The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Review Article

Mechanisms of Disease
F R A N K L I N H . E P S T E I N , M. D. , Editor


reactivating the immune response against viral antigens and autoantigens. Although there is some evidence that infectious agents play a part in the pathogenesis of multiple sclerosis and many other autoimmune diseases (Table 1), it has not yet been proved that molecular mimicry is the initiating factor in any of these diseases. It is thus timely to review the evidence of molecular mimicry as a valid construct to explain the pathogenesis of autoimmune disease.


UTOIMMUNE disease is the consequence of an immune response against self-antigens that results in the damage and eventual dysfunction of target organs. Although the triggering event in most autoimmune diseases is unknown, an infectious cause has long been postulated to explain the development of autoimmunity. Molecular mimicry is one mechanism by which infectious agents (or other exogenous substances) may trigger an immune response against autoantigens. According to this hypothesis a susceptible host acquires an infection with an agent that has antigens that are immunologically similar to the host antigens but differ sufficiently to induce an immune response when presented to T cells. As a result, the tolerance to autoantigens breaks down, and the pathogen-specific immune response that is generated cross-reacts with host structures to cause tissue damage and disease (Fig. 1). This model has persisted for more than three decades because it offers an attractive conceptual link between a physiologic response (defense against infection) and a pathologic process (autoimmunity). Molecular mimicry has been linked to the pathogenesis of several important conditions, such as multiple sclerosis and type 1 diabetes mellitus. In the case of multiple sclerosis, it has been hypothesized that the disease is initiated by an infection early in life by a virus that shares antigenic structures with the host’s central nervous system tissue. The host’s antiviral immune response cross-reacts with central nervous system self-antigens, such as myelin basic protein, leading to demyelination. Subsequent viral infections are thought to cause exacerbations of the disease by


From the Division of Rheumatology, Department of Medicine, Toronto Western Hospital, University Health Network (L.J.A., R.D.I.); and the Departments of Medicine (L.J.A., R.D.I.) and Immunology (R.D.I.), University of Toronto — both in Toronto. Address reprint requests to Dr. Inman at the Arthritis Center of Excellence, Toronto Western Hospital, FP 1-221, 399 Bathurst St., Toronto, ON M5T 2S8, Canada, or at rinman@torhosp. ©1999, Massachusetts Medical Society.

The fate of a T cell, whether it is productive expansion, tolerance, or death, lies in the recognition by the T-cell antigen receptor of an antigenic peptide bound to a major-histocompatibility-complex (MHC) molecule on the surface of an antigen-presenting cell. This recognition event is very flexible, giving T cells the potential to recognize a broad range of foreign antigens.20,21 However, this range of specificities also makes it possible for T-cell antigen receptors to crossreact with autoantigens. Protection against autoimmunity is provided by negative selection of self-reactive T cells in the thymus (resulting in apoptosis) and induction of tolerance in T cells in the periphery (through clonal deletion or induction of anergy or nonresponsiveness).22,23 In the thymus and in the periphery, the fate of a T cell is determined by the avidity of its antigen receptor for the peptide–MHC complex. It appears that the affinity of the receptor for the complex and the number of complexes act in concert to direct the outcome of the reaction between the peptide–MHC complex and the T-cell receptor.24-26 However, some T cells are not deleted in the thymus or rendered tolerant to autoantigens or deleted peripherally, possibly because they are inaccessible to antigen or because the level of antigen is too low to activate them.23 Since these T cells do not recognize their cognate antigens, they are called “ignorant” T cells, and the antigens for which they are specific are referred to as “cryptic.”27 Antibody responses, as well as cellular responses, are important in the development of autoimmune disease. The responses of antibodies reflect the antigenic specificity of the B cells. Diversity exists among antibodies to maximize the host defense, and mechanisms similar to those that allow T cells to survive may allow autoreactive B cells to survive.23 However, most productive B-cell responses depend on help from T cells.28 The development of autoimmunity suggests that tolerance to autoantigens has broken down, allowing previously quiescent, potentially autoreactive T and B cells to become activated.

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The development of peptide-sequence data bases has resulted in the identification of many linear sequencVol ume 341 Numb e r 27 · 2069 Downloaded from www.30 Inappropriate activation of T cells may occur as a result of the up-regulation of MHC molecules and costimulatory molecules on antigen-presenting cells. Thus. 2009 . The red bar represents the barriers to autoreactivity. nonspecific T-cell activation may occur as the result of the binding of bacterial and other proteins known as superantigens. The Peripheral Immune Repertoire and Molecular Mimicry. If these peptides (small red spheres) are similar to host peptides (small green spheres). Memory T cells provide a defense against invading organisms and are potentially reactive with host tissues. Cytotoxic T lymphocytes recognize mimicked antigens in the context of MHC class I molecules on the surface of target tissues and directly cause tissue damage. An immune response is initiated against foreign organisms after the presentation of peptides by antigen-presenting cells to T cells in conjunction with the appropriate stimulatory signals (Panel B). leading to amplification of the response. These “ignorant” T cells do not recognize the antigens for which they are specific (referred to as “cryptic antigens”).nejm.29 Tissue damage and local necrosis of cells may uncover cryptic epitopes of autoantigens that then reactivate resting autoreactive T by SAUL LOPEZ-SILVA MD on October 5. B cells. All rights reserved. . Alternatively. aided by signals from activated helper T cells. Previously cryptic antigens may be released after tissue damage has occurred. which become activated on exposure to the exogenous peptides. Molecular mimicry. the latter being required for the activation of previously unactivated T cells after recognition and binding of MHC–peptide complexes. Circulating T cells have a spectrum of specificities (Panel A). on the other hand. produce antibodies that may cause tissue damage through the activation of complement pathways. Some autoreactive T cells exist. directly involves the specificity of the immune response in an unintended process that results in the breakdown of tolerance. Copyright © 1999 Massachusetts Medical Society. molecular mimicry depends on demonstrating that these T cells can be activated by antigenic determinants of an infectious agent that are similar to the determinants present in the host. Infection may provide the stimulus for the breakdown of tolerance through several nonspecific mechanisms unrelated to molecular mimicry. but they are quiescent.M EC H A NIS MS OF D IS EAS E A T cells Memory T cells (defense) B Endogenous host determinants Complement activation Secreted immunoglobulin Surface immunoglobulin (B-cell antigen receptor) Cross-reactive antigenic epitopes T-cell help Cross-reactive antigenic epitope Helper T cell Foreign organism Co s ti m u la t i o Autoreactive T cells B cell Helper T cell n Target tissue MHC class II Normal inhibitors of autoreactivity Subthreshold presentation of autoantigen Cryptic format of autoantigen No up-regulation of costimulatory molecules required for activation Cytotoxic T lymphocyte MHC class I Figure 1. SEQUENCE OR STRUCTURAL HOMOLOGY CD4+ T cells are the main effectors in most autoimmune diseases. then the immune response will be directed against the host as well. This process is mediated through naive T cells with autoreactive potential.

in this instance. other studies in these transgenic mice point to the importance of cytokines and costimulatory molecules for the activation of T cells. 2009 . In a study of the activation of T-cell clones specific for myelin basic protein (a central nervous system antigen) from patients with multiple sclerosis. However. . Although proof of principle is established by this study. es of amino acids shared by organisms and humans. All rights reserved.12 HLA-DRB1 Heat-shock protein 60 Myelin basic protein 40-kd heat-shock protein (dnaJ) Mycobacterium tuberculosis heat shock protein 65 Multiple viruses Multiple gram-negative bacterial proteins Yersinia enterocolitica T cell (concept controversial in humans) T and B cells T and B cells T cell B cell B cell LCMV–RIP transgenic mouse — Adjuvant arthritis (rat) LCMV–oligodendrocyte transgenic mouse — — Spondyloarthropathies13-17 HLA-B27 Graves’ disease18.19 Thyrotropin receptor *LCMV denotes lymphocytic choriomeningitis virus.. Furthermore. In mice. the beta-cell–specific antigen is created by the transgene construct and is the same antigen used to induce disease (i. the cross-reactivity would not have been predicted on the basis of the linear sequence of amino acids.2 Viral proteins thus become “self-proteins” in these transgenic mice.* IMMUNOLOGIC CROSS-REACTIVITY AUTOIMMUNE DISEASE PROPOSED AUTOANTIGEN PROPOSED PATHOGEN OR EPITOPE ANIMAL MODEL† Type 1 diabetes mellitus1-8 GAD65 Coxsackievirus P2-C Rheumatoid arthritis9 Rheumatoid arthritis10 Multiple sclerosis11.1. a transgene composed of DNA coding for glycoprotein or nucleoprotein of the lymphocytic choriomeningitis virus can be directed to pancreatic beta cells by including DNA from the rat insulin promoter in the transgene construct.34 Several peptides derived from both native and foreign proteins were identified. but many of these sequences lack any clinical correlation. When the mice are infected with lymphocytic choriomeningitis virus.32 The 129 peptides identified that contained one of these so-called mimicry motifs were tested against seven T-cell clones from two patients with multiple sclerosis.33 an observation underscoring the fact that linear-sequence homology is not critical for mimicry. some stimulatory peptides do not share a single amino acid with the original peptide. This model suggests that T cells capable of reacting with beta-cell autoantigens indeed exist but are quiescent in uninfected mice because they do not receive appropriate activation signals from the beta cells. which could be derived from different antigens. in mice Downloaded from www.35 For example. autoantigens). Furthermore. resulting in diabetes mellitus. Furthermore..31 However. autoreactive T cells could be activated by infection with an infectious agent bearing an antigen homologous to one in the host. the mimicry is too exact to prove the existence of molecular mimicry in general. PROPOSED MOLECULAR MIMICRY IN AUTOIMMUNE DISEASES. These structural criteria were used to search a peptide data base. The next level of evidence that molecular mimicry is a mechanism underlying autoimmune disease would be the demonstration that quiescent.nejm. potentially autoreactive T cells ignore the cognate antigen expressed in pancreatic beta cells until they are primed through systemic infection with lymphocytic choriomeningitis virus.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 1. lymphocytic choriomeningitis virus).org by SAUL LOPEZ-SILVA MD on October 5.e.e. This study confirms that some T-cell antigen receptors recognize not just a single peptide but a spectrum of structurally related peptides. antigenic mimicry is probably more complex than simple amino acid– sequence homology. 19 9 9 of which had a greater ability to activate T cells from patients with multiple sclerosis than did myelin basic protein itself. amino acids predicted to be critical for peptide binding to MHC molecules and recognition by T-cell antigen receptors were identified. Additional evidence of the complex process by which T-cell antigen receptors recognize MHC–peptide complexes comes from studies in which a randomly generated peptide library was used to identify peptides capable of stimulating T cells specific for myelin basic protein. and RIP rat insulin promoter. Seven viral peptides and one bacterial peptide activated three of the clones. Copyright © 1999 Massachusetts Medical Society. on the basis of chance alone. †This model is not specific for cross-reactivity between GAD65 and CoxP2-C. it has been calculated that. thus mimicking the peptide of myelin basic protein. up to 10 perfect matches can be found in protein-sequence data bases for a sequence of 5 amino acids. It is not known how many of these peptides might be generated from natural proteins in vivo and subsequently presented to T cells. some 2070 · Dec em b er 3 0 . and possible substitute amino acids were determined. more than 95 percent of them have a cytotoxic T-cell response against viral antigens (i. Thus. for all but one peptide.

40 The transfer of T cells from mice infected with wildtype virus.nejm.. Third.35 KEY ISSUES IN MOLECULAR MIMICRY There are difficulties inherent in proving that infection is the cause of autoimmune disease. Herpes stromal keratitis is an autoimmune disease of the eye in humans that is triggered by herpes simplex virus type 1 and is characterized by T-cell– dependent destruction of corneal tissue. accompanied by local up-regulation of MHC class I molecules on oligodendrocytes and of MHC class II molecules on microglia and other cells. the T-cell responses and autoantibodies subsequently formed might then be only the consequence of tissue injury. The cross-activation of T cells specific for a neural autoantigen by subsequent viral infections provides support for the clinical impression that exacerbations of multiple sclerosis follow infection with several different viruses. antigenic mimicry alone may not be sufficient for pathologic tissue cross-reactivity (in the absence of adequate costimulation and necessary cytokines). the experimental and clinical evidence purported to establish a mechanism for molecular mimicry in the pathogenesis of autoimmune diseases needs to be examined critically.. 2009 .38 This model suggests that cross-reactive T cells alone may be sufficient to induce disease. Finally. In this model. in itself. Herpes protein UL6 has been identified as the viral protein that resembles the corneal protein. those lacking mature T cells). Subsequent infection with lymphocytic choriomeningitis virus leads to further damage in the central nervous system. the infection may itself be occult. Infection with the virus results in acute peripheral infection. because the transfer of T cells caused disease only when there was a concurrent infection with the virus. because the viral infections precipitating disease are excluded from the central nervous system. but the central nervous system is spared. with mimicry occurring as an epiphenomenon.M EC H A NIS MS OF D IS EAS E that have coexpression of the costimulatory molecule B7-1 with viral glycoprotein in the islets. the demonstration of a tissue-specific antibody response is likewise not. Cardiac disease has been linked to infection with chlamydia species through antigenic mimicry.41 In a study in which protein-sequence data bases were screened for peptides having homology with the immunodominant peptide of the heavy chain of cardiacspecific a myosin. All rights reserved. antigenic mimicry may elicit tolerance of the host immune response rather than autoimmunity. Mice that are naturally resistant to herpes simplex virus type 1 infection have a particular variant of a gene coding for antibodies of the IgG2a class that contains a peptide sequence with similarities to a protein expressed in corneal cells. Alternatively. Second. a transgene composed of DNA coding for nucleoprotein or glycoprotein of lymphocytic choriomeningitis virus is expressed exclusively in oligodendrocytes in mice.39 A similar keratitis can be induced experimentally by infecting mice with herpes simplex virus type 1. known as M7Aa. with the recognition of several important principles. it should also be recognized that in certain mouse models of multiple sclerosis apparently mediated by an immune mechanism ( by SAUL LOPEZ-SILVA MD on October 5. Copyright © 1999 Massachusetts Medical Society. into “nude” mice (i. neither antigen homology nor T-cell proliferation in response to complexes of MHC molecules and peptides can alone be considered a specific indicator of pathogenic mimicry. The infectious process may have resolved long before the disease becomes clinically evident. Mimicry might also arise as a secondary phenomenon caused by an alteration of host antigenic determinants through tissue injury and the creation of neoepitopes. Tissue injury also contributes to the development of selfreactive T cells by uncovering previously cryptic epitopes. and keratitis does not develop after they have been infected with herpes simplex virus type 1. spontaneous diabetes develops without an exogenous viral challenge. results in the development of keratitis. thus making it difficult to identify a reliable temporal association between a particular organism and a particular disease.37 EXPERIMENTAL MODELS A model has been developed to test the role of molecular mimicry in the pathogenesis of autoimmune central nervous system disease. These mice are tolerant of the corneal protein. chronic inflammation develops in the central nervous system. These studies suggest that mimicry can induce tolerance as well as disease in the same experimental system (Fig. First. Thus. a specific indicator of pathogenic mimicry and may be due to tissue injury.11 After the virus has been cleared. it is difficult to exclude the possibility that a particular autoimmune disease is the result of an immune response against persistent viable or even nonviable infectious agents. These mechanisms lead to an expanded T-cell response over time. Thus. not the cause of it. infection in the periphery leads to the development of central nervous system inflammation. subsequent infection with unrelated viruses that cross-react with T cells specific for lymphocytic choriomeningitis virus leads to a similar exacerbation of the central nervous system disease. known as “epitope spreading. . However.g. and studies have shown that keratitis develops at a much lower rate in ordinary mice infected with a mutant virus lacking UL6 than in those infected with wild-type virus. In addition. several chlamydia Vol ume 341 Numb e r 27 · 2071 Downloaded from www. 2) but that mimicry alone is insufficient to cause disease. demyelination depends on primary infection of the central nervous system by virus. but not T cells from mice infected with UL6 mutant virus. Theiler’s encephalomyelitis due to viral infection12). independently of any mimicry trigger. however.”36 In view of these considerations. followed immediately by viral infection. with loss of myelin and motor dysfunction.e.

2009 . Copyright © 1999 Massachusetts Medical Society. burgdorferi. is also similar to the corneal protein.45 Monoclonal antibodies that react with group A streptococcal carbohydrate and human cardiac myosin destroy rat heart cells in vitro. Serum from patients with acute rheumatic fever contains antibodies to an antigen in the membrane of the organism.44 In mice. Only a few of these diseases will be considered here. . Molecular mimicry may mediate both tolerance and autoimmunity in this animal model. In the spondyloarthropathies. In some patients infected with the spirochete Borrelia burgdorferi.47 Synovial-fluid T cells from some patients with chronic Lyme arthritis. and the T cells reacted with M7Aa.46 Although these findings suggest that M proteins break down tolerance to epitopes of cardiac myosin and could be important in the pathogenesis of rheumatic carditis. CD11a/CD18. peptides of this M protein that are structurally similar to cardiac myosin are capable of inducing inflammatory infiltration of the myocardium and tolerance to coxsackievirus–induced myocarditis. but not from patients with other forms of arthritis. The mechanistic link between this autoreactivity against LFA-1 and the synovitis of B. particularly Reiter’s syndrome and reactive arthritis.39. Human leukocyte-function–associated antigen 1 (LFA-1. a protein expressed in herpes simplex virus type 1. burgdorferi infection awaits further definition. a connection with microbial infection through a mimicry mechanism has been proposed (Table 1). The impetus to prove a mimicry mechanism is the hope that antimicrobial therapy will provide effective prophylaxis and treatment in some cases of these often devastating diseases. T cells that cross-react with M protein and myosin peptides have not been identified in patients with rheumatic fever. Experimentally Induced Herpes Keratitis. Autoimmunity medi2072 · Decem b er 3 0 . The transfer of T cells from mice immunized with chlamydia peptides caused myocarditis in the recipients. In susceptible mice. react in vitro with the peptide. or integrin aL b 2) has been proposed as an autoantigen in these patients because it contains a peptide sequence that is homologous to one in the outer-surface protein A (OspA) of B. The relation of chlamydia mimicry to the pathogenesis of atherosclerotic coronary artery disease (suggested by epidemiologic data) remains to be determined. All rights reserved. The classic clinical paradigm for molecular mimicry has been acute rheumatic fever after infection with group A b-hemolytic streptococci. There is usually no detectable spirochetal DNA in the affected joints. peptides were identified.14 A systematic search of a sequence data base showed that B27. Early studies provided support for the concept of microbial mimicry of B27 based on monoclonal-antibody cross-reactivity13 and sequence homologies. 19 9 9 ated by a mimicry mechanism might not be restricted to a destructive process. the arthritis is resistant to antibiotic therapy and becomes chronic.43 which crossreacts with myocardial tissue. to a greater de- Downloaded from www. In patients with the appropriate genetic background associated with Lyme arthritis. myocarditis was not documented in these mice. UL6. burgdorferi infection is apparently still required for the development of an autoimmune response to LFA-1. Immunization of mice with these peptides induced myocarditis. there is a clear temporal relation between arthritis and antecedent bacterial infection.42. although it was less severe than in mice immunized with native M7Aa. but might also lead to a functional abnormality. priming by B. CLINICAL CANDIDATES FOR MOLECULAR MIMICRY For many autoimmune diseases. as well as with the intact LFA-1 and OspA proteins.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne IgG2a antibodies Resistance to keratitis (tolerance) CD4+ Cornea T-cell antigen receptor UL6 Corneal protein Keratitis (autoimmunity) Herpes simplex virus type 1 Figure 2. Keratitis can be induced in mice by infecting them with herpes simplex virus type 1. the type 5 streptococcal M protein. this molecular mimicry is thought to be involved in the development of keratitis. as with thyrotropinreceptor–stimulating antibodies in Graves’ hyperthyroidism. combined with a strong host genetic susceptibility (HLA-B27). Lyme arthritis develops as a late sequela. In about 10 percent of these patients.40 Mice that are resistant to keratitis after they have been infected with herpes simplex virus type 1 appear to be tolerant of the corneal protein because of similarities between a peptide sequence expressed in corneal cells and a sequence found within an IgG2aantibody variant that is unique to these animals. Although infection of normal mice with viable Chlamydia trachomatis organisms resulted in the development of an antibody response against myosin. such as the destruction of pancreatic b-cells in diabetes by SAUL LOPEZ-SILVA MD on October 5.nejm.

Lehmann PV. 6. there was no difference in outcome between the treatment groups. and an immune response to the homologous peptides is generated by immunization of mice with full-length proteins. Tian J. Endl J. All rights reserved. Pozza G.180:721-6. Buerki K. Mertens T. autoimmunity is not. Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients.65:305-17. Sequence homology of the diabetes-associated autoantigen glutamate decarboxylase with coxsackie B4-2C protein and heat shock protein 60 mediates no molecular mimicry of autoantibodies. Tobin AJ. Thus. . REFERENCES 1.322:1555-60. 8. an enzyme concentrated in pancreatic beta cells. Otto H. J Exp Med 1994. Kaufman DL. An- Vol ume 341 Numb e r 27 · 2073 Downloaded from www. Clare-Salzler M. Folli F. 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The frequency of shared peptide sequences and the flexibility inherent in immune recognition suggest that mimicry may be ubiquitous in biologic systems. Oldstone MBA. et al. For researchers in this area. et al. 2. 7. the pathogenic importance of this mimicry has not been established. shares an unexpected number of hexapeptides and pentapeptides with gramnegative bacterial proteins. If molecular mimicry is a biologically important phenomenon. either humoral or cellular. in a recent trial comparing immunosuppressive therapy (glucocorticoids plus either azathioprine or cyclosporine) with conventional therapy (diuretics and vasodilators) in patients with viral myocarditis. Copyright © 1999 Massachusetts Medical Society. Darrow BL. Infection is common. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Nonetheless. Oehen S. Lewicki H.54 By the same token.53.50. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes.15 However. Escherichia coli) do not appear on clinical grounds to be pathogens that cause arthritis.52 The patients with markers of immune activation.6-8 Furthermore. Erlander MG. 5. instead of having the deleterious role suggested by the concept of mimicry. peripheral-blood mononuclear cells from patients with diabetes mellitus can be stimulated to proliferate by insulin and several islet-cell antigens as well as GAD65. Jung G. the immune response. the B27 genotype.17 This finding supports the idea that antigenic mimicry may induce tolerance rather than autoimmunity. From the clinical perspective. 3. Kaufman DL. 4. in the pathogenesis of diabetes mellitus. 2009 . Numerous bacteria that have sequence homologies with B27 (e. because it links current concepts of the role of the immune system in the host defense with concepts of autoimmunity. a search of data bases identified 17 viruses with some homology to various fragments of GAD65. in some disorders. actually rendered them tolerant to this shared peptide. instead of predisposing the mice to arthritis. et al. it has important implications for vaccination. and T-cell reactivity against microbial peptides recognized by anti-B27 antibodies has not been established. molecular mimicry retains an intrinsic appeal.99:2405-15. Schoel B. Maclaren NK.51 On the other hand. Southern P. Molecular mimicry has remained an attractive explanation for autoimmune diseases for three decades. Kaufman DL. mimicry related to viral infection has been proposed on the basis of sequence homology between glutamate decarboxylase (GAD65). 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Ohashi PS. Price J.48 indicating that cross-reactivity between GAD65 and coxsackieviruses is not unique.4 Although cross-reactivity between coxsackievirus P2-C and GAD65 has been demonstrated in mice.

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