U and its putative Drosophila homolog tion, particularly in macrophages and regulatory T cells. phages via the transcriptional regulator ATF3. Nat Immunol. 2014 hugin. PLoS Biol 4: e68. Feb;15(2):152-60. doi: 10.1038/ni.2784. Epub 2013 Dec 8. 9. Bauer M, Katzenberger JD, Hamm AC, Bonaus M, Zinke I, Education / Training 4. Beyer M, Thabet Y, Mueller R-U, Sadlon T, Classen S, Lahl K, Education / Training Jaekel J, Pankratz MJ. 2006. Purine and folate metabolism as University of Freiburg, Medicine Fellow, 1992 - 1993 Basu S, Zhou X, Bailey-Bucktrout SL, Krebs W, Schoenfeld EA, University of California, Los Angeles USA, Biochemistry a potential target of sex-specific nutrient allocation in Drosoph- University of Freiburg, Medicine, M.D., 1991 Boettcher J, Golovina T, Mayer CT, Hofmann A, Sommer D, De- PhD, 1986 bey-Pascher S, Endl E, Limmer A, Hippen KL, Blazar BR, Balderas ila and its implication for lifespan-reproduction tradeoff. Physiol University of Freiburg, Medicine, State examination, 1991 Johns Hopkins University, USA, Biology BA, 1980 Genomics 25: 393-404. R, Quast T, Waha A, Mayer G, Famulok M, Knolle PA, Wichen- hauser C, Kolanus W, Schermer B, Bluestone JA, Barry SC, 10. Melcher C, Pankratz MJ. 2005. Candidate gustatory Appointments / Positions Held Appointments / Positions Held Sparwasser T, Riley JL, Schultze JL. 2011. Repression of genome interneurons modulating feeding behavior in the Drosophila 2007 - present organizer SATB1 in regulatory T cells is required for suppressive 2008 - present brain. PLoS Biol 3: e305. W3 Professorship, Genomics & Immunoregulation, University function and inhibition of effector differentiation. Nat Immunol. 12: Full Professorship, Molecular Brain Physiology, University of of Bonn 898-907. Bonn * Corresponding author 2002 - 2007 5. Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Car- 2001 - 2007 C3 Professorship, Tumor Immunology, University of Cologne rera P, Inhester T, Schultze JL, Hoch M. 2010. FOXO-dependent Senior Group Leader, Genetics, Karlsruhe, Institute of 1997 - 2002 regulation of innate immune homeostasis. Nature 463: 369-73. Technology Instructor in Medicine, Adult Oncology, Daner-Farber Cancer 6. Beyer M, Karbach J, Mallmann MR, Zander T, Eggle D, 2001 Institute, MA, USA Classen S, Debey-Pascher S, Famulok M, Jager E, Schultze JL. Habilitation, Genetics, Karlsruhe University 1996 - 1997 2009. Cancer vaccine enhanced, non-tumor-reactive CD8(+) T cells exhibit a distinct molecular program associated with „division 1997 - 2001 Instructor in Medicine, Hematologic Malignancies, arrest anergy“. Cancer Res 69: 4346-54. Daner-Farber Cancer Institute, MA, USA Group Leader, Institute of Genetics, Karlsruhe, Institute of 7. Chemnitz JM, Eggle D, Driesen J, Classen S, Riley JL, 1995 - 1996 Technology Debey-Pascher S, Beyer M, Popov A, Zander T, Schultze JL. 1993 - 1997 Research Associate, Hematology, Daner-Farber Cancer RNA fingerprints provide direct evidence for the inhibitory role of Staff Scientist, Institute of Biophysical Chemistry, Max ­Institute, MA, USA TGFbeta and PD-1 on CD4+ T cells in Hodgkin lymphoma. Blood. Planck Institute 1993 - 1995 2007 Nov 1;110(9):3226-33. Epub 2007 Jul 20. 1988 - 1992 Research Fellow, Hematology, Daner-Farber Cancer Institute, 8. Popov A, Abdullah Z, Wickenhauser C, Saric T, Driesen J, Postdoctoral Fellow, Institute for Genetics and ­Microbiology, MA, USA Hanisch FG, Domann E, Raven EL, Dehus O, Hermann C, Eggle D, Debey S, Chakraborty T, Krönke M, Utermöhlen O, Schultze University of Munich Honors / Awards JL. Indoleamine 2,3-dioxygenase-expressing dendritic cells form 1987 - 1988 2012 - present Vice Dean for Research, Faculty for suppurative granulomas following Listeria monocytogenes infec- Postdoctoral Fellow, Institute for Developmental Biology ­Mathematics and Natural Sciences, University of Bonn tion. J Clin Invest. 2006 Dec;116(12):3160-70. Epub 2006 Nov 16. Max Planck Institute 2010 Patent: A method for lung cancer early detection and 9. Beyer M, Kochanek M, Giese T, Endl E, Weihrauch MR, Knolle prognosis. Zander T, Schultze JL, Wolf J, Staratschek-Jox A, PA, Classen S, Schultze JL. 2006. In vivo peripheral expansion of Honors / Awards Debey-Pascher S, Eggle D, Boffetta P, Linseisen J. naive CD4+CD25high FoxP3+ regulatory T cells in patients with 2003 - 2005 2009 Patent: Anticancer Agent. Hoch M, Schultze JL, Loer B. multiple myeloma. Blood 107: 3940-9. 2009 Patent: Novel Marker Genes for regulatory T cells from Member of the Scientific Advisory Board “Network 10. Trojan A, Schultze JL, Witzens M, Vonderheide RH, Ladetto human blood. Schultze JL, Beyer MD, Warner N, Hingorani R. M, Donovan JW, Gribben JG. 2000. Immunoglobulin frame- of ­Molecular Nutrition Research“, State of Baden-­ 2002 Sofja-Kovalevskaja Award of the Alexander von work-derived peptides function as cytotoxic T-cell epitopes com- Wurttemberg, Germany ­Humboldt-Foundation monly expressed in B-cell malignancies. Nat Med 6: 667-72. 2000 - 2001 2000 Senior Investigator Award of the Multiple Myeloma Consultant for Aventis

164 165 Honors / Awards Honors / Awards 2009 2000 Prof. Thomas Tüting, MD Steigleder prize of the AG Dermatological Histology Prof. Andreas Zimmer, PhD U.S. Department of Health and Human Services Special Department of Dermatology and Allergy 2006 Institute of Molecular Psychiatry Act or Service Award Translational Research prize of the AG Dermatological 1990 - 1992 Research DFG-Fellow 2000 1987 - 1989 Research Award of the Erich Hoffmann Society, Bonn Max-Planck-Fellow 1989 10 Most Relevant Publications for Prof. Thomas Tüting PhD thesis awarded ‘summa cum laude’ 1. Bald T, Landsberg J, Lopez-Ramos D, Renn M, Glodde N, Jansen P, Gaffal E, Steitz J, Tolba R, Kalinke U, Limmer A, 10 Most Relevant Publications for Prof. Andreas Zim- Jönsson G, Hölzel M, Tüting T. Immune-cell poor melanomas mer benefit from PD-1 blockade after targeted type I IFN activation. 1. Albayram O, Alferink J, Pitsch J, Piyanova A, Neitzert K, Cancer Discovery. In press, 2014. Poppensieker K, Mauer D, Michel K, Legler A, Becker A, 2. Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Monory K, Lutz B, Zimmer A, Bilkei-Gorzo A. 2011. Role of Lopez-Ramos D, Kohlmeyer J , Riesenberg,S. van den CB1 cannabinoid receptors on GABAergic neurons in brain Boorn-Konijnenberg D, Hömig-Hölzel C, Reuten R, Schadow aging. Proc Natl Acad Sci U S A, 108(27):11256-61. B, Weighardt I, Wenzel D, Helfrich I, Schadendorf D, Bloch 2. Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, W, Bianchi ME, Koch M, Fleischmann BK, Förster I, Kasten- Altmann KH, Karsak M, Zimmer A. 2008. Beta-caryophyllene müller W, Kolanus W, Hölzel M, Gaffal E, Tüting T. Ultraviolet is a dietary cannabinoid. Proc Natl Acad Sci U S A 105: 9099- Rheinische Friedrich-Wilhelms-Universität Bonn radiation-induced inflammation promotes angiotropism and Rheinische Friedrich-Wilhelms-Universität Bonn 104. Department of Dermatology and Allergy metastasis in melanoma. Nature 507:109-13, 2014. Institute of Molecular Psychiatry, Director 3. Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt E-Mail: [email protected] 3. Hölzel M, Bovier A, Tüting T. Plasticity of tumour and im- E-Mail: [email protected] J, Petrosino S, Starowicz K, Steuder R, Schlicker E, Cravatt mune cells: a source of heterogeneity and a cause for therapy B, Mechoulam R, Buettner R, Werner S, Di Marzo V, Tuting T*, Research Expertise resistance? Nat Rev Cancer. 13:365-76, 2013. Research Expertise Zimmer A*. 2007. Attenuation of allergic contact der- 4. Gaffal E, Cron M, Glodde N, Bald T, Kuner R, Zimmer A, Prof. Zimmer and his groups are interested in the ­molecular matitis through the endocannabinoid system. Science 316: Role of UV irradiation and the immune system in the 1494-7. Lutz B, Tüting T. Cannabinoid 1 receptors in keratinocytes mechanisms of neuropsychiatric disorders with a focus on pathogenesis of melanoma; mechanisms of melanoma 4. Bilkei-Gorzo A, Racz I, Valverde O, Otto M, Michel K, Sas- modulate proinflammatory chemokine secretion and attenuate addiction, pain and affective disorders, ­molecular biology of metastasis and therapy resistance; preclinical and clinical tre M, Zimmer A. 2005. Early age-related cognitive impairment contact allergic inflammation. J. Immunol. 190:4929-36, 2013. modulatory neurotransmitters, and the molecular biology of evaluation of approaches combining immunotherapies and 5. Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, in mice lacking cannabinoid CB1 receptors. Proc Natl Acad aging. other treatment modalities for melanoma; development of Tüting T, Hartmann G, Barchet W. Oxidative damage of DNA Sci U S A 102: 15670-5. novel genetic mouse models to study inflammation-­induced confers resistance to cytosolic nuclease TREX1 degradation 5. Nadeau JH, Balling R, Barsh G, Beier D, Brown SD, Bucan phenotypic plasticity and reciprocal interactions between and potentiates STING-dependent immune sensing. Immunity. Education / Training M, Camper S, Carlson G, Copeland N, Eppig J, Fletcher C, melanoma, immune and endothelial cells in the perivascular 39:482-95, 2013. Max Planck Institute for Biophysical Chemistry, Frankel WN, Ganten D, Goldowitz D, Goodnow C, Guenet JL, niche. 6. Landsberg J, Kohlmeyer J, Renn M, Bald T, Rogava M, Microbiology, PhD, 1989 Hicks G, Hrabe de Angelis M, Jackson I, Jacob HJ, Jenkins N, Cron M, Fatho M, Lennerz V, Wölfel T, Hölzel H, Tüting T. Justus-Liebig Universität Giessen, Biology, Johnson D, Justice M, Kay S, Kingsley D, Lehrach H, Magnu- Education / Training Melanomas resist T-cell therapy through inflammation-induced Diploma, 1986 son T, Meisler M, Poustka A, Rinchik EM, Rossant J, Russell reversible dedifferentiation. Nature. 490:412-416, 2012. LB, Schimenti J, Shiroishi T, Skarnes WC, Soriano P, Stanford University of Frankfurt, Germany, M.D., Thesis, 2000 7. Kohlmeyer J, Cron M, Landsberg J, Bald T, Renn M, Mikus Appointments / Positions Held W, Takahashi JS, Wurst W, Zimmer A. 2001. Sequence inter- University of Mainz, Germany, Dermatology and Allergic S, Bondong S, Wikasari D, Gaffal E, Hartmann G, Tüting T. 2006 - present pretation. Functional annotation of mouse genome sequences. Diseases, Board Certification, 1998 Complete regression of advanced primary and metastatic Professor of Molecular Psychiatry (W3), Director, Institute Science 291: 1251-5. University of Frankfurt School of Medicine, Medicine, M.D., mouse melanomas following combination chemoimmunother- for Molecular Psychiatry, University of Bonn 6. Zimmer A, Zimmer AM, Hohmann AG, Herkenham 1987 apy. Cancer Res 69:6265-74, 2009. 2005 - 2006 M, Bonner TI. 1999. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. 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Section Head, National Institute of Mental Health, USA *These authors contributed equally ­Department of Dermatology, Military Hospital Koblenz and Cancer Res 66: 5427-5435, 2006. 1989 - 1991 University of Mainz, Germany Postdoctoral researcher, DFG-Fellow, National Institute of * These authors contributed equally 1988 - 1991 Mental Health, USA Drafted as Airforce Medical Officer, Fighter- Bomber Wing 33, Cochem, Germany

166 167 First Retreat of the ImmunoSensation Impressions Cluster of Excellence in St. Goar

169 Organigram

International Scienti c assigns Advisory Board Rectorate reports

supervises

Speaker: G. Hartmann Cluster Coordination Oce: Cluster Manager: C. Hömig-Hölzel Vice Speaker: Coordination Cluster Graduate Program IITB: A. Draehn, E. Bartok W. Kolanus Central Administration and Gender Support: N. Dahms Financial Administrator: I. Bartz Public Relations: D. Sigl interact elect Faculties IT and Data Management: A. Kubarenko

Executive Board (8 members, + 8 deputy members) Subcommittees 4 Medical Faculty Recruitment * Gender Equality 2 LIMES Committee * Promotion of Young Researchers 1 DZNE * Academic and Industry Relations 1 caesar

elect

Research Program 2 Leaders per research area

A BCDE Platforms Integration of Consequences of Metabolic sensing & immune sensory immune sensing Immune signaling Local context 2 Representatives nervous-immune system input for sterile receptors sensing per platform system interactions on the cellular and inammation subcellular level in vivo

171 Participating Participating Institutions & CCO Institutions

Medical Faculty LIMES - Life & Medical Sciences University of Bonn University of Bonn Sigmund-Freud-Straße 25 Carl-Troll-Straße 31 D-53127 Bonn D-53115 Bonn www.ukb.uni-bonn.de www.limes-institut-bonn.de

DZNE - German Centre for caesar - center of advanced european Neurodegenerative Diseases studies and research Ludwig-Erhard-Allee 2 Ludwig-Erhard-Allee 2 D-53175 Bonn D-53175 Bonn www.dzne.de www.caesar.de

Cluster Coordination Office University Hospital Bonn Building 311 / 1G / 705 Sigmund-Freud-Straße 25 D-53127 Bonn Phone: +49 (0)228 287 13670 Fax: +49 (0)228 287 13686 Email: [email protected] www.immunosensation.de

173 Cluster Coordination Office (CCO) Cluster Coordination 2014

Dr. Cornelia Hömig-Hölzel Nicole Dahms Office (CCO) Cluster Manager Central Administration & Gender Support Phone +49 228 287 12100 Phone +49 228 287 13670 [email protected] [email protected]

ImmunoSensation Cluster of Excellence University Bonn University Hospital Bonn

Sigmund-Freud-Str. 25 D-53127 Bonn

www.immunosensation.de

Dr. Astrid Draffehn Dr. Eva Bartok Coordination of the Cluster Coordination of the Cluster Graduate Program IITB Graduate Program IITB Phone +49 228 73 62738 Phone +49 228 287 51150 [email protected] [email protected]

Diana Sigl Dr. Andriy Kubarenko Ida Bartz Public Relations IT and Data Management Financial Administrator Phone +49 228 287 13668 Phone +49 228 287 11138 Phone +49 228 287 14733 [email protected] [email protected] [email protected]

175 Imprint Imprint

Editor ImmunoSensation Cluster of Excellence Sigmund-Freud-Str. 25 53127 Bonn

Edited by Dr. Eva Bartok Nicole Dahms Dr. Astrid Draffehn Prof. Gunther Hartmann Dr. Cornelia Hömig-Hölzel Diana Sigl

Text Layout Diana Sigl

Cover The cover image shows the ­formation of the cyclic second messenger c[G(2’,5’)pA(3’,5’)p] that binds in the cGAS ­catalytic pocket. ­Created by Dr. ­Andriy ­Kubarenko and Gao. P from the ­Memorial Sloan-­Kettering Cancer Center, New York. (See: Gao P. et. al., 2013a.; ­Ablasser A. et al.,2013)

Graphic Design Andreas Müller-Gaida MOWMAN DESIGNBUERO Buchholzstr. 44 51061 Cologne Germany

Photography pp. 4, 59, 61, 64, 84, 89, 105-109, 141- 167 Johann F. Saba/UKB p. 100 caesar, p. 11 DFG

Print Unternehmenskommunikation Universitätsklinikum Bonn

Druckerei Eberwein Auf dem Kummgraben 10 53343 Wachtberg-Villip

177 www.immunosensation.de