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Immunopathogenesis of Myasthenia Gravis

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Myasthenia Gravis and Related Disorders

Part of the book series: Current Clinical Neurology ((CCNEU))

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Abstract

Myasthenia gravis (MG) is a prototypic antibody-mediated autoimmune disease and also the best characterized such disease: autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction (NMJ) cause the myasthenic manifestations (1–4). Anti-AChR T-cells play a crucial role in the pathogenesis of MG, because they permit and modulate the synthesis of the high-affinity antibodies that cause AChR loss, damage of the NMJ, and failure of neuromuscular transmission. T-cells may even be the prime movers in MG pathogenesis, because activation of potentially self-reactive CD4+ T-cells, commonly present in healthy people, may trigger autoimmune responses. This might occur because of crossreactivity of self-reactive CD4+ T-cells with microbial antigens, or because of the action of microbial superantigens (5,6).

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References

  1. Conti-Fine BM, Bellone M, Howard JF Jr, Protti MP. Myasthenia Gravis: The Immunobiology of an Autoimmune Disease. Austin, TX, Neuroscience Intelligence Unit, RG Landes, 1997.

    Google Scholar 

  2. Engel AG. The Myasthenic Syndromes. New York, Oxford University Press, 1999.

    Google Scholar 

  3. Richman D. Myasthenia gravis and related diseases. Disorders of the neuromuscular junction. Ann NY Acad Sci 1998; 841: 1–838.

    Article  Google Scholar 

  4. Oosterhuis HJGH. Myasthenia gravis. Groningen, Neurological Press, 1997.

    Google Scholar 

  5. Oldstone MB. Molecular mimicry and immune-mediated diseases. FASEB J 1998; 12: 1255–1265.

    PubMed  CAS  Google Scholar 

  6. Brocke S, Hausmann S, Steinman L, Wucherpfennig KW. Microbial peptides and superantigens in the pathogenesis of autoimmune diseases of the central nervous system. Semin Immunol 1998; 10: 57–67.

    Article  PubMed  CAS  Google Scholar 

  7. Mokhtarian F, Pino M, Ofosu-Appiah W, Grob D. Phenotypic and functional characterization of T cells from patients with myasthenia gravis. J Clin Invest 1990; 86: 2099–2108.

    Article  PubMed  CAS  Google Scholar 

  8. Toyka KV, Drachman DB, Griffin DE, et al. Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N ngEl J Med 1977; 296: 125–131.

    Article  CAS  Google Scholar 

  9. Lindstrom JM, Engel AG, Seybold ME, Lennon VA, Lambert EH. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine receptor antibodies. J Exp Med 1976; 144: 739–753.

    Article  PubMed  CAS  Google Scholar 

  10. Oda K, Korenaga S, Ito Y. Myasthenia gravis: passive transfer to mice of antibody to human and mouse acetylcholine receptor. Neurology 1981; 31: 282–287.

    Article  PubMed  CAS  Google Scholar 

  11. Lennon VA, Lambert EH. Myasthenia gravis induced by monoclonal antibodies to acetylcholine receptors. Nature 1980; 285: 238–240.

    Article  PubMed  CAS  Google Scholar 

  12. Cornelio F, Antozzi C, Confalonieri P, Baggi F, Mantegazza R. Plasma treatment in diseases of the neuromuscular junction. Ann NY Acad Sci 1998; 841: 803–810.

    Article  PubMed  CAS  Google Scholar 

  13. Soliven BC, Lange DJ, Penn AS, et al. Seronegative myasthenia gravis. Neurology 1998; 38: 514–517.

    Article  Google Scholar 

  14. Wang ZY, Karachunski PI, Howard JF Jr, Conti-Fine BM. Myasthenia in SCID mice grafted with myasthenic patient lymphocytes. Role of CD4+ and CD8+ cells. Neurology 1999; 52: 484–497.

    Article  PubMed  CAS  Google Scholar 

  15. Hoch W, McConville J, Helms S, et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001; 7: 365–368.

    Article  PubMed  CAS  Google Scholar 

  16. Lindstrom JM. Acetylcholine receptors and myasthenia. Muscle Nerve 2000; 23: 453–477.

    Article  PubMed  CAS  Google Scholar 

  17. Tzartos SJ, Barkas T, Cung MT, et al. The main immunogenic region of the acetylcholine receptor. Structure and role in myasthenia gravis. Autoimmunity 1991; 8: 259–270.

    Article  PubMed  CAS  Google Scholar 

  18. Beroukhim R, Unwin N. Three-dimensional location of the main immunogenic region of the acetylcholine receptor. Neuron 1995; 15: 323–331.

    Article  PubMed  CAS  Google Scholar 

  19. Lindstrom J, Einarson B. Antigenic modulation and receptor loss in experimental autoimmune myasthenia gravis. Muscle Nerve 1979; 2: 173–179.

    Article  PubMed  CAS  Google Scholar 

  20. Conti-Tronconi BM, Tzartos S, Lindstrom JM. Monoclonal antibodies as a probe of acetylcholine receptor structure. 2. Binding to native receptor. Biochemistry 1981; 20: 2181–2186.

    Article  PubMed  CAS  Google Scholar 

  21. Tzartos SJ, Sophianos D, Efthimiadis A. Role of the main immunogenic region of acetylcholine receptor in myasthenia gravis. An Fab monoclonal antibody protects against antigenic modulation by human sera. J Immunol 1985; 134: 2343–2349.

    PubMed  CAS  Google Scholar 

  22. Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330: 1797–1810.

    Article  PubMed  CAS  Google Scholar 

  23. Lennon VA, Seybold ME, Lindstrom JM, Cochrane C, Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med 1978; 147: 973–983.

    Article  PubMed  CAS  Google Scholar 

  24. Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. Ann NY Acad Sci 1987; 505: 326–332.

    Article  PubMed  CAS  Google Scholar 

  25. Karachunski PI, Ostlie NS, Monfardini C, Conti-Fine BM. Absence of IFN-y or IL-12 has different effects on experimental myasthenia gravis in C57BL 6 mice. J Immunol 2000; 164: 5236–5244.

    PubMed  CAS  Google Scholar 

  26. Conti-Tronconi BM, McLane KE, Raftery MA, Grando SA, Protti MP. The nicotinic acetylcholine receptor: structure and autoimmune pathology. Crit Rev Biochem Mol Biol 1994; 29: 69–123.

    Article  PubMed  CAS  Google Scholar 

  27. Lindstrom JM, Einarson BL, Lennon VA, Seybold ME. Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis. J Exp Med 1976; 144: 726–738.

    Article  PubMed  CAS  Google Scholar 

  28. Granato DA, Fulpius BW, Moody JF. Experimental myasthenia in Balb c mice immunized with rat acetylcholine receptor from rat denervated muscle. Proc Natl Acad Sci USA 1976; 73: 2872–2876.

    Article  PubMed  CAS  Google Scholar 

  29. Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science 1973; 180: 871–872.

    Article  PubMed  CAS  Google Scholar 

  30. Tarrab-Hazdai R, Aharonov A, Abramsky O, Silman I, Fuchs S. Proceedings: animal model for myasthenia gravis: acetylcholine receptor-induced myasthenia in rabbits, guinea pigs and monkeys. Isr J Med Sci 1975; 11: 1390.

    CAS  Google Scholar 

  31. Lennon VA, Lindstrom JM, Seybold ME. Experimental autoimmune myasthenia: a model of myasthenia gravis in rats and guinea pigs. J Exp Med 1975; 141: 1365–1375.

    Article  PubMed  CAS  Google Scholar 

  32. Berman PW, Patrick J. Experimental myasthenia gravis. A murine system. J Exp Med 1980; 151: 204–223.

    Article  PubMed  CAS  Google Scholar 

  33. Zoda T, Yeh TM, Krolick KA. Clonotypic analysis of anti-acetylcholine receptor antibodies from experimental autoimmune myasthenia gravis-sensitive Lewis rats and experimental autoimmune myasthenia gravis-resistant Wistar Furth rats. J Immunol 1991; 146: 663–670.

    PubMed  CAS  Google Scholar 

  34. Biesecker G, Koffler D. Resistance to experimental autoimmune myasthenia gravis in genetically inbred rats. Association with decreased amounts of in situ acetylcholine receptor-antibody complexes. J Immunol 1988; 140: 3406–3410.

    PubMed  CAS  Google Scholar 

  35. Christadoss P, Krco CJ, Lennon VA, David CS. Genetic control of experimental autoimmune myasthenia gravis in mice. II. Lymphocyte proliferative response to acetylcholine receptor is dependent on Lyt-1+23- cells. J Immunol 1981;126:1646– 1647.

    Google Scholar 

  36. Fuchs S, Nevo D, Tarrab-Hazdai R, Yaar I. Strain differences in the autoimmune response of mice to acetylcholine receptors. Nature 1976; 263: 329–330.

    Article  PubMed  CAS  Google Scholar 

  37. Christadoss P, Lindstrom JM, Melvold RW, Talal N. Mutation at I-A R chain prevents experimental autoimmune myasthenia gravis. Immunogenetics 1985; 21: 33–38.

    Article  PubMed  CAS  Google Scholar 

  38. Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976; 26: 1054–1059.

    Article  PubMed  CAS  Google Scholar 

  39. Roses AD, Olanow CW, McAdams MW, Lane RJ. No direct correlation between serum antiacetylcholine receptor antibody levels and clinical state of individual patients with myasthenia gravis. Neurology 1981; 31: 220–224.

    Article  PubMed  CAS  Google Scholar 

  40. Bellone M, Ostlie N, Lei SJ, Wu XD, Conti-Tronconi BM. The I-Abm12 mutation, which confers resistance to experimental myasthenia gravis, drastically affects the epitope repertoire of murine CD4+ cells sensitized to nicotinic acetylcholine receptor. J Immunol 1991; 147: 1484–1491.

    PubMed  CAS  Google Scholar 

  41. Karachunski PI, Ostlie NS, Okita DK, Conti-Fine BM. Interleukin-4 deficiency facilitates development of experimental myasthenia gravis and precludes its prevention by nasal administration of CD4+ epitope sequences of the acetylcholine receptor. J Neuroimmunol 1999; 95: 73–84.

    Article  PubMed  CAS  Google Scholar 

  42. Tzartos S, Hochschwender S, Vasquez P, Lindstrom J. Passive transfer of experimental autoimmune myasthenia gravis by monoclonal antibodies to the main immunogenic region of the acetylcholine receptor. J Neuroimmunol 1987;15:185– 194.

    Google Scholar 

  43. Tzartos SJ, Kokla A, Walgrave SL, Conti-Tronconi BM. Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67–76 of the a subunit. Proc Natl Acad Sci USA 1988; 85: 2899–2903.

    Article  PubMed  CAS  Google Scholar 

  44. Bellone M, Tang F, Milius R, Conti-Tronconi BM. The main immunogenic region of the nicotinic acetylcholine receptor. Identification of amino acid residues interacting with different antibodies. J Immunol 1989; 143: 3568–3579.

    PubMed  CAS  Google Scholar 

  45. Barkas T, Gabriel JM, Mauron A, et al. Monoclonal antibodies to the main immunogenic region of the nicotinic acetylcholine receptor bind to residues 61–76 of the a subunit. J Biol Chem 1988; 263: 5916–5920.

    PubMed  CAS  Google Scholar 

  46. Manfredi AA, Bellone M, Protti MP, Conti-Tronconi BM. Molecular mimicry among human autoantigens. Immunol Today 1991; 12: 46–47.

    Article  PubMed  CAS  Google Scholar 

  47. Gomez CM, Richman DP. Anti-acetylcholine receptor antibodies directed against the a-bungarotoxin binding site induce a unique form of experimental myasthenia. Proc Natl Acad Sci USA 1983; 80: 4089–4093.

    Article  PubMed  CAS  Google Scholar 

  48. Conti-Fine BM, Kaminski HJ. Neuroimmunology. Continuum 2001; 7: 56–95.

    Google Scholar 

  49. Walker MB. Case showing the effect of prostigmin on myasthenia gravis. Proc R Soc Med 1935; 28: 759–751.

    PubMed  CAS  Google Scholar 

  50. Poea S, Guyon T, Bidault J, et al. Modulation of acetylcholine receptor expression in seronegative myasthenia gravis. Ann Neurol 2000; 48: 696–705.

    Article  PubMed  CAS  Google Scholar 

  51. Aarli JA, Skeie GO, Mygland A, Gilhus NE. Muscle striation antibodies in myasthenia gravis. Diagnostic and functional significance. Ann NY Acad Sci 1998; 841: 505–515.

    Article  PubMed  CAS  Google Scholar 

  52. Link H, Sun JB, Lu CZ, et al. Myasthenia gravis: T and B cell reactivities to the abungarotoxin binding protein presynaptic membrane receptor. J Neurol Sci 1992; 109: 173–181.

    Article  PubMed  CAS  Google Scholar 

  53. Takaya M, Kawahara S, Namba T, Grob D. Antibodies against myofibrillar proteins in myasthenia gravis patients. J Exp Clin Med 1992; 17: 35–39.

    CAS  Google Scholar 

  54. Mohan S, Barohn RJ, Jackson CE, Krolick KA. Evaluation of myosin-reactive antibodies from a panel of myasthenia gravis patients. Clin Immunol Immunopathol 1994; 70: 266–273.

    Article  PubMed  CAS  Google Scholar 

  55. Mohan S, Barohn RJ, Krolick KA. Unexpected cross-reactivity between myosin and a main immunogenic region (MIR) of the acetylcholine receptor by antisera obtained from myasthenia gravis patients. Clin Immunol Immunopathol 1992; 64: 218–226.

    Article  PubMed  CAS  Google Scholar 

  56. Kuks JB, Limburg PC, Horst G, Dijksterhuis J, Oosterhuis HJ. Antibodies to skeletal muscle in myasthenia gravis. Part 1. Diagnostic value for the detection of thymoma. J Neurol Sci 1993; 119: 183–188.

    Article  PubMed  CAS  Google Scholar 

  57. Aarli JA. Titin, thymoma, and myasthenia gravis. Arch Neurol 2001; 58: 869–870.

    Article  Google Scholar 

  58. Skeie GO. Skeletal muscle titin: physiology and pathophysiology. Cell Mol Lfei Sci 2000; 57: 1570–1576.

    Article  CAS  Google Scholar 

  59. Baggi F, Andreetta F, Antozzi C, et al. Anti-titin and antiryanodine receptor antibodies in myasthenia gravis patients with thymoma. Ann NY Acad Sci 1998; 841: 538–541.

    Article  PubMed  CAS  Google Scholar 

  60. Hohlfeld R, Toyka KV, Miner LL, Walgrave SL, Conti-Tronconi BM. Amphipathic segment of the nicotinic receptor alpha subunit contains epitopes recognized by T lymphocytes in myasthenia gravis. J Clin Invest 1988; 81: 657–660.

    Article  PubMed  CAS  Google Scholar 

  61. Ahlberg R, Yi Q, Pirskanen R, et al. Treatment of myasthenia gravis with anti-CD4 antibody: improvement correlates to decreased T-cell autoreactivity. Neurology 1994; 44: 1732–1737.

    Article  PubMed  CAS  Google Scholar 

  62. Morgutti M, Conti-Tronconi BM, Sghirlanzoni A, Clementi F. Cellular immune response to acetylcholine receptor in myasthenia gravis: II. Thymectomy and corticosteroids. Neurology 1979; 29: 734–738.

    Article  PubMed  CAS  Google Scholar 

  63. Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 55: 7–15.

    Article  PubMed  CAS  Google Scholar 

  64. Hohlfeld R, Kalies I, Ernst M, Ketelsen UP, Wekerle H. T-lymphocytes in experimental autoimmune myasthenia gravis. Isolation of T-helper cell lines. J Neurol Sci 1982; 57: 265–280.

    Article  PubMed  CAS  Google Scholar 

  65. Zhang GX, Xiao BG, Bakhiet M, et al. Both CD4+ and CD8+ T cells are essential to induce experimental autoimmune myasthenia gravis. J Exp Med 1996;184:349– 356.

    Google Scholar 

  66. Kaul R, Shenoy M, Goluszko E, Christadoss P. Major histocompatibility complex class II gene disruption prevents experimental autoimmune myasthenia gravis. J Immunol 1994; 152: 3152–3157.

    PubMed  CAS  Google Scholar 

  67. Simpson E, Farrant J, Chandler P. Phenotypic and functional studies of human peripheral blood lymphocytes engrafted in SCID mice. Immunol Rev 1991; 124: 97–111.

    Article  PubMed  CAS  Google Scholar 

  68. Schonbeck S, Padberg F, Hohlfeld R, Wekerle H. Transplantation of thymic autoimmune microenvironment to severe combined immunodeifciency mice. A new model of myasthenia gravis. J Clin Invest 1992; 90: 245–250.

    Article  PubMed  CAS  Google Scholar 

  69. Martino G, DuPont BL, Wollmann RL, et al. The human-severe combined immunodeficiency myasthenic mouse model: a new approach for the study of myasthenia gravis. Ann Neurol 1993; 34: 48–56.

    Article  PubMed  CAS  Google Scholar 

  70. 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.

    Article  PubMed  CAS  Google Scholar 

  71. Martin R, Jaraquemada D, Flerlage M, et al. Fine speciifcity 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  CAS  Google Scholar 

  72. Sommer N, Harcourt GC, Willcox N, Beeson D, Newsom-Davis J. Acetylcholine receptor-reactive T lymphocytes from healthy subjects and myasthenia gravis patients. Neurology 1991; 41: 1270–1276.

    Article  PubMed  CAS  Google Scholar 

  73. Kellermann SA, McCormick DJ, Freeman SL, Morris JC, Conti-Fine BM. TSH receptor sequences recognized by CD4+ T cells in Graves’ disease patients and healthy controls. J Autoimmun 1995; 8: 685–698.

    Article  PubMed  CAS  Google Scholar 

  74. Marrack P. T cell tolerance. Harvey Lect 1993–94;89:147–155.

    Google Scholar 

  75. Conti-Fine BM, Navaneetham D, Karachunski PI, et al. T cell recognition of the acetylcholine receptor in myasthenia gravis. Ann NY Acad Sci 1998; 841: 283–308.

    Article  PubMed  CAS  Google Scholar 

  76. Diethelm-Okita B, Wells GB, Kuryatov A, et al. Response of CD4+ T cells from myasthenic patients and healthy subjects of biosynthetic and synthetic sequences of the nicotinic acetylcholine receptor. J Autoimmun 1998; 11: 191–203.

    Article  PubMed  CAS  Google Scholar 

  77. Fujii Y, Lindstrom J. Specificity of the T cell immune response to acetylcholine receptor in experimental autoimmune myasthenia gravis. Response to subunits and synthetic peptides. J Immunol 1988; 140: 1830–1837.

    CAS  Google Scholar 

  78. Oshima M, Pachner AR, Atassi MZ. Profile of the regions of acetylcholine receptor a chain recognized by T-lymphocytes and by antibodies in EAMG-susceptible and non-susceptible mouse strains after different periods of immunization with the receptor. Mol Immunol 1994; 31: 833–843.

    Article  PubMed  CAS  Google Scholar 

  79. Bellone M, Ostlie N, Lei S, Conti-Tronconi BM. Experimental myasthenia gravis in congenic mice: sequence mapping and H-2 restriction of T helper epitopes on the a-subunits of Torpedo calforinica and murine acetylcholine receptor. Eur J Immunol 1991; 21: 2303–2310.

    Article  PubMed  CAS  Google Scholar 

  80. Bellone M, Ostlie N, Karachunski P, Manfredi AA, Conti-Tronconi BM. Cryptic epitopes on the nicotinic acetylcholine receptor are recognized by autoreactive CD4+ cells. J Immunol 1993; 151: 1025–1038.

    PubMed  CAS  Google Scholar 

  81. Vanderlugt CL, Begolka WS, Neville KL, et al. The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol Rev 1998; 64: 63–72.

    Article  Google Scholar 

  82. Hohlfeld R, Toyka KV, Tzartos SJ, Carson W, Conti-Tronconi BM. Human T-helper lymphocytes in myasthenia gravis recognize the nicotinic receptor α subunit. Proc Natl Acad Sci USA 1987; 84: 5379–5383.

    Article  PubMed  CAS  Google Scholar 

  83. Manfredi AA, Protti MP, Wu XD, Howard JF Jr, Conti-Tronconi BM. CD4+ T-epitope repertoire on the human acetylcholine receptor α subunit in severe myasthenia gravis: a study with synthetic peptides. Neurology 1992; 42: 1092–1100.

    Article  PubMed  CAS  Google Scholar 

  84. Manfredi AA, Protti MP, Dalton MW, Howard JF Jr, Conti-Tronconi BM. T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on theã and ä-subunits. J Clin Invest 1993; 92: 1055–1067.

    Article  PubMed  CAS  Google Scholar 

  85. Wang ZY, Okita DK, Howard J Jr, Conti-Fine BM. T-cell recognition of muscle acetylcholine receptor subunits in generalized and ocular myasthenia gravis. Neurology1998; 50: 1045–1054.

    Google Scholar 

  86. Wang ZY, Okita DK, Howard JF Jr, Conti-Fine BM. CD4+ T cell repertoire on the å subunit of muscle acetylcholine receptor in myasthenia gravis. J Neuroimmunol 1998; 91: 33–42.

    Article  PubMed  CAS  Google Scholar 

  87. Wang ZY, Diethelm-Okita B, Okita DK, et al. T cell recognition of muscle acetylcholine receptor in ocular myasthenia gravis. J Neuroimmunol 2000; 108: 29–39.

    Article  PubMed  CAS  Google Scholar 

  88. Horton RM, Manfredi AA, Conti-Tronconi BM. The ‘embryonic’ γ subunit of the nicotinic acetylcholine receptor is expressed in adult extraocular muscle. Neurology 1993; 43: 983–986.

    Article  PubMed  CAS  Google Scholar 

  89. Kaminski HJ, Fenstermaker R, Ruff RL. Adult extraocular and intercostal muscle express theã subunit of fetal AChR. Biophys J 1991; 59: 444a.

    Google Scholar 

  90. Nelson S, Conti-Tronconi BM. Adult thymus expresses an embryonic nicotinic acetylcholine receptor-like protein. J Neuroimmunol 1990; 29: 81–92.

    Article  PubMed  CAS  Google Scholar 

  91. Geuder KI, Marx A, Witzemann V, et al. Pathogenetic signiifcance of fetal-type acetylcholine receptors on thymic myoid cells in myasthenia gravis. Dev Immunol 1992; 2: 69–75.

    Article  PubMed  CAS  Google Scholar 

  92. Protti MP, Manfredi AA, Straub C, et al. Use of synthetic peptides to establish antihuman acetylcholine receptor CD4+ cell lines from myasthenia gravis patients. J Immunol 1990; 144: 1711–1720.

    PubMed  CAS  Google Scholar 

  93. Protti MP, Manfredi AA, Straub C, Howard JF Jr, Conti-Tronconi BM. Immunodominant regions for T helper-cell sensitization on the human nicotinic receptor α subunit in myasthenia gravis. Proc Natl Acad Sci USA 1990; 87: 7792–7796.

    Article  PubMed  CAS  Google Scholar 

  94. Protti MP, Manfredi AA, Wu XD, et al. Myasthenia gravis. T epitopes on the δ subunit of human muscle acetylcholine receptor. J Immunol 1991; 146: 2253–2261.

    PubMed  CAS  Google Scholar 

  95. Protti MP, Manfredi AA, Howard JF Jr, Conti-Tronconi BM. T cells in myasthenia gravis specific for embryonic acetylcholine receptor. Neurology 1991;41:1809– 1814.

    Google Scholar 

  96. Protti MP, Manfredi AA, Wu XD, et al. Myasthenia gravis. CD4+ T epitopes on the embryonic ã subunit of human muscle acetylcholine receptor. J Clin Invest 1992; 90: 1558–1567.

    Article  PubMed  CAS  Google Scholar 

  97. Moiola L, Karachunski P, Protti MP, Howard JF Jr, Conti-Tronconi BM. Epitopes on the ß subunit of human muscle acetylcholine receptor recognized by CD4+ cells of myasthenia gravis patients and healthy subjects. J Clin Invest 1994; 93: 1020–1028.

    Article  PubMed  CAS  Google Scholar 

  98. Collins EJ, Frelinger JA. Altered peptide ligand design: altering immune responses to class I MHC peptide complexes. Immunol Rev 1998; 163: 151–160.

    Article  PubMed  CAS  Google Scholar 

  99. Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 1995; 3: 397–405.

    Article  PubMed  CAS  Google Scholar 

  100. Tsitoura DC, Holter W, Cerwenka A, Gelder CM, Lamb JR. Induction of anergy in human T helper 0 cells by stimulation with altered T cell antigen receptor ligands. J Immunol 1996; 156: 2801–2808.

    PubMed  CAS  Google Scholar 

  101. Wang ZY, Okita DK, Howard J Jr, Conti-Fine BM. Th1 epitope repertoire on the a subunit of human muscle acetylcholine receptor in myasthenia gravis. Neurology 1997; 48: 1643–1653.

    Article  PubMed  CAS  Google Scholar 

  102. Diethelm-Okita BM, Okita DK, Banaszak L, Conti-Fine BM. Universal epitopes for human CD4+ cells on tetanus and diphtheria toxins. J Infect Dis 2000; 181: 1001–1009.

    Article  PubMed  CAS  Google Scholar 

  103. Sommer N, Melms A, Weller M, Dichgans J. Ocular myasthenia gravis. A critical review of clinical and pathological aspects. Documenta Ophthalmol 1993; 84: 309–333.

    Article  CAS  Google Scholar 

  104. Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis? Neurology 1990; 40: 1663–1669.

    Article  PubMed  CAS  Google Scholar 

  105. Kaminski HJ, Ruff RL. Ocular muscle involvement by myasthenia gravis. Ann Ne urol 1997; 41: 419–420.

    Article  CAS  Google Scholar 

  106. Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes: experiments of nature. J Physiol Paris 1998; 92: 113–117.

    Article  PubMed  CAS  Google Scholar 

  107. Kaminski HJ, Kusner LL, Block CH. Expression of acetylcholine receptor isoforms at extraocular muscle endplates. Invest Ophthalmol Vis Sci 1996; 37: 345–351.

    PubMed  CAS  Google Scholar 

  108. Kaminski HJ, Kusner LL, Nash KV, Ruff RL. They-subunit of the acetylcholine receptor is not expressed in the levator palpebrae superioris. Neurology 1995; 45: 516–518.

    Article  PubMed  CAS  Google Scholar 

  109. MacLennan C, Beeson D, Buijs AM, Vincent A, Newsom-Davis J. Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis. Ann Neurol 1997; 41: 423–431.

    Article  PubMed  CAS  Google Scholar 

  110. Raju R, Navaneetham D, Protti MP, et al. TCR V ß usage by acetylcholine receptor-specific CD4+ T cells in myasthenia gravis. J Autoimmun 1997; 10: 203–217.

    Article  PubMed  CAS  Google Scholar 

  111. Melms A, Oksenberg JR, Malcherek G, et al. T-cell receptor gene usage of acetylcholine receptor-specific T-helper cells. Ann NY Acad Sci 1993; 681: 313–314.

    Article  PubMed  CAS  Google Scholar 

  112. Garcia KC, Teyton L, Wilson IA. Structural basis of T cell recognition. Annu Rev Immun ol 1999; 17: 369–397.

    Article  CAS  Google Scholar 

  113. Li H, Llera A, Malchiodi EL, Mariuzza RA. The structural basis of T cell activation by superantigens. Annu Rev Immunol 1999; 17: 435–466.

    Article  PubMed  CAS  Google Scholar 

  114. Hennecke J, Wiley DC. T cell receptor-MHC interactions up close. Cell 2001; 104: 1–4.

    Article  PubMed  CAS  Google Scholar 

  115. Wei S, Charmley P, Robinson MA, Concannon P. The extent of the human germ-line T-cell receptor V O gene segment repertoire. Immunogenetics 1994; 40: 27–36.

    Article  PubMed  CAS  Google Scholar 

  116. Papageorgiou AC, Acharya KR. Microbial superantigens: from structure to function. Trends Microbiol 2000; 8: 369–375.

    Article  PubMed  CAS  Google Scholar 

  117. Rose NR. The role of infection in the pathogenesis of autoimmune disease. Semin Immun ol 1998; 10: 5–13.

    Article  CAS  Google Scholar 

  118. Todd JA, Steinman L. The enviroment strikes back. Curr Opin Immunol 1993; 5: 863–865.

    Article  PubMed  CAS  Google Scholar 

  119. Blackman MA, Woodland DL. Role of the T cell receptor α-chain in superantigen recognition. Immunol Res 1996; 15: 98–113.

    Article  PubMed  CAS  Google Scholar 

  120. Tesch H, Hohlfeld R, Toyka KV. Analysis of immunoglobulin and T cell receptor gene rearrangements in the thymus of myasthenia gravis patients. J Neuroimmunol 1989; 21: 169–176.

    Article  PubMed  CAS  Google Scholar 

  121. Grunewald J, Ahlberg R, Lefvert AK, et al. Abnormal T-cell expansion and V-gene usage in myasthenia gravis patients. J Immunol 1991; 34: 161–168.

    CAS  Google Scholar 

  122. Truffault F, Cohen-Kaminsky S, Khalil I, Levasseur P, Berrih-Aknin S. Altered intra-thymic T-cell repertoire in human myasthenia gravis. Ann Neurol 1997; 41: 731–741.

    Article  PubMed  CAS  Google Scholar 

  123. Xu BY, Giscombe R, Soderlund A, et al. Abnormal T cell receptor V gene usage in myasthenia gravis: prevalence and characterization of expanded T cell populations. Clin Exp Immunol 1998; 113: 456–464.

    Article  PubMed  CAS  Google Scholar 

  124. Navaneetham D, Penn AS, Howard JF Jr, Conti-Fine BM. TCR-V â usage in the thymus and blood of myasthenia gravis patients. J Autoimmun 1998; 11: 621–633.

    Article  PubMed  CAS  Google Scholar 

  125. Navaneetham D, Diethelm-Okita B, Protti MP, Conti-Fine BM. Manuscript in preparation.

    Google Scholar 

  126. Yang XD, Tisch R, McDevitt HO. Selective targets for immunotherapy in autoimmune disease. Chem Immunol 1995; 60: 20–31.

    Article  PubMed  CAS  Google Scholar 

  127. Vandenbark AA, Hashim GA, Offner H. T cell receptor peptides in treatment of autoimmune disease: rationale and potential. J Neurosci Res 1996; 43: 391–402.

    Article  PubMed  CAS  Google Scholar 

  128. Miller SD, McRae BL, Vanderlugt CL, et al. Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunol Rev 1995; 144: 225–244.

    Article  PubMed  CAS  Google Scholar 

  129. Dong C, Flavell RA. Th1 and Th2 cells. Curr Opin Hematol 2001; 8: 47–51.

    Article  PubMed  CAS  Google Scholar 

  130. Feldmann M, Brennan FM, Maini R. Cytokines in autoimmune disorders. Int Rev Immunol 1998; 17: 217–228.

    Article  PubMed  CAS  Google Scholar 

  131. O’ Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998; 8: 275–283.

    Article  Google Scholar 

  132. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383: 787–793.

    Article  PubMed  CAS  Google Scholar 

  133. Yi Q, Ahlberg R, Pirskanen R, Lefvert AK. Acetylcholine receptor-reactive T cells in myasthenia gravis: evidence for the involvement of different subpopulations of T helper cells. J Neuroimmunol 1994; 50: 1771–1786.

    Article  Google Scholar 

  134. Yi Q, Lefvert AK. Idiotype-and anti-idiotype-reactive T lymphocytes in myasthenia gravis. Evidence for the involvement of different subpopulations of T helper lymphocytes. J Immunol 1994; 153: 3353–3359.

    PubMed  CAS  Google Scholar 

  135. Link J, Fredrikson S, Soderstrom M, et al. Organ-speciifc autoantigens induce transforming growth factor-â mRNA expression in mononuclear cells in multiple sclerosis and myasthenia gravis. Ann Neurol 1994; 35: 197–203.

    Article  PubMed  CAS  Google Scholar 

  136. Moiola L, Protti MP, McCormick D, Howard JF, Conti-Tronconi BM. Myasthenia gravis. Residues of the á and ã subunits of muscle acetylcholine receptor involved in formation of immunodominant CD4+ epitopes. J Immunol 1994; 152: 4686–4698.

    PubMed  CAS  Google Scholar 

  137. Moiola L, Galbiati F, Martino G, et al. IL-12 is involved in the induction of experimental autoimmune myasthenia gravis, an antibody-mediated disease. Eur J Immunol1998; 28: 2487–2497.

    Google Scholar 

  138. Balasa B, Deng C, Lee J, et al. Interferon y (IFN-y) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J Exp Med 1997; 186: 385–391.

    Article  PubMed  CAS  Google Scholar 

  139. Balasa B, Deng C, Lee J, Christadoss P, Sarvetnick N. The Th2 cytokine IL-4 is not required for the progression of antibody-dependent autoimmune myasthenia gravis. J Immunol 1998; 161: 2856–2862.

    PubMed  CAS  Google Scholar 

  140. Zhang GX, Xiao BG, Bai XF, et al. Mice with IFN-y receptor deficiency are less susceptible to experimental autoimmune myasthenia gravis. J Immunol 1999; 162: 3775–3781.

    PubMed  CAS  Google Scholar 

  141. Ostlie NS, Karachunski PI, Wang W, et al. Transgenic expression of IL-10 in T cells facilitates development of experimental myasthenia gravis. J Immunol 2001; 166: 4853–4862.

    PubMed  CAS  Google Scholar 

  142. Sitaraman S, Metzger DW, Belloto RJ, Infante AJ, Wall KA. Interleukin-12 enhances clinical experimental autoimmune myasthenia gravis in susceptible but not resistant mice. J Neuroimmunol 2000; 107: 73–82.

    Article  PubMed  CAS  Google Scholar 

  143. Karachunski PI, Ostlie NS, Okita DK, Conti-Fine BM. Prevention of experimental myasthenia gravis by nasal administration of synthetic acetylcholine receptor T epitope sequences. J Clin Invest 1997; 100: 3027–3035.

    Article  PubMed  CAS  Google Scholar 

  144. Baggi F, Andreetta F, Caspani E, et al. Oral administration of an immunodominant T-cell epitope downregulates Th1 Th2 cytokines and prevents experimental myasthenia gravis. J Clin Invest 1999; 104: 1287–1295.

    Article  PubMed  CAS  Google Scholar 

  145. Im SH, Barchan D, Fuchs S, Souroujon MC. Mechanism of nasal tolerance induced by a recombinant fragment of acetylcholine receptor for treatment of experimental myasthenia gravis. J Neuroimmunol 2000; 111: 161–168.

    Article  PubMed  CAS  Google Scholar 

  146. Wang ZY, Link H, Ljungdahl A, et al. Induction of interferon-y, interleukin-4, and transforming growth factor-O in rats orally tolerized against experimental autoimmune myasthenia gravis. Cell Immunol 1994; 157: 353–368.

    Article  PubMed  CAS  Google Scholar 

  147. Karachunski PI, Ostlie NS, Okita DK, Garman R, Conti-Fine BM. Subcutaneous administration of T-epitope sequences of the acetylcholine receptor prevents experimental myasthenia gravis. J Neuroimmunol 1999; 93: 108–121.

    Article  PubMed  CAS  Google Scholar 

  148. Im SH, Barchan D, Fuchs S, Souroujon MC. Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment. J Clin Invest 1999; 104: 1723–1730.

    Article  PubMed  CAS  Google Scholar 

  149. Monfardini C, Milani M, Ostlie N, et al. Adoptive protection from experimental myasthenia gravis with T cells from mice treated nasally with acetylcholine receptor epitopes. J Neuroimmunol 2002; 123: 123–134.

    Article  PubMed  CAS  Google Scholar 

  150. Hagenbaugh A, Sharma S, Dubinett SM, et al. Altered immune responses in interleukin 10 transgenic mice. J Exp Med 1997; 185: 2101–2110.

    Article  PubMed  CAS  Google Scholar 

  151. Poussin MA, Goluszko E, Hughes TK, Duchicella SI, Christadoss P. Suppression of experimental autoimmune myasthenia gravis in IL-10 gene-disrupted mice is associated with reduced B cells and serum cytotoxicity on mouse cell line expressing AChR. J Neuroimmunol 2000; 111: 152–160.

    Article  PubMed  CAS  Google Scholar 

  152. Ding L, Linsley PS, Huang LY, Germain RN, Shevach EM. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol 1993; 151: 1224–1234.

    PubMed  CAS  Google Scholar 

  153. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991; 147: 3815–3822.

    PubMed  CAS  Google Scholar 

  154. Macatonia SE, Doherty TM, Knight SC, O’Garra A. Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN-y production. J Immunol 1993; 150: 3755–3765.

    PubMed  CAS  Google Scholar 

  155. Enk AH, Angeloni VL, Udey MC, Katz SI. Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance. J Immunol 1993; 151: 2390–2398.

    PubMed  CAS  Google Scholar 

  156. Aste-Amezaga M, Ma X, Sartori A, Trinchieri G. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J Immunol 1998; 160: 5936–5944.

    PubMed  CAS  Google Scholar 

  157. de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993; 150: 4754–4765.

    PubMed  Google Scholar 

  158. Taga K, Mostowski H, Tosato G. Human interleukin-10 can directly inhibit T-cell growth. Blood 1993; 81: 2964–2971.

    PubMed  CAS  Google Scholar 

  159. Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996; 184: 19–29.

    Article  PubMed  CAS  Google Scholar 

  160. Schwartz RH. Models of T cell anergy: is there a common molecular mechanism? J Exp Med 1996; 184: 1–8.

    Article  PubMed  CAS  Google Scholar 

  161. Georgescu L, Vakkalanka RK, Elkon KB, Crow MK. Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand. J Clin Invest 1997; 100: 2622–2633.

    Article  PubMed  CAS  Google Scholar 

  162. Bromberg JS. IL-10 immunosuppression in transplantation. Curr Opin Immunol 1995; 7: 639–643.

    Article  PubMed  CAS  Google Scholar 

  163. Akdis CA, Blaser K. IL-10-induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. FASEB J1999; 13: 603–609.

    Google Scholar 

  164. Llorente L, Zou W, Levy Y, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 1995; 181: 839–844.

    Article  PubMed  CAS  Google Scholar 

  165. Cross JT, Benton HP. The roles of interleukin-6 and interleukin-10 in B cell hyperactivity in systemic lupus erythematosus. Inflamm Res 1999; 48: 255–261.

    Article  PubMed  CAS  Google Scholar 

  166. Huang YM, Kivisakk P, Ozenci V, Pirskanen R, Link H. Increased levels of circulating acetylcholine receptor (AChR)-reactive IL-10-secreting cells are characteristic for myasthenia gravis (MG). Clin Exp Immunol 1999; 118: 304–308.

    Article  PubMed  CAS  Google Scholar 

  167. Wogensen L, Lee MS, Sarvetnick N. Production of interleukin 10 by islet cells accelerates immune-mediated destruction of R cells in nonobese diabetic mice. J Exp Med 1994; 179: 1379–1384.

    Article  PubMed  CAS  Google Scholar 

  168. Moritani M, Yoshimoto K, Tashiro F, et al. Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int Immunol 1994; 6: 1927–1936.

    Article  PubMed  CAS  Google Scholar 

  169. Pennline KJ, Roque-Gaffney E, Monahan M. Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol 1994; 71: 169–175.

    Article  PubMed  CAS  Google Scholar 

  170. Moritani M, Yoshimoto K, Ii S, et al. Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes. J Clin Invest 1996; 98: 1851–1859.

    Article  PubMed  CAS  Google Scholar 

  171. Kong KM, Waldmann H, Cobbold S, et al. Pathogenic mechanisms in murine autoimmune thyroiditis: short-and long-term effects of in vivo depletion of CD4+ and CD8+ cells. Clin Exp Immunol 1989; 77: 428–433.

    PubMed  CAS  Google Scholar 

  172. Pummerer C, Berger P, Fruhwirth M, et al. Cellular infiltrate, major histocompatibility antigen expression and immunopathogenic mechanisms in cardiac myosin-induced myocarditis. Lab Invest 1991; 65: 538–547.

    PubMed  CAS  Google Scholar 

  173. Mozes E, Kohn LD, Hakim F, et al. Resistance of MHC class I-deficient mice to experimental systemic lupus erythematosus. Science 1993; 261: 91–93.

    Article  PubMed  CAS  Google Scholar 

  174. Rodriguez M, Dunkel AJ, Thiemann RL. Abrogation of resistance to Theiler’s virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin. J Immunol 1993; 151: 266–276.

    PubMed  CAS  Google Scholar 

  175. Shenoy M, Kaul R, Goluszko E, et al. Effect of MHC class I and CD8 cell deficiency on experimental autoimmune myasthenia gravis. J Immunol 1994; 153: 5330–5335.

    PubMed  CAS  Google Scholar 

  176. Shenoy M, Baron S, Wu B, et al. IFN-alpha treatment suppresses the development of experimental autoimmue myasthenia gravis. J Immunol 1995; 154: 6203–6208.

    PubMed  CAS  Google Scholar 

  177. Zhang GX, Ma CG, Xiao BG, et al. Depletion of CD8+ T cells suppresses the development of experimental autoimmune myasthenia gravis in Lewis rats. Eur J Immunol 1995; 25: 1191–1198.

    Article  PubMed  CAS  Google Scholar 

  178. Miller AE, Hudson J, Tindall RS. Immune regulation in myasthenia gravis: evidence for an increased suppressor T-cell population. Ann Neurol 1982; 12: 341–347.

    Article  PubMed  CAS  Google Scholar 

  179. Skolnik PR, Lisak RP, Zweiman B. Monoclonal antibody analysis of blood T-cell subsets in myasthenia gravis. Ann Neurol 1982; 11: 170–176.

    Article  PubMed  CAS  Google Scholar 

  180. Protti MP, Manfredi AA, Straub C, Howard JF Jr, Conti-Tronconi BM. CD4+ T cell response to human acetylcholine receptor a subunit correlates with myasthenia gravis severity. A study with synthetic peptides. J Immunol 1990;144:1276– 1281.

    Google Scholar 

  181. Lisak RP, Laramore C, Levinson AI, Zweiman B, Moskovitz AR. Suppressor T cells in myasthenia gravis and antibodies to acetylcholine receptor. Ann Neurol 1986; 19: 87–89.

    Article  PubMed  CAS  Google Scholar 

  182. Lisak RP, Laramore C, Levinson AI, et al. In vitro synthesis of antibodies to acetylcholine receptor by peripheral blood cells: role of suppressor T cells in normal subjects. Neurology 1984; 34: 802–805.

    Article  PubMed  CAS  Google Scholar 

  183. Yuen MH, Protti MP, Diethelm-Okita B, et al. Immunoregulatory CD8+ cells recognize antigen-activated CD4+ cells in myasthenia gravis patients and in healthy controls. J Immunol 1995; 154: 1508–1520.

    PubMed  CAS  Google Scholar 

  184. Hohlfeld R, Wekerle H. The thymus in myasthenia gravis. Neurol Clin 1994; 12: 331–342.

    PubMed  CAS  Google Scholar 

  185. Levinson AI, Wheatley LM. The thymus and the pathogenesis of myasthenia gravis. Clin Immunol Immunopathol 1996; 78: 1–5.

    Article  PubMed  CAS  Google Scholar 

  186. Aharonov A, Tarrab-Hazdai R, Abramsky O, Fuchs S. Immunological relationship between acetylcholine receptor and thymus: a possible significance in myasthenia gravis. Proc Natl Acad Sci USA 1975; 72: 1456–1459.

    Article  PubMed  CAS  Google Scholar 

  187. Engel EK, Trotter JL, McFarlin DE, McIntosh CL. Thymic epithelial cell contains acetylcholine receptor. Lancet 1977; 1: 1310–1311.

    Article  PubMed  CAS  Google Scholar 

  188. Ueno S, Wada K, Takahashi M, Tarui S. Acetylcholine receptor in rabbit thymus: antigenic similarity between acetylcholine receptors of muscle and thymus. Clin Exp Immunol 1980; 42: 463–469.

    PubMed  CAS  Google Scholar 

  189. Schluep M, Willcox N, Vincent A, Dhoot GK, Newsom-Davis J. Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study. Ann Neurol 1987; 22: 212–222.

    Article  PubMed  CAS  Google Scholar 

  190. Kawanami S, Conti-Tronconi B, Racs J, Raftery MA. Isolation and characterization of nicotinic acetylcholine receptor-like protein from fetal calf thymus. J Neurol Sci 1988; 87: 195–209.

    Article  PubMed  CAS  Google Scholar 

  191. Kirchner T, Tzartos S, Hoppe F, et al. Pathogenesis of myasthenia gravis. Acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. Am J Pathol 1988; 130: 268–280.

    PubMed  CAS  Google Scholar 

  192. Kao I, Drachman DB. Thymic muscle cells bear acetylcholine receptors: possible relation to myasthenia gravis. Science 1977; 195: 74–75.

    Article  PubMed  CAS  Google Scholar 

  193. Zheng Y, Wheatley LM, Liu T, Levinson AI. Acetylcholine receptor a subunit mRNA expression in human thymus: augmented expression in myasthenia gravis and upregulation by interferon-y. Clin Immunol 1999; 91: 170–177.

    Article  PubMed  CAS  Google Scholar 

  194. Wakkach A, Guyon T, Bruand C, et al. Expression of acetylcholine receptor genes in human thymic epithelial cells: implications for myasthenia gravis. J Immunol 1996; 157: 3752–3760.

    PubMed  CAS  Google Scholar 

  195. Andreetta F, Baggi F, Antozzi C, et al. Acetylcholine receptor a-subunit isoforms are differentially expressed in thymuses from myasthenic patients. Am J Pathol 1997; 150: 341–348.

    PubMed  CAS  Google Scholar 

  196. Navaneetham D, Penn AS, Howard JF Jr, Conti-Fine BM. Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the S subunit. Muscle Nerve 2001; 24: 203–210.

    Article  PubMed  CAS  Google Scholar 

  197. Marx A, Wilisch A, Gutsche S, et al. Low levels of acetylcholine receptor S subunit message and protein in human thymuses suggest the occurrence of triplet receptors in thymic myoid cells. In: Christadoss P, ed. Myasthenia Gravis: Disease Mechanisms and Immunointervention. New Delhi, Narosa, 2000, pp. 28–34.

    Chapter  Google Scholar 

  198. Kaminski HJ, Fenstermaker RA, Abdul-Karim FW, Clayman J, Ruff RL. Acetylcholine receptor subunit gene expression in thymic tissue. Muscle Nerve 1993; 16: 1332–1337.

    Article  PubMed  CAS  Google Scholar 

  199. Geuder KI, Marx A, Witzemann V, et al. Pathogenetic significance of fetal-type acetylcholine receptors on thymic myoid cells in myasthenia gravis. Dev Immunol 1992; 2: 69–75.

    Article  PubMed  CAS  Google Scholar 

  200. Wheatley LM, Urso D, Tumas K, et al. Molecular evidence for the expression of nicotinic acetylcholine receptor a-chain in mouse thymus. J Immunol 1992; 148: 3105–3109.

    PubMed  CAS  Google Scholar 

  201. Kornstein MJ, Asher O, Fuchs S. Acetylcholine receptor a-subunit and myogenin mRNAs in thymus and thymomas. Am J Pathol 1995; 146: 1320–1324.

    PubMed  CAS  Google Scholar 

  202. Hara H, Hayashi K, Ohta K, Itoh N, Ohta M. Nicotinic acetylcholine receptor mRNAs in myasthenic thymuses: association with intrathymic pathogenesis of myasthenia gravis. Biochem Biophys Res Commun 1993; 194: 1269–1275.

    Article  PubMed  CAS  Google Scholar 

  203. Wakkach A, Poea S, Chastre E, et al. Establishment of a human thymic myoid cell line. Phenotypic and functional characteristics. Am J Pathol 1999; 155: 1229–1240.

    Article  PubMed  CAS  Google Scholar 

  204. Wilisch A, Gutsche S, Hoffacker V, et al. Association of acetylcholine receptor a-subunit gene expression in mixed thymoma with myasthenia gravis. Neurology 1999; 52: 1460–1466.

    Article  PubMed  CAS  Google Scholar 

  205. Sine SM, Claudio T. y-and 8-subunits regulate the affinity and the cooperativity of ligand binding to the acetylcholine receptor. J Biol Chem 1991;266:19,369–19,377.

    Google Scholar 

  206. Schonbeck S, Chrestel S, Hohlfeld R. Myasthenia gravis: prototype of the anti-receptor autoimmune diseases. Int Rev Neurobiol 1990; 32: 175–200.

    Article  PubMed  CAS  Google Scholar 

  207. Kirchner T, Hoppe F, Schalke B, Muller-Hermelink HK. Microenvironment of thymic myoid cells in myasthenia gravis. Virchows Arch B Cell Pathol 1988; 54: 295–302.

    CAS  Google Scholar 

  208. Siara J, Rudel R, Marx A. Absence of acetylcholine-induced current in epithelial cells from thymus glands and thymomas of myasthenia gravis patients. Neurology 1991; 41: 128–131.

    Article  PubMed  CAS  Google Scholar 

  209. Rose NR. The role of infection in the pathogenesis of autoimmune disease. Semin Immunol 1998; 10: 5–13.

    Article  PubMed  CAS  Google Scholar 

  210. Fujinami RS, Oldstone MB. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 1985; 230: 1043–1045.

    Article  PubMed  CAS  Google Scholar 

  211. Todd JA, Steinman L. The environment strikes back. Curr Opin Immunol 1993; 5: 863–865.

    Article  PubMed  CAS  Google Scholar 

  212. Gautam AM, Lock CB, Smilek DE, et al. Minimum structural requirements for peptide presentation by major histocompatibility complex class II molecules: implications in induction of autoimmunity. Proc Natl Acad Sci USA 1994; 91: 767–771.

    Article  PubMed  CAS  Google Scholar 

  213. Ohno S. Many peptide fragments of alien antigens are homologous with host proteins, thus canalizing T-cell responses. Proc aNtl Acad Sci USA 1991; 88: 3065–3068.

    Article  CAS  Google Scholar 

  214. Farris AD, Keech CL, Gordon TP, McCluskey J. Epitope mimics and determinant spreading: pathways to autoimmunity. Cell Mol Lfei Sci 2000; 57: 569–578.

    Article  CAS  Google Scholar 

  215. Conrad B, Weidmann E, Trucco G, et al. Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology. Nature 1994; 371: 351–355.

    Article  PubMed  CAS  Google Scholar 

  216. Paliard X, West SG, Lafferty JA, et al. Evidence for the effects of a superantigen in rheumatoid arthritis. Science 1991; 253: 325–329.

    Article  PubMed  CAS  Google Scholar 

  217. Brocke S, Veromaa T, Weissman IL, Gijbels K, Steinman L. Infection and multiple sclerosis: a possible role for superantigens? Trends Microbiol 1994; 2: 250–254.

    Article  PubMed  CAS  Google Scholar 

  218. Brocke S, Gaur A, Piercy C, et al. Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen. Nature 1993;365:642– 644.

    Google Scholar 

  219. Olson JK, Croxford JL, Miller SD. Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T-cell-mediated autoimmune disease. Viral Immunol 2001; 14: 227–250.

    Article  PubMed  CAS  Google Scholar 

  220. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12: 991–1045.

    Article  PubMed  CAS  Google Scholar 

  221. Blacklaws BA, Nash AA. Immunological memory to herpes simplex virus type 1 glycoproteins B and D in mice. J Gen Virol 1990; 71: 863–871.

    Article  PubMed  CAS  Google Scholar 

  222. Eng H, Lefvert AK, Mellstedt H, Osterborg A. Human monoclonal immunoglobulins that bind the human acetylcholine receptor. Eur J Immunol 1987; 17: 1867–1869.

    Article  PubMed  CAS  Google Scholar 

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  1. Bianca M. Conti-Fine
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  2. Brenda Diethelm-Okita
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  3. Norma Ostlie
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  4. Wei Wang
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  1. Departments of Neurology and Neurosciences, University Hospitals of Cleveland, Louis Stokes Cleveland Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, OH, USA

    Henry J. Kaminski MD

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Conti-Fine, B.M., Diethelm-Okita, B., Ostlie, N., Wang, W., Milani, M. (2003). Immunopathogenesis of Myasthenia Gravis. In: Kaminski, H.J. (eds) Myasthenia Gravis and Related Disorders. Current Clinical Neurology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-341-5_3

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