Abstract
Various mechanisms have been proposed for the initiation of autoimmune responses by autoreactive T‐cell clones. One of these, the molecular mimicry hypothesis, postulates that myelin‐reactive T‐cell clones are activated by foreign antigens. Until recently, sequence homology between self‐ and foreign antigens was considered necessary for cross‐recognition to occur in multiple sclerosis. This article reviews current progress in T‐cell receptor immunology that led to modify this view and proposes a role for degenerate T‐cell antigen recognition in the induction of autoimmunity. Ann Neurol 1999;45:559–567
References
- 1. Martin R, McFarland HF, McFarlin DE. Immunological aspects of demyelinating diseases. Annu Rev Immunol 1992; 10: 153–187 [DOI] [PubMed] [Google Scholar]
- 2. Fujinami RS, Oldstone MBA. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 1985; 230: 1043–1045 [DOI] [PubMed] [Google Scholar]
- 3. Oldstone MBA. Molecular mimicry and autoimmune disease. Cell 1987; 50: 819–820 [DOI] [PubMed] [Google Scholar]
- 4. Traugott U, Reinherz EL, Raine CS. Multiple sclerosis. Distribution of T cells, T cell subsets and Ia‐positive macrophages in lesions of different ages. J Neuroimmunol 1983; 4: 201–221 [DOI] [PubMed] [Google Scholar]
- 5. Hvas J, Oksenberg JR, Fernando R, et al. Gamma delta T cell receptor repertoire in brain lesions of patients with multiple sclerosis. J Neuroimmunol 1993; 46: 225–234 [DOI] [PubMed] [Google Scholar]
- 6. Esiri MM. Multiple sclerosis: a quantitative and qualitative study of immunoglobulin‐containing cells in the central nervous system. Neuropathol Appl Neurobiol 1980; 6: 9–21 [DOI] [PubMed] [Google Scholar]
- 7. Vartdal F, Sollid LM, Vandvik B, et al. Patients with multiple sclerosis carry DQB1 genes which encode shared polymorphic aminoacid sequences. Hum Immunol 1989; 25: 103–110 [DOI] [PubMed] [Google Scholar]
- 8. Naito S, Kuroiwa Y, Itoyama T, et al. HLA and Japanese MS. Tissue Antigens 1978; 12: 19–24 [PubMed] [Google Scholar]
- 9. Marrosu HG, Muntoni F, Murru MR, et al. Sardinian multiple sclerosis is associated with HLA‐DR4: a serological and molecular analysis. Neurology 1988; 38: 1749–1753 [DOI] [PubMed] [Google Scholar]
- 10. Sawcer S, Jones HB, Feakes R, et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 1996; 13: 464–468 [DOI] [PubMed] [Google Scholar]
- 11. Haines JL, Ter‐Minassian M, Bazyk A, et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex. The Multiple Sclerosis Genetics Group . Nat Genet 1996; 13: 469–471 [DOI] [PubMed] [Google Scholar]
- 12. Ebers GC, Kukay K, Bulman DE, et al. A full genome search in multiple sclerosis. Nat Genet 1996; 13: 472–476 [DOI] [PubMed] [Google Scholar]
- 13. Paty DW, Li DKB, UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group . Interferon beta‐1b is effective in relapsing‐remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double‐blind, placebo‐controlled trial. Neurology 1993; 43: 662–667 [DOI] [PubMed] [Google Scholar]
- 14. The Interferon‐Beta Multiple Sclerosis Study Group . Interferon beta‐1b is effective in relapsing‐remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double‐blind, placebo‐controlled trial. Neurology 1993; 43: 655–661 [DOI] [PubMed] [Google Scholar]
- 15. Weiner HL, Mackin GA, Orav EJ, the NCMST . Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 1993; 43: 910–918 [DOI] [PubMed] [Google Scholar]
- 16. Panitch HS, Hirsch RL, Schindler J, Johnson KP. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 1987; 37: 1097–1102 [DOI] [PubMed] [Google Scholar]
- 17. Lucchinetti CF, Bruck W, Rodriguez M, Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol 1996; 6: 259–274 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Raine CS. The neuropathology of multiple sclerosis In: Raine CS, McFarland HF, Tourtellotte WW, eds. Multiple sclerosis: clinical and pathogenetic basis. London, Chapman and Hall, 1997: 151–171 [Google Scholar]
- 19. Raine CS. The lesion in multiple sclerosis and chronic relapsing experimental allergic encephalomyelitis: a structural comparison In: Raine CS, McFarland HF, Tourtellotte WW, eds. Multiple sclerosis: clinical and pathogenetic basis. London, Chapman and Hall, 1997: 243–286 [Google Scholar]
- 20. Schlüsener H, Wekerle H. Autoaggressive T lymphocyte lines recognize the encephalitogenic region of myelin basic protein; in vitro selection from unprimed rat T lymphocyte populations. J Immunol 1985; 135: 3128–3133 [PubMed] [Google Scholar]
- 21. Fritz RB, Skeen MJ, Jen‐Chou CH, et al. Major histocompatibility complex‐linked control of the murine immune response to myelin basic protein. J Immunol 1985; 134: 2328–2332 [PubMed] [Google Scholar]
- 22. Wekerle H, Linington C, Lassmann H, Meyermann R. Cellular immune reactivity within the CNS. Trends Neurosci 1986; 9: 271–277 [Google Scholar]
- 23. Burns J, Rosenzweig A, Zweiman B, Lisak RP. Isolation of myelin basic protein‐reactive T‐cell lines from normal human blood. Cell Immunol 1983; 81: 435–440 [DOI] [PubMed] [Google Scholar]
- 24. Martin R, Jaraquemada D, Flerlage M, et al. Fine specificity and HLA restriction of myelin basic protein‐specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J Immunol 1990; 145: 540–548 [PubMed] [Google Scholar]
- 25. Pette M, Fujita K, Kitze B, et al. Myelin basic protein‐specific T lymphocyte lines from MS patients and healthy individuals. Neurology 1990; 40: 1770–1776 [DOI] [PubMed] [Google Scholar]
- 26. Zhang J, Markovic‐Plese S, Lacet B, et al. Increased frequency of interleukin‐2‐responsive T cells specific for myelin basic protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1994; 179: 973–984 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Ota K, Matsui M, Milford EL, et al. T‐cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 1990; 346: 183–187 [DOI] [PubMed] [Google Scholar]
- 28. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985; 1: 1313–1315 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Panitch HS. Influence of infection on exacerbations of multiple sclerosis. Ann Neurol 1994; 36(Suppl): S25–28 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Kurtzke JF. Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev 1993; 6: 382–427 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Talbot PJ, Paquette J‐S, Ciurli C, et al. Myelin basic protein and human coronavirus 229E cross‐reactive T cells in multiple sclerosis. Ann Neurol 1996; 39: 233–240 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell‐mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 1974; 248: 701–702 [DOI] [PubMed] [Google Scholar]
- 33. Germain RN. MHC‐dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994; 76: 287–299 [DOI] [PubMed] [Google Scholar]
- 34. Croft M. Activation of naive, memory and effector T cells. Curr Opin Immunol 1994; 6: 431–437 [DOI] [PubMed] [Google Scholar]
- 35. Olsson T. Cytokine‐producing cells in experimental autoimmune encephalomyelitis and multiple sclerosis. Neurology 1995; 45(Suppl 6): S11–S15 [DOI] [PubMed] [Google Scholar]
- 36. Dubey C, Croft M, Swain SL. Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. J Immunol 1996; 157: 3280–3289 [PubMed] [Google Scholar]
- 37. Gautam AM, Liblau R, Chelvanayagam G, et al. A viral peptide with limited homology to a self peptide can induce clinical signs of experimental autoimmune encephalomyelitis. J Immunol 1998; 161: 60–64 [PubMed] [Google Scholar]
- 38. van Eden W, Hogervorst EJ, Hensen EJ, et al. A cartilage‐mimicking T‐cell epitope on a 65K mycobacterial heat‐shock protein: adjuvant arthritis as a model for human rheumatoid arthritis. Curr Top Microbiol Immunol 1989; 145: 27–43 [DOI] [PubMed] [Google Scholar]
- 39. Davies JM. Molecular mimicry: can epitope mimicry induce autoimmune disease? Immunol Cell Biol 1997; 75: 113–126 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Hammer J, Valsasnini P, Tolba K, et al. Promiscuous and allele‐specific anchors in HLA‐DR binding peptides. Cell 1993; 74: 197–203 [DOI] [PubMed] [Google Scholar]
- 41. Evavold BD, Sloan‐Lancaster J, Hsu BL, Allen PM. Separation of T helper 1 clone cytolysis from proliferation and lymphokine production using analog peptides. J Immunol 1993; 150: 3131–3140 [PubMed] [Google Scholar]
- 42. Kersh GJ, Allen PM. Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands. J Exp Med 1996; 184: 1259–1268 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. von Boehmer H, Kisielow P. Self‐nonself discrimination by T cells. Science 1990; 248: 1369–1373 [DOI] [PubMed] [Google Scholar]
- 44. Vogt AB, Kropshofer H, Kalbacher H, et al. Ligand motifs of HLA‐DRB5*0101 and DRB1*1501 molecules delineated from self‐peptides. J Immunol 1994; 153: 1665–1673 [PubMed] [Google Scholar]
- 45. Wucherpfennig KW, Sette A, Southwood S, et al. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 1994; 179: 279–290 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell‐mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995; 80: 695–705 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Vergelli M, Hemmer B, Utz U, et al. Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99). Eur J Immunol 1996; 26: 2624–2634 [DOI] [PubMed] [Google Scholar]
- 48. Vergelli M, Hemmer B, Kalbus M, et al. Modifications of peptide ligands enhancing T cell responsiveness imply large numbers of stimulatory ligands for autoreactive T cells. J Immunol 1997; 158: 3746–3752 [PubMed] [Google Scholar]
- 49. Hemmer B, Vergelli M, Gran B, et al. Predictable TCR antigen recognition based on peptide scans leads to the identification of agonist ligands with no sequence homology. J Immunol 1998; 160: 3631–3636 [PubMed] [Google Scholar]
- 50. Ausubel LJ, Kwan CK, Sette A, et al. Complementary mutations in an antigenic peptide allow for crossreactivity of autoreactive T‐cell clones. Proc Natl Acad Sci USA 1996; 93: 15317–15322 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Houghten RA, Pinilla C, Blondelle SE, et al. Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 1991; 354: 84–86 [DOI] [PubMed] [Google Scholar]
- 52. Udaka K, Wiesmüller K‐H, Kienle S, et al. Decrypting the structure of major histocompatibility complex class I‐restricted cytotoxic T lymphocyte epitopes with complex peptide libraries. J Exp Med 1995; 181: 2097–2108 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Hemmer B, Vergelli M, Pinilla C, et al. Probing degeneracy in T‐cell recognition using combinatorial peptide libraries. Immunol Today 1998; 19: 163–168 [DOI] [PubMed] [Google Scholar]
- 54. Hemmer B, Fleckenstein B, Vergelli M, et al. Identification of high potency microbial and self ligands for a human autoreactive class II‐restricted T cell clone. J Exp Med 1997; 185: 1651–1659 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Mason D. A very high level of crossreactivity is an essential feature of the T‐cell receptor. Immunol Today 1998; 19: 395–404 [DOI] [PubMed] [Google Scholar]
- 56. Evavold BD, Allen PM. Separation of IL‐4 production from Th cell proliferation by an altered T cell receptor ligand. Science 1991; 252: 1308–1310 [DOI] [PubMed] [Google Scholar]
- 57. Hemmer B, Stefanova I, Vergelli M, et al. Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells. J Immunol 1998; 160: 5807–5814 [PubMed] [Google Scholar]
- 58. Sloan‐Lancaster J, Allen PM. Altered peptide ligand‐induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu Rev Immunol 1996; 14: 1–27 [DOI] [PubMed] [Google Scholar]
- 59. Wekerle H, Bradl M, Linington C, et al. The shaping of the brain‐specific T lymphocyte repertoire in the thymus. Immunol Rev 1996; 149: 231–243 [DOI] [PubMed] [Google Scholar]
- 60. Nossal GJ. Negative selection of lymphocytes. Cell 1994; 76: 229–239 [DOI] [PubMed] [Google Scholar]
- 61. von Boehmer H. Positive selection of lymphocytes. Cell 1994; 76: 219–228 [DOI] [PubMed] [Google Scholar]
- 62. Ashton‐Rickardt PG, Bandeira A, Delaney JR, et al. Evidence for a differential avidity model of T cell selection in the thymus. Cell 1994; 76: 651–663 [DOI] [PubMed] [Google Scholar]
- 63. Ashton‐Rickardt PG, Tonegawa S. A differential‐avidity model for T‐cell selection. Immunol Today 1994; 15: 362–366 [DOI] [PubMed] [Google Scholar]
- 64. Jameson SC, Bevan MJ. T‐cell selection. Curr Opin Immunol 1998; 10: 214–219 [DOI] [PubMed] [Google Scholar]
- 65. Rudensky AY. Endogenous peptides associated with MHC class II and selection of CD4 T cells. Semin Immunol 1995; 7: 399–409 [DOI] [PubMed] [Google Scholar]
- 66. Fritz RB, Zhao M‐L. Thymic expression of myelin basic protein (MBP). Activation of MBP‐specific T cells by thymic cells in the absence of exogenous MBP. J Immunol 1996; 157: 5249–5253 [PubMed] [Google Scholar]
- 67. Mor F, Boccaccio GL, Unger T. Expression of autoimmune disease‐related antigens by cells of the immune system. J Neurosci Res 1998; 54: 254–262 [DOI] [PubMed] [Google Scholar]
- 68. Sospedra M, Ferrer‐Francesch X, Dominguez O, et al. Transcription of a broad range of self‐antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. J Immunol 1998; 161: 5918–5929 [PubMed] [Google Scholar]
- 69. Egwuagu CE, Charukamnoetkanok P, Gery I. Thymic expression of autoantigens correlates with resistance to autoimmune disease. J Immunol 1997; 159: 3109–3112 [PubMed] [Google Scholar]
- 70. Heath VL, Moore NC, Parnell SM, Mason DW. Intrathymic expression of genes involved in organ specific autoimmune disease. J Autoimmun 1998; 11: 309–318 [DOI] [PubMed] [Google Scholar]
- 71. Heath VL, Saoudi A, Seddon BP, et al. The role of the thymus in the control of autoimmunity. J Autoimmun 1996; 9: 241–246 [DOI] [PubMed] [Google Scholar]
- 72. Fairchild PJ, Wildgoose R, Atherton E, et al. An autoantigenic T cell epitope forms unstable complexes with class II MHC: a novel route for escape from tolerance induction. Int Immunol 1993; 5: 1151–1158 [DOI] [PubMed] [Google Scholar]
- 73. Zal T, Volkmann A, Stockinger B. Mechanisms of tolerance induction in major histocompatibility complex class II‐restricted T cells specific for a blood‐borne self‐antigen. J Exp Med 1994; 180: 2089–2099 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74. Bevan MJ. In thymic selection, peptide diversity gives and takes away. Immunity 1997; 7: 175–178 [DOI] [PubMed] [Google Scholar]
- 75. Ignatowicz L, Kappler J, Marrack P. The repertoire of T cells shaped by a single MHC/peptide ligand. Cell 1996; 84: 521–529 [DOI] [PubMed] [Google Scholar]
- 76. Hu Q, Bazemore Walker CR, Girao C, et al. Specific recognition of thymic self‐peptides induces the positive selection of cytotoxic T lymphocytes. Immunity 1997; 7: 221–231 [DOI] [PubMed] [Google Scholar]
- 77. Kirberg J, Berns A, von Boehmer H. Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex‐encoded molecules. J Exp Med 1997; 186: 1269–1275 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Lohse AW, Dinkelmann M, Kimmig M, et al. Estimation of the frequency of self‐reactive T cells in health and inflammatory diseases by limiting dilution analysis and single cell cloning. J Autoimmun 1996; 9: 667–675 [DOI] [PubMed] [Google Scholar]
- 79. Dutton RW, Bradley LM, Swain SL. T cell memory. Annu Rev Immunol 1998; 16: 201–223 [DOI] [PubMed] [Google Scholar]
- 80. Traugott U, Scheinberg LC, Raine CS. On the presence of Ia‐positive endothelial cells and astrocytes in multiple sclerosis lesions and its relevance to antigen presentation. J Neuroimmunol 1985; 8: 1–14 [DOI] [PubMed] [Google Scholar]
- 81. De Simone R, Giampaolo A, Giometto B, et al. The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions. J Neuropathol Exp Neurol 1995; 54: 175–187 [DOI] [PubMed] [Google Scholar]
- 82. Horwitz MS, Bradley LM, Harbertson J, et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat Med 1998; 4: 781–785 [DOI] [PubMed] [Google Scholar]
- 83. Evans CF, Horwitz MS, Hobbs MV, Oldstone MBA. Viral infection of transgenic mice expressing a viral protein in oligodendrocytes leads to chronic central nervous system autoimmune disease. J Exp Med 1996; 184: 2371–2384 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84. Targoni OS, Lehmann PV. Endogenous myelin basic protein inactivates the high avidity T cell repertoire. J Exp Med 1998; 187: 2055–2063 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85. Lee SC, Raine CS. Multiple sclerosis: oligodendrocytes in active lesions do not express class II major histocompatibility complex molecules. J Neuroimmunol 1989; 25: 261–266 [DOI] [PubMed] [Google Scholar]
- 86. Ohashi PS, Oehen S, Buerki K, et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 1991; 65: 305–317 [DOI] [PubMed] [Google Scholar]
- 87. Oldstone MBA, Nerenberg M, Southern P, et al. Virus infection triggers insulin‐dependent diabetes mellitus in a transgenic model: role of anti‐self (virus) immune response. Cell 1991; 65: 319–331 [DOI] [PubMed] [Google Scholar]
- 88. Johnson RT. The virology of demyelinating diseases. Ann Neurol 1994; 36(Suppl): S54–S60 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89. Sobel RA, Hafler DA, Castro EE, et al. The 2H4 (CD45R) antigen is selectively decreased in multiple sclerosis lesions. J Immunol 1988; 140: 2210–2214 [PubMed] [Google Scholar]
- 90. Bevilacqua MP. Endothelial‐leukocyte adhesion molecules. Annu Rev Immunol 1993; 11: 767–804 [DOI] [PubMed] [Google Scholar]
- 91. Cannella B, Cross AH, Raine CS. Adhesion‐related molecules in the central nervous system. Upregulation correlates with inflammatory cell influx during relapsing experimental autoimmune encephalomyelitis. Lab Invest 1991; 65: 23–31 [PubMed] [Google Scholar]
- 92. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T‐cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992; 358: 155–157 [DOI] [PubMed] [Google Scholar]
- 93. Vanderlugt CJ, Miller SD. Epitope spreading. Curr Opin Immunol 1996; 8: 831–836 [DOI] [PMC free article] [PubMed] [Google Scholar]