DOCSLIB.ORG

Emerging and Unexpected Regulatory Roles for Complement in The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Emerging and Unexpected Regulatory Roles for Complement in The 10/29/2013 Disclosures - V. Michael Holers, MD Types of financial relationships and the companies with whom Emerging and Unexpected Regulatory Roles for I have relationships are as follows: Complement in the Rheumatic Diseases Licensed intellectual property rights/patents: Taligen/Alexion Pharmaceuticals, Inc. ACR Annual Meeting Royalties: Taligen/Alexion Pharmaceuticals, Inc. Basic Science Symposium October 30, 2013 Contracted research: Taligen/Alexion Pharmaceuticals, Inc. Consulting fees: Alexion Pharmaceuticals, Inc. V. Michael Holers, MD Scoville Professor and Head, Division of Rheumatology University of Colorado Denver School of Medicine Pivotal Role of Complement in Induction and Topics Maintenance of Experimental Inflammatory Injury Injury/Insult • Complement System Overview Recognition by complement • Predominant Role of the Alternative Pathway in Tissue Injury • Current Status of the Complement Inhibitor Field – Paroxysmal Nocturnal Hemoglobinuria Recruitment of Cells – Atypical Hemolytic Uremic Syndrome (aHUS) – Positive/Supportive Clinical Trials/Pilot Studies • Complement and Rheumatic Disease: Mechanisms/Insights Release of Mediators from Studies of Inflammatory Arthritis Models (enzymes, cytokines) – Effector Pathways – Modulation of Humoral Autoimmunity • New Concepts Tissue Damage – In Vivo Imaging of Complement Activation Holers MV. Immunological Reviews. 2008; 223: 300–316. 4 Complement Pathway – Central Roles of Complement Pathway “Activators”: Injury, Immunity, Infection C3 and C5 in Activation Steps C3 fragment (C3b/ C3a/C5a iC3b/C3d) receptors MAC • Inflammation (host defense) • B cell response • Inflammation • T cell response • Apoptotic cell/debris clearance • Hemolysis Classical Alternative Lectin • Tissue repair/regeneration • Immune complex clearance • Neisseria control • Immune complexes • “Tickover” • Repeating simple • Opsonization and RES clearance (natural IgM, IgG) sugars C3a C5a • C-reactive protein (CRP) • Amplification pathway • G0 carbohydrate (chromatin, Streptococcus) glycoforms on IgM Classical Classical,Lectin Classical, Lectin • SIGN-R1 • Endotoxin • Acetylated sugars C3 Convertases C5 Convertases Lectin • Apoptotic bodies • IgA I.C. • Cytokeratin-1 C3 C3b C5 C5b MAC • Beta-amyloid fibrils • Polysaccharides Alternative Alternative Alternative C3 Convertases C5 Convertases • Serum amyloid P (SAP) • C3 nephritic factor • Phosphatidylserine Amplific. • Mitochondrial products Holers MV. Immunological Reviews. 2008; 223: 300–316. 1 10/29/2013 Complement Pathway “Activators”: Injury, Immunity, Infection, Spontaneous/ The Tickover Mechanism Continuous Classical Alternative Lectin • Immune complexes • “Tickover” • Repeating simple C3 Spontaneous conversion (natural IgM, IgG) sugars (~1%/hour) • C-reactive protein (CRP) • Amplification pathway • G0 carbohydrate (chromatin, Streptococcus) glycoforms on IgM C3(H2O) Factor B • SIGN-R1 • Endotoxin • Acetylated sugars • Apoptotic bodies • IgA I.C. • Cytokeratin-1 Factor D • Beta-amyloid fibrils • Polysaccharides C3(H2O) Bb • Serum amyloid P (SAP) • C3 nephritic factor • Phosphatidylserine C3 C3b • Mitochondrial products Holers MV. Immunological Reviews. 2008; 223: 300–316. Amplification Loop Begins When Circulating Why Does Tickover Exist? C3 is Acted Upon by Convertases and Fixed as C3b to a Surface • Provides capability for immediate response to foreign pathogens • Does not require any other recognition molecules to work – Independent of antibody and other innate immune mechanisms • Helps to separate “self” from “non-self” – “Self” tissues express regulators that block C3b from engaging factor B and continuing to activate system – “Non-self” does not have same regulatory molecules and thus is susceptible to continued complement activation • Lack of appropriate control of complement initiation through tickover and subsequent amplification steps underlies fundamental pathogenesis of PNH and aHUS Janssen, Nature 444:213.-216, 2006 9 Amplification Loop Uses Alternative Pathway Engagement of the Amplification Loop; Components for Next C3 Convertase Exponential Activity Can Generate the Majority Formation of Effector Factors in Vivo C3 C3b (On)B C3bB Factor D Properdin C3bBbP F. Forneris, D. Ricklin, J. Wu, A. Tzekou, R.S. Wallace, J. Lambris and P. Gros, Science 330, 1816-1820 (2010) Holers MV. Immunological Reviews. 2008; 223: 300–316. 12 2 10/29/2013 Alternative Pathway/Amplification Loop – Evidence The Alternative Pathway of Complement is Required Supporting Role as Primary Pathogenic Process in for Many Experimental Models of Human Disease, Human Disease Regardless of Classical/Lectin Pathway Dependence • Genetically programmed deficiency states that primarily affect the Human Disease Model(s) Pathway Requirements Classical/ Alternative/ alternative pathway (either rare germ line mutations or Lectin Amplification acquired somatic cell mutations) 1. Rheumatoid Arthritis K/BxN serum transfer N Y - Paroxysmal Nocturnal Hemoglobinuria, Atypical Hemolytic Anti-CII Ab transfer N Y Uremic Syndrome 2. Antiphospholipid aPL Ab Transfer Y Y Syndrome • Linkage by Genome Wide Association Studies (GWAS) of 3. Lupus Nephritis MRL/lpr strain ? Y C4-/-/B6 lpr strain N ? polymorphisms in complement alternative pathway activation 4. Asthma Ova, ragweed N Y and regulatory protein encoding genes with human diseases immunization/inhalation 5. Ischemia-Reperfusion Intestinal/Skeletal Y Y (Human Genome Project trailblazing – in both GWAS and Injury Renal N Y dense sequencing projects) 6. Atypical Hemolytic- NA ? Y Uremic Syndrome - Age-Related Macular Degeneration 7. Type II Membrano- fH-/- strain N Y • Informative animal models - Thurman and Holers, J. Immunol. Proliferative GN 8. Macular Degeneration CNV N Y 2006; Holers Immunology Reviews 2008 9. Spontaneous Fetal Crry-/- strain N Y Loss Thurman and Holers, J. Immunol. 2006; Holers Immunology Reviews 2008 The Alternative Pathway of Complement is Required Effector Mechanisms for Many Experimental Models of Human Disease, Effects on Adaptive Immunity In Complement •Enhance humoral immunity Regardless of Classical/Lectin Pathway Dependence •Modulate natural Ab repertoire Activation •Regulate tolerance •Modify T cell immunity Human Disease Model(s) Pathway Requirements Classical Alternative/ Lectin Amplification Complement 1. Rheumatoid Arthritis K/BxN serum transfer N Y Activation Anti-CII Ab transfer N Y Opsonization by C3b 2. Antiphospholipid aPL Ab Transfer Y Y Direct Effects of C5a and/or Syndrome C3a generation Direct Lytic 3. Lupus Nephritis MRL/lpr strain ? Y Effects C4-/-/B6 lpr strain N ? C5aR/C5L2/C3aR MAC of MAC C3b 4. Asthma Ova, ragweed N Y immunization/inhalation 5. Ischemia-Reperfusion Intestinal/Skeletal Y Y Injury Renal N Y 6. Atypical Hemolytic- NA ? Y Uremic Syndrome 7. Type II Membrano- fH-/- strain N Y Proliferative GN 8. Macular Degeneration CNV N Y Cell Activating Effects 9. Spontaneous Fetal Crry-/- strain N Y •Pro-coagulant state Loss •Adhesion Molecules Thurman and Holers, J. Immunol. 2006; Holers Immunology Reviews 2008 •Pro-inflammatory mediators Complement Therapeutics: Topics Indications • Complement System Overview • Approved • Predominant Role of the Alternative Pathway in Tissue Injury – Hereditary Angioedema (C1-INH replacement) – Paroxysmal Nocturnal Hemoglobinuria (Anti-C5) • Current Status of the Complement Inhibitor Field – Atypical Hemolytic Uremic Syndrome (aHUS) (Anti-C5) – Paroxysmal Nocturnal Hemoglobinuria – Atypical Hemolytic Uremic Syndrome (aHUS) – Positive/Supportive Clinical Trials/Pilot Studies • Positive/Supportive Human Clinical Trials/Pilot Studies: • Complement and Rheumatic Disease: Mechanisms/Insights – Neuromyelitis Optica from Studies of Inflammatory Arthritis Models – Age-related macular degeneration (AMD) – Effector Pathways – Acute humoral renal transplant rejection – Modulation of Humoral Autoimmunity – Myasthenia gravis • New Concepts – C3 nephropathy – Catastrophic anti-phospholipid antibody syndrome (CAPS) – In Vivo Imaging of Complement Activation 3 10/29/2013 Overview:Conformational Interaction Change Inhibitors of C3 upon& Monoclonal Cleavage Antibodies to C3a/C3b ConformationalOverview: ChangeSoluble Complementof C3 upon Cleavage Regulators to C3a/C3b Targets: Numerous, at any level Targets: C3b, Convertases, MAC anti-C1q On Market: Eculizumab On Market: none High specificity & affinity Physiological approach Administration (non-oral) Act at the central level of activation Production costs (proteins/mAb) No oral bioavalability High production costs sCR1-sLex anti-C5 anti-FD anti-FB anti-C5 aptamer anti-C5 minibody anti-C5a spiegelmer TP-20 Eculizumab/Soliris N/A TA106, Bikaciomab ARC1905 MUBODINA NOX-D15 [Avant] [Alexion] [Genentech] [Alexion], [Novelmed] [Ophthotech] [Adienne] [NOXXON] APT070 CD59- sCR1 Mirococept Prodaptin CDX1135 [MRC] [Inflazyme] [Celldex] MCP-DAF CAB-2 FH-CR2 anti-C3 peptide sCRIg [Millenium] TT30 rFH anti-MASP anti-Properdin anti-C3b Compstatin anti-C5 proteins [Genentech] N/A N/A S77 POT-4 [Potentia/Alcon, Apellis] OmCI (Ticks) [Alexion] [Optherion] [Omeros] [Novelmed] [Genentech] Cp30/Cp40 [Anosos] SSL7 (Staph) Ricklin and Lambris, Nature Biotechnology. 25:1265-75, 2007 (updates /slide courtesy of Dan Ricklin) Ricklin and Lambris, Nature Biotechnology. 25:1265-75, 2007 (updates /slide courtesy of Dan Ricklin) Paroxysmal Nocturnal Hemoglobinuria (PNH): A Paroxysmal Nocturnal Hemoglobinuria (PNH): An Disease of Unregulated Alternative Pathway Orphan Disease of Unregulated Alternative Activation Pathway Activation • Rare
Load more

Recommended publications
  • Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia
    BASIC RESEARCH www.jasn.org Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia Yoshiyasu Ueda,1 Takashi Miwa,1 Damodar Gullipalli,1 Sayaka Sato,1 Daisuke Ito,1 Hangsoo Kim,1 Matthew Palmer,2 and Wen-Chao Song1 Departments of 1Systems Pharmacology and Translational Therapeutics and 2Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ABSTRACT Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of comple- ment-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain. Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FHR/R), that causes aHUS and systemic thrombophilia with high mortality. Results Pdeficiency completely rescued FHR/R mice from premature death and prevented thrombocyto- penia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FHR/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FHR/R mice after 4 weeks of anti-P mAb treatment. One half of the FHR/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FHR/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice.
    [Show full text]
  • Are Complement Deficiencies Really Rare?
    G Model MIMM-4432; No. of Pages 8 ARTICLE IN PRESS Molecular Immunology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Molecular Immunology j ournal homepage: www.elsevier.com/locate/molimm Review Are complement deficiencies really rare? Overview on prevalence, ଝ clinical importance and modern diagnostic approach a,∗ b Anete Sevciovic Grumach , Michael Kirschfink a Faculty of Medicine ABC, Santo Andre, SP, Brazil b Institute of Immunology, University of Heidelberg, Heidelberg, Germany a r a t b i c s t l e i n f o r a c t Article history: Complement deficiencies comprise between 1 and 10% of all primary immunodeficiencies (PIDs) accord- Received 29 May 2014 ing to national and supranational registries. They are still considered rare and even of less clinical Received in revised form 18 June 2014 importance. This not only reflects (as in all PIDs) a great lack of awareness among clinicians and gen- Accepted 23 June 2014 eral practitioners but is also due to the fact that only few centers worldwide provide a comprehensive Available online xxx laboratory complement analysis. To enable early identification, our aim is to present warning signs for complement deficiencies and recommendations for diagnostic approach. The genetic deficiency of any Keywords: early component of the classical pathway (C1q, C1r/s, C2, C4) is often associated with autoimmune dis- Complement deficiencies eases whereas individuals, deficient of properdin or of the terminal pathway components (C5 to C9), are Warning signs Prevalence highly susceptible to meningococcal disease. Deficiency of C1 Inhibitor (hereditary angioedema, HAE) Meningitis results in episodic angioedema, which in a considerable number of patients with identical symptoms Infections also occurs in factor XII mutations.
    [Show full text]
  • Widely Used Commercial Elisa Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin As a Potential Second Member of the Zonulin Family
    ORIGINAL RESEARCH published: 05 February 2018 doi: 10.3389/fendo.2018.00022 Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family Lucas Scheffler1, Alyce Crane1, Henrike Heyne1, Anke Tönjes2, Dorit Schleinitz1, Christian H. Ihling3, Michael Stumvoll2, Rachel Freire4, Maria Fiorentino4, Alessio Fasano4, Peter Kovacs1* and John T. Heiker5* 1 Leipzig University Medical Center, IFB Adiposity Diseases, Leipzig, Germany, 2 Divisions of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany, 3 Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle, Germany, 4 Mucosal Immunology And Biology Research Center, Massachusetts General Hospital––Harvard Medical School, Boston, MA, United States, 5 Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, University of Leipzig, Leipzig, Germany Background: There is increasing evidence for the role of impaired intestinal permeability Edited by: in obesity and associated metabolic diseases. Zonulin is an established serum marker for Dr Saumen Kumar Maitra, Visva-Bharati University, India intestinal permeability and identical to pre-haptoglobin2. Here, we aimed to investigate Reviewed by: the relationship between circulating zonulin and metabolic traits related to obesity. Yicong Li, Johns Hopkins Medicine, Methods: Serum zonulin was measured by using a widely used commercial ELISA kit in United States 376 subjects from the metabolically well-characterized cohort of Sorbs from Germany. In Asamanja Chattoraj, addition, haptoglobin genotype was determined in DNA samples from all study subjects. Institute of Bio-Resources and Sustainable Development, India Results: As zonulin concentrations did not correlate to the haptoglobin genotypes, *Correspondence: we investigated the specificity of the zonulin ELISA assay using antibody capture John T.
    [Show full text]
  • O) 2 Platelets Mediated by Properdin and C3(H Complement Activation on Stimulated Identification of a Novel Mode Of
    Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2 O) This information is current as of October 1, 2021. Gurpanna Saggu, Claudio Cortes, Heather N. Emch, Galia Ramirez, Randall G. Worth and Viviana P. Ferreira J Immunol 2013; 190:6457-6467; Prepublished online 15 May 2013; doi: 10.4049/jimmunol.1300610 Downloaded from http://www.jimmunol.org/content/190/12/6457 Supplementary http://www.jimmunol.org/content/suppl/2013/05/17/jimmunol.130061 Material 0.DC1 http://www.jimmunol.org/ References This article cites 72 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/190/12/6457.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2O) Gurpanna Saggu,*,1 Claudio Cortes,*,†,1 Heather N.
    [Show full text]
  • Investigating an Increase in Florida Manatee Mortalities Using a Proteomic Approach Rebecca Lazensky1,2, Cecilia Silva‑Sanchez3, Kevin J
    www.nature.com/scientificreports OPEN Investigating an increase in Florida manatee mortalities using a proteomic approach Rebecca Lazensky1,2, Cecilia Silva‑Sanchez3, Kevin J. Kroll1, Marjorie Chow3, Sixue Chen3,4, Katie Tripp5, Michael T. Walsh2* & Nancy D. Denslow1,6* Two large‑scale Florida manatee (Trichechus manatus latirostris) mortality episodes were reported on separate coasts of Florida in 2013. The east coast mortality episode was associated with an unknown etiology in the Indian River Lagoon (IRL). The west coast mortality episode was attributed to a persistent Karenia brevis algal bloom or ‘red tide’ centered in Southwest Florida. Manatees from the IRL also had signs of cold stress. To investigate these two mortality episodes, two proteomic experiments were performed, using two‑dimensional diference in gel electrophoresis (2D‑DIGE) and isobaric tags for relative and absolute quantifcation (iTRAQ) LC–MS/MS. Manatees from the IRL displayed increased levels of several proteins in their serum samples compared to controls, including kininogen‑1 isoform 1, alpha‑1‑microglobulin/bikunen precursor, histidine‑rich glycoprotein, properdin, and complement C4‑A isoform 1. In the red tide group, the following proteins were increased: ceruloplasmin, pyruvate kinase isozymes M1/M2 isoform 3, angiotensinogen, complement C4‑A isoform 1, and complement C3. These proteins are associated with acute‑phase response, amyloid formation and accumulation, copper and iron homeostasis, the complement cascade pathway, and other important cellular functions.
    [Show full text]
  • Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis
    Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis This information is current as Damodar Gullipalli, Fengkui Zhang, Sayaka Sato, of September 29, 2021. Yoshiyasu Ueda, Yuko Kimura, Madhu Golla, Takashi Miwa, Jianxiang Wang and Wen-Chao Song J Immunol 2018; 201:1021-1029; Prepublished online 13 June 2018; doi: 10.4049/jimmunol.1800384 Downloaded from http://www.jimmunol.org/content/201/3/1021 References This article cites 37 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/201/3/1021.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis Damodar Gullipalli,* Fengkui Zhang,† Sayaka Sato,* Yoshiyasu Ueda,* Yuko Kimura,* Madhu Golla,* Takashi Miwa,* Jianxiang Wang,† and Wen-Chao Song* Paroxysmal nocturnal hemoglobinuria (PNH) is a serious blood disorder characterized by dysregulated complement activation on blood cells.
    [Show full text]
  • Unexpected Role for Properdin in Complement C3 Glomerulopathies
    EDITORIAL www.jasn.org Unexpected Role for uncontrolled C3 activation results in accumulation of C3 activation products in the kidney was obtained through the Properdin in Complement C3 investigation of mice with gene-targeted fH mutations. fH- Glomerulopathies deficient mice develop uncontrolled AP activation and a sec- ondary deficiency of C3. Elegant studies from Pickering et al.6 demonstrate that these mice develop marked accumu- Mohamed R. Daha lation of C3 along the glomerular basement membrane Leiden University Medical Center, and University Medical Center, (GBM) and glomerular inflammation resembling membra- Groningen, The Netherlands noproliferative GN. A similar pathology has also been de- 7 J Am Soc Nephrol 24: ccc–ccc, 2013. scribed in a breed of pigs with spontaneous fH deficiency. doi: 10.1681/ASN.2012111110 Renal accumulation of C3 in the murine model is de- pendent on AP activation, because mice with a combined deficiency of fH together with a deficiency in fB do not de- The complement system is a major component of innate im- velop renal injury or hypercatabolism of C3.8 In addition, de- munity and plays a key role in our defense against foreign position of C3 along the GBM is dependent on factor I (fI), an pathogens.1 In normal steady state conditions, the comple- enzyme that cleaves C3b to inactive C3b (iC3b), rendering it ment system has no significant biologic activity. There are incapable of binding fB and initiating further AP and terminal three main pathways to generate biologic activity by initiation pathway activation. Studies in mice with a combined defi- of complement activation, including the classic pathway ciency of fH and fI suggest that it is iC3b that deposits along (CP), the lectin pathway (LP), and the alternative pathway the GBM during uncontrolled activation of the AP.
    [Show full text]
  • A Molecular Concept of the Properdin Pathway (Complement Activation/Initiating Factor/Properdin Activation/Properdin Receptor/Multisubunit Enzymes) RUDOLF G
    Proc. Nat. Acad. Sci. USA Vol. 73, No. 2, pp. 612-616, February 1976 Immunology A molecular concept of the properdin pathway (complement activation/initiating factor/properdin activation/properdin receptor/multisubunit enzymes) RUDOLF G. MEDICUS, ROBERT D. SCHREIBER, OTTO GOTZE, AND HANS J. MJLLER-EBERHARD Department of Molecular Immunology, Scripps Clinic and Research Foundation, La Jolla, California 92037 Contributed by Hans J. Mitler-Eberhard, November 14,1975 ABSTRACT The sequential events of the properdin sys- mation of the properdin-dependent convertase which cata- tem were analyzed. Properdin-depleted serum allows the for- lyzes opsonization and activation of the membrane attack mation of a Factor B- and D-dependent C3 convertase. This enzyme, called the properdin-receptor-forming enzyme, was system. shown to utilize a novel serum component, the initiating fac- Initiation of the properdin pathway without tor. The protein is a a-globulin in recursor form and is dis- properdin (P) tinct from immunoglobulins. The function of the enzyme is to deposit C3b on the surface of activator particles. Appar- In exploring the possible role of P in the initiation of the ently doublets of C3b are required for the formation of the pathway, serum was immunochemically depleted of P. In properdin-activating principle. It consists of a complex con- addition, to block the classical pathway, C4 was removed taining surface-bound C3b and activated Factor B. Properdin precursor is activated by binding to this complex without de- from the same serum. Treatment of the depleted serum with tectable change in molecular weight. The transition of pro- yeast cell walls (zymosan) resulted in uptake of C3 by the perdin precursor to activated properdin is probably caused particles.
    [Show full text]
  • Independent Docking of Properdin That Activates the Alternative
    RESEARCH ARTICLE Soluble collectin-12 mediates C3- independent docking of properdin that activates the alternative pathway of complement Jie Zhang1,2, Lihong Song1,3, Dennis V Pedersen4, Anna Li1,2, John D Lambris5, Gregers Rom Andersen4, Tom Eirik Mollnes6,7,8, Ying Jie Ma1*, Peter Garred1* 1The Laboratory of Molecular Medicine, Department of Clinical Immunology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; 3Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China; 4Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark; 5Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 6Department of Immunology, Oslo University Hospital, and University of Oslo, Oslo, Norway; 7Research Laboratory, Nordland Hospital, K. G. Jebsen TREC, University of Tromsø, Bodø, Norway; 8Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway Abstract Properdin stabilizes the alternative C3 convertase (C3bBb), whereas its role as pattern- recognition molecule mediating complement activation is disputed for decades. Previously, we *For correspondence: have found that soluble collectin-12 (sCL-12) synergizes complement alternative pathway (AP) [email protected] (YJM); activation. However, whether this observation is C3 dependent is unknown. By application of the [email protected] (PG) C3-inhibitor Cp40, we found that properdin in normal human serum bound to Aspergillus fumigatus Competing interest: See solely in a C3b-dependent manner. Cp40 also prevented properdin binding when properdin- page 15 depleted serum reconstituted with purified properdin was applied, in analogy with the findings Funding: See page 15 achieved by C3-depleted serum.
    [Show full text]
  • New Cancer Therapeutic Strategies Are Proposed Based on Evidence from Stroma Liquid Biopsy™ Biomarkers Ingrid M
    New Cancer Therapeutic Strategies are Proposed Based on Evidence from Stroma Liquid Biopsy™ Biomarkers Ingrid M. Verhamme, Ph.D.; Vanderbilt University Medical Center, Nashville TN Swapan Roy, Ph.D., Matthew Kuruc, Sowmya Avadhani; Biotech Support Group LLC, Monmouth Junction NJ www.biotechsupportgroup.com For reprint or more information: [email protected] Poster first presented at 26th International Molecular Med TRI-CON, March 10-15, 2019, San Francisco, CA USA Abstract Tumors are more than simply a collection of immortalized cells as the supporting microenvironments or stroma also contributes to pathogenesis. Because of this, tumor characterization cannot be fully characterized solely through the analyses of the tumor cell genome – the current emphasis of liquid biopsy platforms. So because tumors are more than just a mass of proliferating cells, cancer progression must take into consideration the influence of the multiple cell types and networks of proteins dynamically interacting in active tumorigenesis. These are not simply passive bystanders. The unique significance of the Stroma Liquid Biopsy™ pan-cancer profile is that dysregulation was categorically intertwined with the most rudimentary needs of cancer: space, nutrients and immune evasion. Moreover, the changes within the 13 biomarker panel all occur within an interdependent network of cascading proteolytic events. Because proteolysis is irreversible, all species of life have evolved molecular regulatory systems to control aberrancies. The most distinguished is a protease inhibitory family of regulators known as SERPINs. Although SERPINs circulate in a variety of functional on/off sub-forms, conventionally they are observed and reported in aggregate (i.e., ELISA). As a result, their influence on disease is missed.
    [Show full text]
  • The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes
    pathogens Review The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes Cassidy Anderson and Catherine A. Brissette * Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-701-777-6412 Abstract: Lyme disease (LD) has become the most common vector-borne illness in the northern hemisphere. The causative agent, Borrelia burgdorferi sensu lato, is capable of establishing a persistent infection within the host. This is despite the activation of both the innate and adaptive immune responses. B. burgdorferi utilizes several immune evasion tactics ranging from the regulation of surface proteins, tick saliva, antimicrobial peptide resistance, and the disabling of the germinal center. This review aims to cover the various methods by which B. burgdorferi evades detection and destruction by the host immune response, examining both the innate and adaptive responses. By understanding the methods employed by B. burgdorferi to evade the host immune response, we gain a deeper knowledge of B. burgdorferi pathogenesis and Lyme disease, and gain insight into how to create novel, effective treatments. Keywords: Lyme disease; Borrelia; immune response; innate; adaptive; complement Citation: Anderson, C.; Brissette, C.A. The Brilliance of Borrelia: 1. Introduction Mechanisms of Host Immune Since the first investigations conducted by Steere and Malawista in 1975 [1,2], Lyme Evasion by Lyme Disease-Causing borreliosis, otherwise known as Lyme disease (LD), has become the most common vector- Spirochetes. Pathogens 2021, 10, 281. borne illness in the northern hemisphere [3]. LD is caused by infection with a member of https://doi.org/10.3390/pathogens the Borrelia burgdorferi sensu lato (s.l.) complex.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2008/0193414 A1 Proudfoot Et Al
    US 2008O193414A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0193414 A1 Proudfoot et al. (43) Pub. Date: Aug. 14, 2008 (54) USE OF AN IMMUNOGLOBULIN (30) Foreign Application Priority Data DOMAN-CONTAINING CELL SURFACE RECOGNITION MOLECULE FOR TREATING May 6, 2005 (EP) .................................. 05103791.9 DISEASES Publication Classification (76) Inventors: Amanda Proudfoot, Chens Sur (51) Int. Cl. Leman (FR); Bruno Antonsson, A638/17 (2006.01) Billiat (FR); Linda Kontula, A638/2 (2006.01) Geneva (CH); Francis Vilbois, A63L/7088 (2006.01) Minzier (FR) A6IR 39/44 (2006.01) A6IR 48/00 (2006.01) Correspondence Address: A6IP3L/2 (2006.01) SALWANCHIK LLOYD & SALWANCHIK A6IP3L/00 (2006.01) A PROFESSIONAL ASSOCATION A6IP33/00 (2006.01) PO BOX 142950 A6IP37/00 (2006.01) A6IP35/00 (2006.01) GAINESVILLE, FL 32614-2950 (US) A6IP 9/00 (2006.01) (21) Appl. No.: 11/913,620 A6IP 7/00 (2006.01) (52) U.S. Cl. ................ 424/85.6; 514/12: 514/13: 514/8: (22) PCT Filed: May 4, 2006 514/11: 514/44; 424/178.1; 424/85.4; 424/93.2 (57) ABSTRACT (86). PCT No.: PCT/EPO6/62O63 The invention relates to the use of INSP052 for treatment and/or prevention of infectious disease, properdin-related S371 (c)(1), disease, MBL2-related disease, MASP1-related disease, (2), (4) Date: Nov. 5, 2007 MASP2-related disease, Antithrombin III-related disease, Complement factor H-related disease and/or Albumin-related Related U.S. Application Data disease. Combinations of INSP052 with an interferon, a TNF (60) Provisional application No. 60/681,651, filed on May antagonist or a further anti-infectious or anti-blood clotting 17, 2005.
    [Show full text]