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Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation

Jérôme C. Martin, Kerstin Wolk, Gaëlle Bériou, Ahmed Abidi, Ellen Witte-Händel, Cédric Louvet, Georgios Kokolakis, Lucile Drujont, Laure Dumoutier,
This information is current as of September 25, 2021.

Jean-Christophe Renauld, Robert Sabat and Régis Josien J Immunol 2017; 198:3671-3678; Prepublished online 29 March 2017; doi: 10.4049/jimmunol.1700021

http://www.jimmunol.org/content/198/9/3671

References This article cites 47 articles, 12 of which you can access for free at:

http://www.jimmunol.org/content/198/9/3671.full#ref-list-1

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The Journal of Immunology

Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation

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  • Kerstin Wolk,{,‖,#,1 Gaelle Beriou,*{ Ahmed Abidi,* **
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Ellen Witte-Handel, Cedric Louvet,* Georgios Kokolakis, Lucile Drujont,*

  • ¨
  • Jerome C. Martin,*{,‖

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Laure Dumoutier,††,‡‡ Jean-Christophe Renauld,††,‡‡ Robert Sabat,{,‖,xx,2 and

,†,‡,x,2

  • ´
  • Regis Josien*

Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency (Il22ra22/2) displayed exacerbated disease that associated with enhanced expression of IL-22–inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti–IL- 22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22–inducible molecules (IL-20, IL-24, IL-36g, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis. The Journal of Immunology, 2017, 198: 3671–3678.

soriasis is a chronic inflammatory skin disease that affects ∼2% of the Caucasian population (1). Typical macrocruitment of further immune cells into the skin to create a selfsustained inflammatory milieu. Moreover, the high keratinocyte production of antimicrobial peptides prevents infections of the highly disturbed psoriatic epidermis. Among a range of immune mediators present in the psoriatic skin, an essential role for IL-23 and its downstream cytokine IL-17A in the maintenance of psoriatic lesions has been recently confirmed by the dramatic clinical success of their therapeutic blockade in these patients (4–7). Another major IL-23 downstream cytokine is the IL-10 family member IL-22. IL-22 is also present in large quantities in psoriatic lesions (8). Main producers of IL-22 include different CD4+ T cell

Pscopic skin alterations present as sharply demarcated, red,

and slightly raised lesions with silver-whitish scales. It is generally acknowledged that these skin changes result from chronic dysregulated activation of the cutaneous immune system that—by secreted cytokines—alters the biology of local tissue cells (2, 3). Epidermal keratinocytes respond by hyperproliferation and impairment of their terminal differentiation, leading to epidermal thickening, hypogranularity, and hyperkeratosis. At the same time, these cells secrete high amounts of chemokines enabling the re-

  • ´
  • Europeen des Sciences de la Transplantation et de l’Immunologie (IHU-Cesti) Proj-

ect. The IHU-Cesti Project is also supported by Nantes Metropole and the Pays de la Loire region. J.C.M. was supported by a grant from Centre Hospitalier Universitaire (CHU) Nantes (Appel d’Offre Interne 2013 RC14_0042); J.C.M. also received sup-
*Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Universite de Nantes, 44093 Nantes Cedex 1, France; †Institut de Transplantation
´
Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex
´
´

‡

  • ´
  • ´
  • ´
  • 1, France; Faculte de Medecine, Universite de Nantes, 44093 Nantes Cedex 1,

France; xLaboratoire d’Immunologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France; {Psoriasis Research and Treatment Center,

  • ´
  • ´

port from CHU Nantes through Annee Supplementaire d’Internat. G.B. was sup-

  • ported by the Pays de la Loire Region through the IMmunoBIOtherapies et
  • ´

  • ´
  • Dermatology/Medical Immunology, University Hospital Charite, D-10117 Berlin,
  • Cellules Dendritiques Network. A.A. was supported by a French-Tunisian UTIQUE

grant from the 2015 Hubert Curien program. K.W. and R.S. were supported by Grant 01ZX1312A from the German Federal Ministry of Education and Research.
Germany; ‖Interdisciplinary Group of Molecular Immunopathology, University

  • Hospital Charite, D-10117 Berlin, Germany; #Berlin-Brandenburg Center for Re-
  • ´

  • generative Therapies, University Hospital Charite, 13353 Berlin, Germany;
  • ´

**Faculte des Sciences Mathematiques, Physiques et Naturelles, Universite de

  • ´ ˆ
  • Address correspondence and reprint requests to Dr. Jerome C. Martin at the current

address: Department of Oncological Science, Icahn School of Medicine at Mount

  • ´
  • ´
  • ´

Tunis El Manar, 2092 Tunis, Tunisia ††Ludwig Institute for Cancer Research,

  • ´
  • Sinai, 1470 Madison Avenue, New York, NY 10029, Prof. Regis Josien, INSERM

‡‡

B-1200 Brussels, Belgium; Institut de Duve, Universite Catholique de Louvain,
´

  • ˆ
  • ´
  • UMR1064-ITUN, CHU Nantes Hotel Dieu, Universite de Nantes, 30 Boulevard Jean

Monnet, 44093 Nantes Cedex 1, France, or Dr. Robert Sabat, Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University
B-1200 Brussels, Belgium; and xxResearch Center Immunosciences, University

  • ´
  • Hospital Charite, D-10117 Berlin, Germany

1J.C.M. and K.W. contributed equally to this work and are cofirst authors. 2R.S. and R.J. contributed equally to this work and are colast authors.
Hospital Charite, Chariteplatz 1, D-10117 Berlin, Germany. E-mail addresses: [email protected] (J.C.M.), [email protected] (R.J.), or robert. [email protected] (R.S.)

  • ´
  • ´

ORCIDs: 0000-0002-7689-4130 (K.W.); 0000-0002-8042-7885 (G.K.); 0000-0003- 1736-2131 (J.-C.R.); 0000-0001-7900-7413 (R.J.).

Abbreviations used in this article: IL-22BP, IL-22 binding protein; IMID, immunemediated inflammatory disease; PASI, psoriasis area and severity index; qRT-PCR,

  • quantitative RT-PCR.
  • Received for publication January 5, 2017. Accepted for publication March 1, 2017.

This work was supported by the National Research Agency via Investment into the Future Program Grant ANR-10-IBHU-005 for the Institut-Hospitalo Universitaire–Centre
Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700021

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  • IL-22BP LIMITS IL-22–DEPENDENT INFLAMMATION IN PSORIASIS

23 reagent (rodent samples) (both from Applied Biosystems) and the StepOne Plus device (Applied Biosystems). Primers and double-labeled fluorescent probes were either self-designed (human IL-20, IL-22, IL-24, IL-22BP, and BD2) (26) or purchased from Applied Biosystems (all others). Expressions were normalized to HPRT using the 2-DD cycle threshold method, and results were expressed in arbitrary units.

populations and group 3 innate lymphoid cells (9). Because the expression of the membrane IL-22R is restricted to epithelial/ epithelioid cells (8), IL-22 assumes major cross-talk functions between immune and epithelial cells, especially at body barriers (10, 11). By inducing antimicrobial peptides and proinflammatory chemokines, as well as by inhibiting the terminal differentiation of keratinocytes, IL-22 has been shown to largely contribute to inflammation and epithelial remodeling of the psoriatic skin (12–16). Interestingly, the IL-22 activity is regulated by IL-22 binding protein (IL-22BP). IL-22BP is a soluble single chain receptor encoded by the gene IL22RA2 that specifically prevents the binding of IL-22 to IL-22R (17–20). Recently, we and others showed that conventional dendritic cell–derived IL-22BP exerts important inhibitory functions that impair the IL-22–mediated protection during acute colitis in rodents, although preventing potentially dangerous long-lasting proliferative effects on intestinal epithelial cells (21–23). Whether IL-22BP is expressed and plays a role in psoriatic skin inflammation is, however, unknown so far. Our study answers these questions in a translational approach using skin and blood samples from healthy control donors and psoriasis patients, in vitro experiments with human keratinocytes and reconstituted epidermis, and genetic deletion and pharmacological blockade approaches in rodents.

ELISA

Detection of blood serum levels of IL-22 and IL-22BP was performed using ELISA kits from Bio-Techne (Quantikine system) and Biozol (CloudClone), respectively.

Imiquimod-induced psoriasis-like skin inflammation

Psoriasis-like skin inflammation was induced in the right ear of Il22ra2+/+ and Il22ra22/2 rats, and in the back skin of C57BL/6J mice as previously described (27). Briefly, topical application of Aldara cream (3M Pharmaceuticals) was performed daily for 5 d. Skin thickness was measured daily with a Digimatic Caliper and the percentage of skin thickness increase relative to day 0 was calculated every day. Animals were sacrificed at day 5 for qRT-PCR and histopathological analyses on skin tissues. Skin sections were stained with H&E.

In vivo neutralization of IL-22BP

Anti–IL-22BP neutralizing Ab (28) or control isotype was injected i.p. at a dose of 10 mg/kg at days 21, 0, 2, and 4 in Aldara-treated mice.

Statistical analysis

Materials and Methods

Patients

Statistical analysis was performed with GraphPad Prism Software (GraphPad Software, San Diego, CA) or IBM SPSS Statistics 23.0 software (IBM, New York). Mean comparisons of unpaired samples were performed using the Mann–Whitney U test. The Wilcoxon matched-pairs signed-rank test (two-tailed) was used for paired samples. Correlations were calculated using the Spearman rank correlation test. The p values ,0.05 were considered statistically significant.
For analyses of skin expression, biopsies were obtained from adult healthy participants (22–63 y old [mean 6 SD: 44.0 6 10.9], 28.6% female), patients with plaque psoriasis (25–67 y old [mean 6 SD: 46.4 6 12.8], 22.7% female, 68.2% moderate to severe disease [psoriasis area and severity index (PASI) $10]), and patients with atopic dermatitis (22–40 y old [mean 6 SD: 30.0 6 7.7], 50.0% female, 100% moderate to severe disease). For analyses of blood mediators, blood samples were obtained from adult control participants (26–57 y old [mean 6 SD: 38.3 6 9.3], 72.0% female) and patients with plaque psoriasis (19–64 y old [mean 6 SD: 41.2 6 13.7], 61.1% female, 27.8% moderate to severe disease). The skin and blood samples were approved by the clinical institutional review board of

Results

Psoriatic skin shows relative IL-22BP deficiency

To assess whether IL-22BP could exert a regulatory role in psoriasis, we first analyzed IL22RA2 expression in the skin from psoriasis patients as well as from atopic dermatitis patients and healthy donors as comparison groups. Confirming our previous works (17, 20), constitutive expression of IL-22BP was found in healthy donors’ skin. IL-22BP was also detected in the nonaffected skin of psoriasis patients. However, although IL-22BP expression in atopic dermatitis appeared rather increased as compared with healthy donors, levels in the nonaffected skin of psoriasis patients were in fact lower (Fig. 1A). We next analyzed IL-22 and IL-22BP expression in paired biopsies from nonaffected, perilesional, and lesional skin of psoriasis patients. In line with previous studies including ours (8, 15, 29), IL-22 expression was almost absent in nonlesional skin but showed a strong upregulation in perilesional (∼1200-fold) and lesional (2500-fold) skins

(Fig. 1B). Importantly, in contrast to IL-22, the increase of IL-22BP expression was minimal in perilesional and lesional psoriatic skin (∼2-fold induction) (Fig. 1B). Thus, the very small IL-22/IL-22BP

ratio in nonlesional skin (0.01) was largely increased in perilesional and lesional psoriatic skin to ∼3 and 7, respectively.

´the Charite University Medicine, Berlin. Written consent was obtained from all participants. The study was conducted according to the principles of the Declaration of Helsinki.

Epidermis model

Underdeveloped EpiDerm-201 human epidermis models (MatTek) were cultured in inserts at the air–liquid interface as described previously (24) and stimulated or not (control) by supplementing the culture medium with either 20 ng/ml IL-22, 10 ng/ml IL-17A, a mixture of both, or 20 ng/ml IL-24 (all from R&D Systems, Wiesbaden-Nordenstadt, Germany). After 72 h, samples were taken for quantitative RT-PCR (qRT-PCR) analysis.

Animals

Il22ra22/2 and Il22ra2+/+ control littermate rats were generated on the Sprague-Dawley background using zinc-finger nucleases (Sigma-Aldrich, St. Louis, MO) at our local Rats Transgenesis Platform facility IBISA- CNRS as described previously (22). C57BL/6J mice were purchased from Centre d’Elevage Janvier (Le Genest-Saint-Isle, France). All animals were kept under specific pathogen-free conditions. All animal studies were conducted in accordance with the EU Directive 2010/ 63/EU for animal experiments, and the guidelines of the French Agriculture Ministry. These studies were approved by the Veterinary Departmental Services committee (E.44011).

Taken together, these data suggest that constitutive low levels of IL-22BP in nonlesional psoriatic skin and their limited upregulation in lesional skin could enable broadly unregulated IL-22 to be effective and therefore might contribute to the development and maintenance of epidermal alterations in these patients.

qRT-PCR analysis

Snap frozen skin samples or epidermis models were mechanically homogenized (25). Total cellular RNA was isolated using Invisorb RNA kit II (Invitek/Stratec Molecular) (human samples) or TRIzol reagent (Invitrogen) (rodent samples) according to the manufacturers’ instructions. Reverse transcription was performed using murine moloney leukemia virus reverse transcriptase (Invitrogen) following the manufacturer’s instructions. Quantitative PCR on reverse transcribed mRNA was performed using the Maxima Probe/ROX qPCR Master Mix (Thermo Fisher Scientific/ Fermentas) (human samples) or the TaqMan Fast Advanced Master Mix

IL-22BP deficiency exacerbates imiquimod-induced skin inflammation in the rat

In order to demonstrate that IL-22BP deficiency indeed strengthens IL-22–mediated pathogenicity in vivo during skin inflammation, we first took advantage of IL-22BP–deficient rats we generated recently (22) and characterized the impact of IL-22BP deficiency

  • The Journal of Immunology
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FIGURE 1. Psoriatic skin shows a relative deficiency in IL-22BP expression. (A) Skin from healthy control donors (n = 11) and nonlesional skin from psoriasis patients (n = 9) and atopic dermatitis patients (n = 4) was analyzed for IL-22BP (IL22RA2) expression by qRT-PCR. Expression was normalized to HPRT transcripts. Mean 6 SEM data are shown; data were analysed using Mann–Whitney U test. (B) Paired nonlesional, perilesional, and lesional skin from psoriasis patients (n = 6–7) was analyzed for IL-22 and IL-22BP expression as in (A). Mean 6 SEM data are shown. Data were analysed using Wilcoxon matched-pairs signed-rank test. *p , 0.05, **p , 0.01, ***p , 0.001. n.s., not significant.

on the severity of skin lesions in the model of skin inflammation induced by imiquimod (30). Following daily topical application, TLR7 activation by imiquimod and inflammasome activation by the vehicle lead to an acute skin inflammatory process that critically depends on IL-23 and downstream mediators IL-17 and IL-22 (30–32). As expected, imiquimod application on the right ear of Il22ra2+/+ rats led to skin erythema and thickening within 5 d (Fig. 2A, 2B). Histological analyses confirmed the induction of

FIGURE 2. IL-22BP deficiency exacerbates imiquimod-induced psoriasis-like skin disease. Psoriasis-like skin disease was induced in the right ear of Il22ra2+/+ and Il22ra22/2 rats (n = 12 each). (A) Representative pictures of skin lesions at days 0 and 5. (B) Percentage of skin thickness increase (mean 6 SEM). (C) Representative hematoxylin–eosin–saffron staining of ear skin at days 0 and 5. Original magnification 3100 (D) Kinetics of IL-22 and IL-22BP (Il22ra2) expression in imiquimod-treated skin were assessed by qRT-PCR (n = 3 for each time point). (E) IL-17A, IFN-g, TNF-a, and IL-22 expression were analyzed by qRT-PCR at day 5 of imiquimod application. Expression was normalized to HPRT transcripts. Each symbol (square or triangle) corresponds to one rat. (F) Lipocalin-2 (Lcn2) and b-defensin-2 (Defb4) expression were analyzed by qRT-PCR at day 5 of imiquimod application. Expression was normalized to HPRT transcripts. Each symbol (square or triangle) corresponds to one rat. *p , 0.05, **p , 0.01, ***p , 0.001, Mann–Whitney U test.

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  • IL-22BP LIMITS IL-22–DEPENDENT INFLAMMATION IN PSORIASIS

acanthosis, parakeratosis, Munro’s microabscesses, and dermal immune infiltration (Fig. 2C). Importantly, skin alterations were characterized by a strong induction of IL-22 and a moderate increase of IL-22BP, somehow mimicking the regulation of these two molecules in human psoriatic skin (Fig. 2D). Confirming our expectation that IL-22BP should negatively regulate IL-22 pathogenicity during skin inflammation, clinical and histological skin alterations were severely worsened in Il22ra22/2 versus Il22ra2+/+ littermate controls (Fig. 2A–C). In agreement with their more severe phenotype, enhanced expression of inflammatory cytokines, including IL-17A, TNF-a, and IFN-g, was detected in lesional skin of Il22ra22/2 rats (Fig. 2E). Moreover, concordant with exacerbated actions of IL-22 in the absence of IL-22BP, b-defensin-2 (BD2) and lipocalin-2 (LCN2), two antimicrobial peptides known to be induced by IL-22 in rodent epithelial cells (33, 34), showed significantly higher expression in the lesional skin of Il22ra22/2 versus Il22ra2+/+ littermate controls (Fig. 2F). Of note, there was no significant difference in the expression of these inflammatory cytokines and antimicrobial peptides in the skin of Il22ra22/2 rat versus Il22ra2+/+ littermate controls at steady state (data not shown).
Collectively, data obtained from rodent experiments thus argued in favor of a protective role of IL-22BP during skin inflammation through its ability to neutralize IL-22 pathogenic actions on keratinocytes.

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    Cao et al. BMC Medical Genomics 2017, 10(Suppl 4):70 DOI 10.1186/s12920-017-0304-z RESEARCH Open Access Differential responses of innate immunity triggered by different subtypes of influenza a viruses in human and avian hosts Yingying Cao1, Yaowei Huang1,KeXu1, Yuanhua Liu1, Xuan Li2,YeXu3*, Wu Zhong4* and Pei Hao1* From 16th International Conference on Bioinformatics (InCoB 2017) Shenzhen, China. 20-22 September 2017 Abstract Background: Innate immunity provides first line of defense against viral infections. The interactions between hosts and influenza A virus and the response of host innate immunity to viral infection are critical determinants for the pathogenicity or virulence of influenza A viruses. This study was designed to investigate global changes of gene expression and detailed responses of innate immune systems in human and avian hosts during the course of infection with various subtypes of influenza A viruses, using collected and self-generated transcriptome sequencing data from human bronchial epithelial (HBE), human tracheobronchial epithelial (HTBE), and A549 cells infected with influenza A virus subtypes, namely H1N1, H3N2, H5N1 HALo mutant, and H7N9, and from ileum and lung of chicken and quail infected with H5N1, or H5N2. Results: We examined the induction of various cytokines and chemokines in human hosts infected with different subtypes of influenza A viruses. Type I and III interferons were found to be differentially induced with each subtype. H3N2 caused abrupt and the strongest response of IFN-β and IFN-λ, followed by H1N1 (though much weaker), whereas H5N1 HALo mutant and H7N9 induced very minor change in expression of type I and III interferons.
  • Xo GENE PANEL

    Xo GENE PANEL

    xO GENE PANEL Targeted panel of 1714 genes | Tumor DNA Coverage: 500x | RNA reads: 50 million Onco-seq panel includes clinically relevant genes and a wide array of biologically relevant genes Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4
  • THESIS for DOCTORAL DEGREE (Ph.D.)

    THESIS for DOCTORAL DEGREE (Ph.D.)

    From DEPARTMENT OF CLINICAL NEUROSCIENCE Karolinska Institutet, Stockholm, Sweden GENETIC LANDSCAPE OF MULTIPLE SCLEROSIS SUSCEPTIBILITY BY LEVERAGING MULTI-OMICS DATA Tojo James Stockholm 2018 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Eprint AB 2018 © Tojo James, 2018 ISBN 978-91-7831-181-1 Genetic landscape of multiple sclerosis susceptibility by leveraging multi-omics data THESIS FOR DOCTORAL DEGREE (Ph.D.) By Tojo James Principal Supervisor: Opponent: Professor Ingrid Kockum Dr. Calliope Dendrou Karolinska Institutet University of Oxford Department of Clinical Neuroscience Nuffield Department of Medicine Division of Wellcome Trust Centre for Human Co-supervisor(s): Genetics Dr. David Gomez-Cabrero Karolinska Institutet Examination Board: Department of Medicine Associate Professor Carsten Daub Karolinska Institutet Associate Professor Maja Jagodic Department of Biosciences and Nutrition Karolinska Institutet Department of Clinical Neuroscience Professor Ann-Christine Syvänen Uppsala Universitet Professor Tomas Olsson Department of Medical Sciences, Molecular Karolinska Institutet Medicine Department of Clinical Neuroscience Dr. Sven Nelander Uppsala Universitet Department of Immunology, Genetics and Pathology To my family ABSTRACT The main objective of the research studies presented in this thesis is to study the genetic variants and the expression of genes that relate to Multiple Sclerosis (MS). MS is a polygenic disease with HLA-DRB1*15:01 allele
  • Supporting Information

    Supporting Information

    Supporting Information Voigt et al. 10.1073/pnas.1705165114 SI Materials and Methods the HTCR includes obtaining written informed consent from all Mice. BALB/c mice were purchased from Janvier. C57BL/6 mice patients with lung cancer and has been approved by the Ethics were purchased from Charles River. Mice were 5 wk old at the Committee of the Medical Faculty, LMU Munich (no. 025-12) and − − onset of experiments. Spleens from IL-1R / mice were provided by the Bavarian State Medical Association. All operations of from T. Stöger, Helmholtz Center Munich, Munich, and spleens Biobank are certified according to ISO 9001:2008 (57). Written − − from IL-23 / mice were a gift from K. Savvatis, Charité, Berlin. informed consent was obtained from all patients with breast cancer before collection of specimens, in line with the respective in- Cell Lines. The murine lung cancer cell line 1 (Line-1) was kindly stitutional policies and in accordance with to the Declaration of provided by Nejat K. Egilmez, University of Louisville, Louisville, Helsinki. Tumor specimens were obtained from patients un- KY (55), and cells were cultured in complete RPMI 1640 medium dergoing clinically indicated surgery. Histological analysis of (Lonza). If not stated otherwise, growth media used were supple- NSCLC or breast cancer was made by a pathologist as part of mented with 10% FBS, 100 μg/mL streptomycin, 1 IU/mL peni- standard of care. Ethical approval was obtained from the Ethics cillin, and 2 mM L-glutamine (Life Technologies). The 4T1murine Committee of the Medical Faculty, LMU Munich (reference breast cancer cell line was kindly provided by Maria Wartenberg, nos.
  • KRAS Mutations Are Negatively Correlated with Immunity in Colon Cancer

    KRAS Mutations Are Negatively Correlated with Immunity in Colon Cancer

    www.aging-us.com AGING 2021, Vol. 13, No. 1 Research Paper KRAS mutations are negatively correlated with immunity in colon cancer Xiaorui Fu1,2,*, Xinyi Wang1,2,*, Jinzhong Duanmu1, Taiyuan Li1, Qunguang Jiang1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China 2Queen Mary College, Medical Department, Nanchang University, Nanchang, Jiangxi, People's Republic of China *Equal contribution Correspondence to: Qunguang Jiang; email: [email protected] Keywords: KRAS mutations, immunity, colon cancer, tumor-infiltrating immune cells, inflammation Received: March 27, 2020 Accepted: October 8, 2020 Published: November 26, 2020 Copyright: © 2020 Fu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The heterogeneity of colon cancer tumors suggests that therapeutics targeting specific molecules may be effective in only a few patients. It is therefore necessary to explore gene mutations in colon cancer. In this study, we obtained colon cancer samples from The Cancer Genome Atlas, and the International Cancer Genome Consortium. We evaluated the landscape of somatic mutations in colon cancer and found that KRAS mutations, particularly rs121913529, were frequent and had prognostic value. Using ESTIMATE analysis, we observed that the KRAS-mutated group had higher tumor purity, lower immune score, and lower stromal score than the wild- type group. Through single-sample Gene Set Enrichment Analysis and Gene Set Enrichment Analysis, we found that KRAS mutations negatively correlated with enrichment levels of tumor infiltrating lymphocytes, inflammation, and cytolytic activities.
  • Human Colon Cancer Primer Library

    Human Colon Cancer Primer Library

    Human Colon Cancer Primer Library Catalog No: HCCR-1 Supplier: RealTimePrimers Lot No: XXXXX Supplied as: solid Stability: store at -20°C Description Contains 88 primer sets directed against cytokine and chemokine receptor genes and 8 housekeeping gene primer sets. Provided in a 96-well microplate (20 ul - 10 uM). Perform up to 100 PCR arrays (based on 20 ul assay volume per reaction). Just add cDNA template and SYBR green master mix. Gene List: • CCR1 chemokine (C-C motif) receptor 1 • IL11RA interleukin 11 receptor, alpha • CCR2 chemokine (C-C motif) receptor 2 • IL11RB interleukin 11 receptor, beta • CCR3 chemokine (C-C motif) receptor 3 • IL12RB1 interleukin 12 receptor, beta 1 • CCR4 chemokine (C-C motif) receptor 4 • IL12RB2 interleukin 12 receptor, beta 2 • CCR5 chemokine (C-C motif) receptor 5 • IL13RA1 interleukin 13 receptor, alpha 1 • CCR6 chemokine (C-C motif) receptor 6 • IL13RA2 interleukin 13 receptor, alpha 2 • CCR7 chemokine (C-C motif) receptor 7 • IL15RA interleukin 15 receptor, alpha • CCR8 chemokine (C-C motif) receptor 8 • IL15RB interleukin 15 receptor, beta • CCR9 chemokine (C-C motif) receptor 9 • IL17RA interleukin 17 receptor A • CCR10 chemokine (C-C motif) receptor 10 • IL17RB interleukin 17 receptor B • CX3CR1 chemokine (C-X3-C motif) receptor 1 • IL17RC interleukin 17 receptor C • CXCR1 chemokine (C-X-C motif) receptor 1 • IL17RD interleukin 17 receptor D • CXCR2 chemokine (C-X-C motif) receptor 2 • IL17RE interleukin 17 receptor E • CXCR3 chemokine (C-X-C motif) receptor 3 • IL18R1 interleukin 18 receptor
  • Human Inflammation Panel a Gene Set You Can Count On

    Human Inflammation Panel a Gene Set You Can Count On

    PRODUCT BULLETIN nCounter® Human Inflammation Panel A Gene Set You Can Count On The nCounter Human Inflammation Panel is a comprehensive assay of 249 human genes known to be differentially expressed in inflammation. The gene list represents a broad range of inflammation-related pathways, including: • Chemokine • Integrin signaling • Cytokine • Oxidative stress response • Interleukin • B cell activation • Toll receptor • T cell activiation This gene list was compiled by querying several public databases for inflammation-related genes. Each gene was verified to be differentially expressed under conditions leading to inflammation. Verification was performed using MSigDB, a repository of gene expression data developed by researchers at the Massachusetts Institute of Technology and the Broad Institute1. Other public databases were used to obtain functional gene expression information for each gene. The final nCounter Human Inflammation Panel consists of 249 inflammation-related genes and six internal reference genes. For the gene list and additional information about this panel, visit the nCounter Pre-built Panels product page at nanostring.com. Product Highlights nCounter Analysis System Overview • Simple No need for cross-referencing databases The nCounter Analysis System from NanoString offers a cost- effective way to easily profile hundreds of gene transcripts • Highly Curated simultaneously with high sensitivity and precision. The digital Our expert bioinformaticists use a very detection of target molecules and high levels of multiplexing rigorous process in selecting the most eliminate the compromise between data quality and data meaningful set of genes quantity, bringing better sensitivity, reproducibility, and linearity to your results. It is ideal for studying defined gene sets across • Efficient a large sample set, e.g., microarray validation, pathway analysis, Multiplexed assay profiles 249 human biomarker validation, and splice variation analysis.
  • Annotated Gene List HTG Edgeseq Precision Immuno-Oncology Panel

    Annotated Gene List HTG Edgeseq Precision Immuno-Oncology Panel

    Annotated Gene List HTG EdgeSeq Precision Immuno-Oncology Panel For Research Use Only. Not for use in diagnostic procedures. Apoptosis APAF1 BCL2L1 CARD11 CASP4 CD5L FADD KSR2 OPTN SAMD12 TCF19 BAX BCL2L11 CASP1 CASP5 CORO1A FAS LRG1 PLA2G6 SAMD9 XAF1 BCL10 BCL6 CASP10 CASP8 DAPK2 FASLG MECOM PYCARD SPOP BCL2 BID CASP3 CAV1 DAPL1 GLIPR1 MELK RIPK2 TBK1 Cancer Antigens ANKRD30A BAGE2_BAGE3 CEACAM6 CTAG1A_1B LIPE MAGEA3_A6 MAGEC2 PAGE3 SPANXACD SPANXN4 XAGE1B_1E ARMCX6 BAGE4_BAGE5 CEACAM8 CTAG2 MAGEA1 MAGEA4 MTFR2 PAGE4 SPANXB1 SPANXN5 XAGE2 BAGE CEACAM1 CT45_family GAGE_family MAGEA10 MAGEB2 PAGE1 PAGE5 SPANXN1 SYCP1 XAGE3 BAGE_family CEACAM5 CT47_family HPN MAGEA12 MAGEC1 PAGE2 PBK SPANXN3 TEX14 XAGE5 Cell Adhesion ADAM17 CDH15 CLEC5A DSG3 ICAM2 ITGA5 ITGB2 LAMC3 MBL2 PVR UPK2 ADD2 CDH5 CLEC6A DST ICAM3 ITGA6 ITGB3 LAMP1 MTDH RRAS2 UPK3A ADGRE5 CLDN3 CLEC7A EPCAM ICAM4 ITGAE ITGB4 LGALS1 NECTIN2 SELE VCAM1 ALCAM CLEC12A CLEC9A FBLN1 ITGA1 ITGAL ITGB7 LGALS3 OCLN SELL ZYX CD63 CLEC2B DIAPH3 FXYD5 ITGA2 ITGAM ITLN2 LYVE1 OLR1 SELPLG CD99 CLEC4A DLGAP5 IBSP ITGA3 ITGAX JAML M6PR PECAM1 THY1 CDH1 CLEC4C DSC3 ICAM1 ITGA4 ITGB1 L1CAM MADCAM1 PKP1 UNC5D Cell Cycle ANAPC1 CCND3 CDCA5 CENPH CNNM1 ESCO2 HORMAD2 KIF2C MELK ORC6 SKA3 TPX2 ASPM CCNE1 CDCA8 CENPI CNTLN ESPL1 IKZF1 KIF4A MND1 PATZ1 SP100 TRIP13 AURKA CCNE2 CDK1 CENPL CNTLN ETS1 IKZF2 KIF5C MYBL2 PIF1 SP110 TROAP AURKB CCNF CDK4 CENPU DBF4 ETS2 IKZF3 KIFC1 NCAPG PIMREG SPC24 TUBB BEX1 CDC20 CDK6 CENPW E2F2 EZH2 IKZF4 KNL1 NCAPG2 PKMYT1 SPC25 ZWILCH BEX2 CDC25A CDKN1A CEP250 E2F7 GADD45GIP1