T Cell Epitopes of the Acetylcholine Receptor and the Pathogenesis of Myasthenia Gravis

  • Arthur Melms
  • Robert Weissert
  • Alexej Schmidt
  • Claudia Müller
  • Günther Jung
  • Georg Malcherek


CD4-positive T cells are required for sustained antibody production. T and B lymphocytes recognize cognate determinants of an antigen and communicate by direct cell to cell interactions including the CD40/CD40-ligand and B7-CTLA4 pairs of accessory molecules (reviewed in Clark and Ledbetter, 1994). In addition, T cell derived cytokines promote growth and differentiation signals for antibody-producing B cells (Coffman et al., 1988). In the animal model of myasthenia gravis (MG), experimental autoimmune myasthenia gravis (EAMG), the depletion of T lymphocytes prevents the production of autoantibodies after immunization with acetylcholine receptor (AChR; Lennon et al., 1976). T helper cells recognize antigen in the context of MHC class II molecules. Inhibition of antigen recognition by monoclonal antibodies to MHC class II molecules has been reported to suppress the immune response to AChR and prevent EAMG in vivo (Waldor et al., 1983). MHC class II molecules bind peptides in a preformed binding groove and allelic products differ in their binding requirements which have been described as allele-specific ligand or binding motifs (Rammensee et al., 1995). For example, the bm-12 mutation of murine MHC class II molecules I-A alters the peptide binding site of MHC class II molecules, hence, animals with the bm-12 mutation respond to a different set of AChR peptides compared to the wild type and are resistant to the induction of EAMG (Bellone et al., 1991). This underscores the strong influnence of MHC class II molecules on the determinant selection and the immune response regarding the susceptibility to develop an autoimmune disease.


Acetylcholine Receptor Cell Epitope Tetanus Toxin Nicotinic Receptor Alpha Binding Requirement 
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  1. Bellone M, Ostile N, Lei S, Wu XD, Conti-Tronconi B. 1991. The I-Abml2mutation, which confers resistence to experimental autoimmune myasthenia gravis, drastically affects the epitope repertoire of murine CD4+ cells sensitized to nicotinic acetylcholine receptor. J Immunol. 147:1484–1491.PubMedGoogle Scholar
  2. Brocke S, Brautbar C, Steinman L, Abramsky O, Rothbard J, Neumann D, Fuchs S, Mozes E. 1988. In vitro proliferative responses and antibody titers specific to human acetylcholine receptor synthetic peptides in patients with myasthenia gravis and relation to HLA class II genes. J. Clin. Invest. 82:1894–1900.PubMedCrossRefGoogle Scholar
  3. Clark EA, Ledbetter JA. 1994. How T and B cells talk to each other. Nature 367:425–428.PubMedCrossRefGoogle Scholar
  4. Coffman RL, Seymour BW, Lebman DA, Hiraki DD, Christiansen JA, Shrader B, Cherwinski HM, Savelkoul HF, Finkelman FD, Bond MW, Mossmann TR. 1988. The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol. Rev. 102:5–28.PubMedCrossRefGoogle Scholar
  5. Compston DAS, Vincent A, Newsom Davis J, Batchelor JR. 1980. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 103, 579–601.PubMedCrossRefGoogle Scholar
  6. Fujinami RS, Oldstone MBA. 1985. Amino acid homology between the encephalithogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230:1043–1045.PubMedCrossRefGoogle Scholar
  7. Fuji Y, Lindstrom J. 1988. Specificity of the T cell response to acetylcholine receptor in experimental autoimmune myasthenia gravis. Response to subunits and synthetic peptides. J. Immunol. 140:1830–1837.Google Scholar
  8. Gammon G, Sercarz E. 1989. How some T cells escape tolerance induction. Nature 342:183–185.PubMedCrossRefGoogle Scholar
  9. Gilhus NE, Willcox N, Harcourt G, Nagvekar N, Beeson D, Vincent A, Newsom-Davis J. 1995. Antigen-presentation by thymoma epithelial cells from myasthenia gravis patients to potentially pathogenic T cells. J. Neuroimmunol. 56:65–76.PubMedCrossRefGoogle Scholar
  10. Hawke S, Nagvekar, Nicolle M, Malcherek G, Melms A, Willcox N. 1996. Autoimmune T cells in myasthenia gravis: Heterogeneity and potential as target for therapy. Immunol today in pressGoogle Scholar
  11. Hohlfeld R, Toyka KV, Tzartos SJ, Carson W, Conti-Tronconi B. 1987. Human T helper lymphocytes in myasthenia gravis recognize the nicotinic receptor alpha subunit. Proc. Natl. Acad. Sci. USA 84:5379–5383.PubMedCrossRefGoogle Scholar
  12. Kirchner T, Tzartos S, Hoppe F, Schalke B, Wekerle H, Müller-Hermelink HK. 1988. Pathogenesis of myasthenia gravis: Acetylcholine receptor-related determinants in tumor-free thymuses and thymic epithelial tumors. Am. J. Pathol. 130:268–280.PubMedGoogle Scholar
  13. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. 1992. Spreading of T cell autoimmunity to cryptic determinants of an autoantigen. Nature 358:155–157.PubMedCrossRefGoogle Scholar
  14. Lennon VA, Lindstrom JM, Seybold ME. 1976. Experimental autoimmune myasthenia gravis: Cellular and humoral immune responses. Ann. N.Y. Acad. Sci. 274, 283–299.PubMedCrossRefGoogle Scholar
  15. Liu GY, Fairchild PJ, Smith RM, Prowle JR, Kioussis D, Wraith DC. 1995. Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 3:407–415.PubMedCrossRefGoogle Scholar
  16. Malcherek G, Falk K, Rötzschke O, Rammensee H-G, Stevanovic S, Gnau V, Jung G, Melms A. 1993. Peptide motif of two HLA molecules associated with myasthenia gravis. Intl. Immunol. 5:1229–1237.CrossRefGoogle Scholar
  17. Malcherek G, Gnau V, Stevanovic S, Rammensee HG, Jung G, Melms A. 1994. Characterization of allele-specific contact sites of DR 17 ligands. J. Immunol. 154:1141–1149.Google Scholar
  18. Marx A, O’Connor R, Geuder KI, Hoppe F, Schalke B, Tzartos S, Kalies I, Kirchner T, Müller-Hermelink HK. 1990. Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis associated thymomas. Lab. Invest. 62:279–286.PubMedGoogle Scholar
  19. Marx A, Schömig D, Schultz A, Gattenlöhner S, Jung S, Kirchner T, Melms A, Müller-Hermelink HK. 1994. Distribution of molecules mediating thymocyte-stroma interactions in human thymus, thymitis and thymic epithelial tumours. Thymus 23:83–93.PubMedGoogle Scholar
  20. Matsuo H, Batocchi A-P, Hawke S, Nicolle M, Jacobson L, Vincent A, Newsom-Davis J, Willcox, N. 1995. Peptide-selected T cell lines from myasthenia gravis patients and controls recognize epitopes that are not processed from whole acetylcholine receptor. J. Immunol. 155:3683–3692.PubMedGoogle Scholar
  21. Melms A, Schalke B, Kirchner T, Albert E, Müller-Hermelink HK, Wekerle H. 1988. Thymus in myasthenia gravis: Isolation of T lymphocyte lines specific for the nicotinic acetylcholine receptor from myasthenic patients. J. Clin. Invest. 81:902–908.PubMedCrossRefGoogle Scholar
  22. Protti MP, Manfredi A, Horton RM, Bellone M, Conti-Tronconi BM. 1993. Myasthenia gravis: recognition of a human autoantigen at the molecular level. Immunol. Today 14:363–368.PubMedCrossRefGoogle Scholar
  23. Rammensee HG, Friede T, Stevanovic S. 1995. MHC ligands and peptide motifs: first listing. Immunogenetics 41:178–228.PubMedCrossRefGoogle Scholar
  24. Schild HJ, Rötzschke O, Kalbacher H, Rammensee HG. 1990. Limit of T cell tolerance to self proteins by peptide presentation. Science 247:1587–1589.PubMedCrossRefGoogle Scholar
  25. Sommer N, Willcox N, Harcourt GC, Newsom-Davis J. 1990. Myasthenic thymus and thymoma are selectively enriched in acetylcholine receptor-reactive T cells. Ann. Neurol. 28:312–319.PubMedCrossRefGoogle Scholar
  26. Tzartos SJ, Kokla A, Walgrave SL, Conti-Tronconi BM. 1988. Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67–76 of the α-subunit. Proc. Natl. Acad. Sci. USA 85:2899–2903.PubMedCrossRefGoogle Scholar
  27. Waldor MK, Sriram S, McDevitt HO, Steinman LS. 1983. In-vivo therapy with monoclonal anti-I-A antibody suppresses immune response to acetylcholine receptor. Proc. Natl. Acad. Sci. USA 80:2713–2717.PubMedCrossRefGoogle Scholar
  28. Wekerle H. 1993. The thymus in myasthenia gravis. Ann. N.Y. Acad. Sci. 681:47–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Arthur Melms
    • 1
  • Robert Weissert
    • 1
  • Alexej Schmidt
    • 1
  • Claudia Müller
    • 2
  • Günther Jung
    • 3
  • Georg Malcherek
    • 1
  1. 1.Department of NeurologyUniversity of TübingenTübingenGermany
  2. 2.Department of Medicine, Tübingen University Medical CenterUniversity of TübingenTübingenGermany
  3. 3.Institute of Organic ChemistryUniversity of TübingenTübingenGermany

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