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Molecular Mimicry: Cross-Reactivity Between Microbes and Host Proteins as a Cause of Autoimmunity PDF

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Current Topics in Microbiology 145 and Immunology Editors R. W. Compans, Birmingham/Alabama . M. Cooper, Birmingham/Alabama . H. Koprowski, Philadelphia 1. McConnell, Edinburgh . F. Melchers, Basel V. Nussenzweig, NewY ork . M. Oldstone, La Jolla/California . S. Olsnes, Oslo . H. Saedler, Cologne . P. K Vogt, Los Angeles . H. Wagner, Ulm 1. Wilson, La Jolla/California Molecular Mimicry Cross-Reactivity Between Microbes and Host Proteins as a Cause of Autoimmunity Edited by M. B. A. Oldstone With 28 Figures Springer-Verlag Berlin Heidelberg NewY ork London Paris Tokyo Hong Kong MICHAEL B. A. OLDSTONE, M.D. Dept. ofImmunology, Scripps Clinic and Research Foundation 10666 N. Torrey Pines Road, La Jolla, CA 92037, USA ISBN-13: 978-3-642-74596-6 e-ISBN-13:978-3-642-74594-2 DOl: 10.1007/978-3-642-74594-2 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1989 Softcover reprint of the hardcover 1st edition 1989 Library of Congress Catalog Card Number 15-12910 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and terefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained on this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 2123/3020-543210 - Printed on acid-free paper Table of Contents M. B. A. OLDSTONE: Overview: Infectious Agents as Etiologic Triggers of Autoimmune Disease. . . . J. FROUDE, A. GIBOFSKY, D. R. BUSKIRK, A. KHANNA and J. B. ZABRISKIE: Cross-Reactivity Between Streptococcus and Human Tissue: A Model of Molecular Mimicry and Autoimmunity. . . . . . . . . . .. 5 W. VAN EDEN, E. J. M. HOGERVORST, E. J. HENSEN, R. VAN DER ZEE, J. D. A. VAN EMBDEN, and 1. R. COHEN: A Cartilage-Mimicking T-Cell Epitope on a 65K Mycobacterial Heat-Shock Protein: Adjuvant Arthritis as a Model for Human Rheumatoid Arthritis. . . . . 27 P. L. SCHWIMMBECK and M. B. A. OLDSTONE: Klebsiella pneumoniae and HLA B27-Associated Diseases of Reiter's Syndrome and Ankylosing Spondylitis. . . . 45 M. E. DIEPERINK and K. STEFANSSON: Molecular Mimicry and Microorganisms: A Role in the Pathogenesis of Myasthenia Gravis? . . . . . . . . . . . . . . . 57 M. F. KAGNOFF: Celiac Disease: Adenovirus and Alpha Gliadin. . . . . . . . . . . . . . . . . . . . . 67 G. B. TAKLE and L. HUDSON: Autoimmunity and Chagas' Disease. . . . . . . . . . . . . . . . . . . . . 79 R. S. FUJINAMI: Immune Responses Against Myelin Basic Protein and/or Galactocerebroside Cross-React with Viruses: Implications for Demyelinating Disease. . . 93 R. T. DAMIAN: Molecular Mimicry: Parasite Evasion and Host Defense . . . . . . . . . . . . . . !OI T. DYRBERG: Molecular Mimicry and Diabetes. . . . . 117 M. B. A. OLD STONE : Molecular Mimicry as a Mechanism for the Cause and as a Probe Uncovering Etiologic Agent(s) of Autoimmune Disease. 127 Subject Index . . . . . . . . . . . . . . . . . . . 137 List of Contributors You will find the addresses at the beginning of the respective contribution BUSKIRK, D. R. KAGNOFF, M. F. COHEN, I. R. KHANNA,A. DAMIAN, R. T. OLDSTONE, M. B. A. DIEPERINK, M. E. SCHWIMMBECK, P. L. DYRBERG, T. STEFANSSON, K. FROUDE,J. TAKLE, G. B. FUJINAMI, R. S. VAN DER ZEE, R. GIBOFSKY, A. VANEDEN,W. HENSEN, E. J. VAN EMBDEN, J. D. A. HUDSON, L. ZABRISKIE, J. B. HOGERVORST, E. J. M. Overview: Infectious Agents as Etiologic Triggers of Autoimmune Disease M. B. A. OLDSTONE Infectious agents, particularly viruses, are implicated in autoimmunity on the basis of three findings. First, autoimmune responses are made de novo or those already present are enhanced concomitant with infection by a wide variety of human DNA and RNA viruses. This point is strengthened by the second finding that, in experimental animals, both acute and persistent virus infections can induce, accelerate, or enhance autoimmune responses and cause autoimmune disease. For example, it has been shown that with the New Zealand mouse family, a genetically defined group of mice from which certain strains spontaneously develop autoimmunity, autoimmune manifestations normally present in NZB mice (DNA-specific antibodies, red blood cell-specific antibodies) or their (NZB x W) F 1 relatives (DNA-specific antibodies) are enormously enhanced by persistent infection with either a DNA (polyoma) or RNA (lymphocytic choriomeningitis, LCMV) virus; that is, antibodies form earlier and reach higher titers in the infected mice than in their uninfected counterparts (ToNIETTI et al. 1970; LAMPERT and OLDSTONE 1973). Further, NZW mice, which normally do not develop these autoimmune responses, do so upon polyoma or LCMV infections. Indeed, the responses in NZB, (NZB x W) F l' or NZW mice are so marked that autoimmune diseases occur at a higher incidence with earlier time of death (NZB, (NZB x W) Fll or appear de novo (NZW). These events were subsequently repeated with a number of viruses, including retroviruses (reviewed OLDSTONE 1972). Third, utilizing an investigative approach that focuses on one potential mechanism where by microbes cause autoimmunity, molecular mimicry, a number of etiologic agents have been defined as potential causes of autoimmune disease (OLDSTONE 1987). Microbial agents can induce autoimmune responses by a variety of unique mecha- nisms, and several of these might occur during anyone infection. For example, certain microbes have a mitogenic effect on unique lymphocyte subsets and hence can act as polyclonal activators. Because agents like mycoplasma can activate lymphocytes, and mycoplasma may contaminate bacterial and viral stocks, stringent evidence must be presented that the activation is directly due to the bacteria or virus and not mycoplasma contamination. Microbes can also direct the release of lymphokines and monokines. These molecules are important modulators of immune responses by acting as growth or differentiation factors or by regulating the expression of class I and class II major histocompatibility molecules. Hence, an infectious agent could release a lymphokine like interferon and induce the expression of class II molecules on cells Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037, USA Current Topics in Microbiology and Immunology, Vol. 145 © Springer-Verlag Berlin' Heidelberg 1989 2 M. B. A. Oldstone like epithe10id cells in the thyroid or ~ cells in the islets of Langerhans of the pancreas. Such cells, which usually express limited or negligible amounts of MHC class II glycoproteins, may then present self-antigens (i.e., thyroglobulin, insulin receptor, etc.) in the context of induced class II molecules. The end result is hypothesized to be the priming of an immune response against self (BOTTAZZO et al. 1983). Additional microbes, especially viruses, can infect and selectively replicate in unique lymphocyte subsets (reviewed MCCHESNEY and OLDSTONE 1987). By their presence, activation, or replication, the microbe can cause immunosuppression or immunoenhancement. Finally, microbes can contain chemical structures that mimic normal host "self' proteins, an event termed molecular mimicry. Thus, an effector immune response, either B (humoral) or T (cytotoxic T cell), directed against the microbe might then also cross-react with "self' protein and induce autoimmunity. Several of the ways that infectious agents can trigger autoimmunity are: • Polyclonal activator of B or T lymphocytes • Enhanced expression of MHC class II molecules • Enhanced expression of MHC class I molecules • Bystander activation of immunocompetent cells through release of lymphokines or monokines • Alteration of lymphocyte/macrophage function Tropism for and lysis of unique cell subset(s) - Tropism for and alteration of differentiated function of unique cell subset(s) (no lysis) • Molecular mimicry This volume focuses on the evidence for or against molecular mimicry as a cause of autoimmunity. Major contributors in this area of research have provided chapters analyzing the evidence available. The group of investigators at the Rockefeller University have a long-term interest in the role of streptococcus in rheumatic heart diease. John Zabriskie reviews the story for streptococcal M protein, its shared homology and immunologic cross-reactivity primarily with myocardial tissue. The second chapter by W. van Eden relates a recent study implicating myobacteria, cartilage proteoglycans, and heat shock proteins with a cross-reactive T cell epitope in causing arthritis. Peter Schwimmbeck's chapter reviews the evidence suggesting that HLA B27 is an autoantigen that cross-reacts with Klebsiella pneumoniae and other bacteria. He argues that this may be the etiology and pathogenic mechanism for the nonrheumatoid arthritides, ankylosing spondylitis, and Reiter's syndrome. K. Stefansson explores the role of cross-reactive bacterial and viral antigens with the acetylcholine receptor as a possible cause of myasthenia gravis. Martin Kagnoff details his observation of the sequence and immunologic cross-reactivity of alpha gliadin and an adenovirus subtype as meaningful events in celiac disease. Trypanosoma cruzi causes the American form of trypanosomiasis called Chagas' disease. Drs. Hudson and Takle review the evidence supporting an autoimmune etiology for this parasitic infection. The next two chapters provide data suggesting a link for demyelinating disease and for diabetes with infectious agents and autoimmune response. Robert Fujinami has been interested in developing experimental animal models that help establish the principles of molecular mimicry (FUTINAMI and OLDSTONE 1985). In his contribution, Dr. FUJINAMI explores experimental and clinical findil)gs relating a role for molecular mimicry in demyelinating and central nervous Overview: Infectious Agents as Etiologic Triggers of Autoimmune Disease 3 system disease. The chapter provided by Dr. DYRBERG is perhaps the most teasing. He provides preliminary data of a cross-reactivity between the insulin receptor, thyroid protein, and acetylcholine receptor with several infectious agents. His finding of a clinical condition associated with antibodies to the insulin receptor and of events in which a cross-reactivity between papillomavirus and the receptor occurred is most interesting. The chapter by Dr. DAMIAN provides a balance. Reviewing the evidence for shared determinants between parasites and host cell antigens, Dr. DAMIAN argues for molecular mimicry as a basis of avoidance of immunologic recognition and cross- reactive immune response. Thus, in this view molecular mimicry may be beneficial and serve as a line of host defense. The final chapter is positioned to review the overall perspective of molecular mimicry, how to use its principles in clinical investigation and list the conceptual traits by which autoimmune disease can occur. Acknowledgements: This is publication number 5624-IMM from the Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037. This work was supported in part by USPHS grants AI-07007. NS-12428 and AG 04342. References Bottazzo GF, Pijal-Borrell PR, Hanafusa T (1983) Hypothesis: role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet ii: 1115-1119 Fujinami, RS, and Oldstone, MBA (1985) Amino acid homology between the encephalitogenic site of myelin basic protein and virus: Mechanism for autoimmunity Lampert PW, Oldstone MBA (1973) Host IgG and C3 deposits in the choroid plexus during spontaneous immune complex disease. Science 180: 408-410 McChesney MB, Oldstone MBA (1987) Viruses perturb lymphocyte functions: selected principles characterizing virus-induced immunosuppression. Ann Rev Immunol 5: 279-304 Oldstone MBA (1972) Virus induced autoimmune disease: viruses in the production and prevention of autoimmune disease. In: Membranes and viruses in immunopathology. Academic, New York, pp 469-475 Oldstone MBA (1987) Molecular mimicry and autoimmune disease. Cell 50: 819-820 Tonietti G, Old stone MBA, Dixon FJ (1970) The effect of induced chronic viral infections on the immunologic diseases of New Zealand mice. J Exp Med 132: 89-109 Cross-Reactivity Between Streptococcus and Human Tissue: A Model of Molecular Mimicry and Autoimmunity J. FROUDE1 , A. GIBOFSKy2, D. R. BUSKIRK1 , A. KHANNA1 , and J. B. ZABRISKIE1 Introduction 5 2 Hyaluronic Acid 7 2.1 Biochemical Homology 7 2.2 Serological Homology 7 2.3 Biological Homology 8 3 M Protein 8 3.1 Structural Homology 9 3.2 Serological Homology. 10 3.3 Biological Significance 11 4 Carbohydrate 12 4.1 Structural Homology 12 4.2 Serological Homology 12 4.3 Biological Homology 13 5 Membrane Antigens 13 5.1 Structural Homology 13 5.2 Serological Homology 14 5.2.1 Heart 14 5.2.2 Brain 14 5.2.3 Kidney 15 5.2.4 Skin 15 5.3 HistocompatihiIity Antigens 16 6 Disease ASSOCiations 17 6.1 Rheumatic Fever 17 6.2 Post-Streptococcal Glomerulonephritis 18 7 Conclusions 20 References 22 1 Introduction Structural homology between mammalian tissues and microbes has been demonstrated for over 50 years. Twenty years ago the term "molecular mimicry" was coined to describe antigenic structures common to host and protozoal parasites (DAMIAN 1964). This term has since been expanded to include other microorganisms, and 1 Laboratory of Bacteriology and Immunology, Rockefeller University, New York, NY, USA 2 Multipurpose Arthritis Center, Hospital for Special Surgery, Cornell University Medical College, NY, USA Current Topics in Microbiology and Immunology, Vol. 145 © Springer-Verlag Berlin· Heidelberg 1989 6 J. Froude et al. Table 1. A selection of cross-reactions between microbes and mammalian tissues Organism Tissue Possible Ref. Disease Association Streptococcus pyogenes Heart, brain, Rheumatic fever ZABRISKIE 1985 kidney, etc. Streptococcus mutans Heart ? VAN DE RUN et al. 1976 Klebsiella HLA-BW27 Ankylosing EBRINGER 1978; SEAGER et aJ. lymphocytes spondylitis 1979; SCHWIMMBECK et al. Reiter's syndrome 1987 Salmonella Mouse tissues Salmonella infection ROWLEY and JENKINS 1962 Pneumococci 50 % Blood group ? Susceptibility FINLAND and CURNEN 1940; gram-negative bacteria substances to infection SPRINGER et al. 1961 Escherichia coli Colon tissue Ulcerative colitis PERLMAN et aJ. 1965 Tubercle bacillus Cartilage Rheumatoid arthritis VAN EDEN et al. 1985 proteoglycanase Trypanosoma cruzi High density Chagas' disease PRIOLI et al. 1987 lipoprotein Coxsackie B virus Cardiac myosin Cardiomyopathy ROSE et al. 1986 Cell wall Protein (M, R,Tl Group • Valvular Carbohydrate tissue Mucopeptide Protoplast Membrane. Myocardial sarcolemma a Vascular Intima .skin ____ • HLA antigens? Fig. 1. Schematic representation of the various structures of the group A streptococcus. Note the wide variety of cross-reactions between its antigens and mammalian tissues

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