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. 1995 Feb 1;181(2):547–557. doi: 10.1084/jem.181.2.547

Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction

PMCID: PMC2191877  PMID: 7836911

Abstract

Abnormal humoral responses toward motor end plate constituents in muscle induce myasthenia gravis (MG). To study the etiology of this disease, and whether it could be induced by host defense molecules, we examined the consequences of interferon (IFN) gamma production within the neuromuscular junction of transgenic mice. The transgenic mice exhibited gradually increasing muscular weakness, flaccid paralysis, and functional disruption of the neuromuscular junction that was reversed after administration of an inhibitor of acetylcholinesterase, features which are strikingly similar to human MG. Furthermore, histological examination revealed infiltration of mononuclear cells and autoantibody deposition at motor end plates. Immunoprecipitation analysis indicated that a previously unidentified 87-kD target antigen was recognized by sera from transgenic mice and also by sera from the majority of human MG patients studied. These results suggest that expression of IFN-gamma at motor end plates provokes an autoimmune humoral response, similar to human MG, thus linking the expression of this factor with development of this disease.

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Selected References

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  1. Aoki T., Drachman D. B., Asher D. M., Gibbs C. J., Jr, Bahmanyar S., Wolinsky J. S. Attempts to implicate viruses in myasthenia gravis. Neurology. 1985 Feb;35(2):185–192. doi: 10.1212/wnl.35.2.185. [DOI] [PubMed] [Google Scholar]
  2. Baekkeskov S., Aanstoot H. J., Christgau S., Reetz A., Solimena M., Cascalho M., Folli F., Richter-Olesen H., De Camilli P., Camilli P. D. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990 Sep 13;347(6289):151–156. doi: 10.1038/347151a0. [DOI] [PubMed] [Google Scholar]
  3. Berman P. W., Patrick J. Experimental myasthenia gravis. A murine system. J Exp Med. 1980 Jan 1;151(1):204–223. doi: 10.1084/jem.151.1.204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berman P. W., Patrick J., Heinemann S., Klier F. G., Steinbach J. H. Factors affecting the susceptibility of different strains of mice to experimental myasthenia gravis. Ann N Y Acad Sci. 1981;377:237–257. doi: 10.1111/j.1749-6632.1981.tb33736.x. [DOI] [PubMed] [Google Scholar]
  5. Bottazzo G. F., Pujol-Borrell R., Hanafusa T., Feldmann M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet. 1983 Nov 12;2(8359):1115–1119. doi: 10.1016/s0140-6736(83)90629-3. [DOI] [PubMed] [Google Scholar]
  6. Brooks E. B., Pachner A. R., Drachman D. B., Kantor F. S. A sensitive rosetting assay for detection of acetylcholine receptor antibodies using BC3H-1 cells: positive results in 'antibody-negative' myasthenia gravis. J Neuroimmunol. 1990 Jun;28(1):83–93. doi: 10.1016/0165-5728(90)90043-m. [DOI] [PubMed] [Google Scholar]
  7. Butler M. H., Solimena M., Dirkx R., Jr, Hayday A., De Camilli P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. J Exp Med. 1993 Dec 1;178(6):2097–2106. doi: 10.1084/jem.178.6.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carr C., Fischbach G. D., Cohen J. B. A novel 87,000-Mr protein associated with acetylcholine receptors in Torpedo electric organ and vertebrate skeletal muscle. J Cell Biol. 1989 Oct;109(4 Pt 1):1753–1764. doi: 10.1083/jcb.109.4.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DESMEDT J. E. Nature of the defect of neuromuscular transmission in myasthenic patients: post-tetanic exhaustion. Nature. 1957 Jan 19;179(4551):156–157. doi: 10.1038/179156a0. [DOI] [PubMed] [Google Scholar]
  10. Drachman D. B. The biology of myasthenia gravis. Annu Rev Neurosci. 1981;4:195–225. doi: 10.1146/annurev.ne.04.030181.001211. [DOI] [PubMed] [Google Scholar]
  11. Drachman D. B., de Silva S., Ramsay D., Pestronk A. Humoral pathogenesis of myasthenia gravis. Ann N Y Acad Sci. 1987;505:90–105. doi: 10.1111/j.1749-6632.1987.tb51285.x. [DOI] [PubMed] [Google Scholar]
  12. Engel A. G., Tsujihata M., Lindstrom J. M., Lennon V. A. The motor end plate in myasthenia gravis and in experimental autoimmune myasthenia gravis. A quantitative ultrastructural study. Ann N Y Acad Sci. 1976;274:60–79. doi: 10.1111/j.1749-6632.1976.tb47676.x. [DOI] [PubMed] [Google Scholar]
  13. Fambrough D. M., Drachman D. B., Satyamurti S. Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science. 1973 Oct 19;182(4109):293–295. doi: 10.1126/science.182.4109.293. [DOI] [PubMed] [Google Scholar]
  14. Fuchs S., Nevo D., Tarrab-Hazdai R., Yaar I. Strain differences in the autoimmune response of mice to acetylcholine receptors. Nature. 1976 Sep 23;263(5575):329–330. doi: 10.1038/263329a0. [DOI] [PubMed] [Google Scholar]
  15. Fujinami R. S., Oldstone M. B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science. 1985 Nov 29;230(4729):1043–1045. doi: 10.1126/science.2414848. [DOI] [PubMed] [Google Scholar]
  16. Granato D. A., Fulpius B. W., Moody J. F. Experimental myasthenia in Balb/c mice immunized with rat acetylcholine receptor from rat denervated muscle. Proc Natl Acad Sci U S A. 1976 Aug;73(8):2872–2876. doi: 10.1073/pnas.73.8.2872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kott E., Hahn T., Huberman M., Levin S., Schattner A. Interferon system and natural killer cell activity in myasthenia gravis. Q J Med. 1990 Sep;76(281):951–960. [PubMed] [Google Scholar]
  18. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  19. Lee M. S., Sarvetnick N. Induction of vascular addressins and adhesion molecules in the pancreas of IFN-gamma transgenic mice. J Immunol. 1994 May 1;152(9):4597–4603. [PubMed] [Google Scholar]
  20. Lennon V. A., Lindstrom J. M., Seybold M. E. Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs. J Exp Med. 1975 Jun 1;141(6):1365–1375. doi: 10.1084/jem.141.6.1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lindstrom J. M., Seybold M. E., Lennon V. A., Whittingham S., Duane D. D. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology. 1976 Nov;26(11):1054–1059. doi: 10.1212/wnl.26.11.1054. [DOI] [PubMed] [Google Scholar]
  22. Lindstrom J., Shelton D., Fujii Y. Myasthenia gravis. Adv Immunol. 1988;42:233–284. doi: 10.1016/s0065-2776(08)60847-0. [DOI] [PubMed] [Google Scholar]
  23. Luther M. A., Schoepfer R., Whiting P., Casey B., Blatt Y., Montal M. S., Montal M., Linstrom J. A muscle acetylcholine receptor is expressed in the human cerebellar medulloblastoma cell line TE671. J Neurosci. 1989 Mar;9(3):1082–1096. doi: 10.1523/JNEUROSCI.09-03-01082.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Martinou J. C., Merlie J. P. Nerve-dependent modulation of acetylcholine receptor epsilon-subunit gene expression. J Neurosci. 1991 May;11(5):1291–1299. doi: 10.1523/JNEUROSCI.11-05-01291.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Maselli R. A., Richman D. P., Wollmann R. L. Inflammation at the neuromuscular junction in myasthenia gravis. Neurology. 1991 Sep;41(9):1497–1504. doi: 10.1212/wnl.41.9.1497. [DOI] [PubMed] [Google Scholar]
  26. Mossman S., Vincent A., Newsom-Davis J. Myasthenia gravis without acetylcholine-receptor antibody: a distinct disease entity. Lancet. 1986 Jan 18;1(8473):116–119. doi: 10.1016/s0140-6736(86)92259-2. [DOI] [PubMed] [Google Scholar]
  27. Newsom-Davis J., Willcox N., Schluep M., Harcourt G., Vincent A., Mossman S., Wray D., Burges J. Immunological heterogeneity and cellular mechanisms in myasthenia gravis. Ann N Y Acad Sci. 1987;505:12–26. doi: 10.1111/j.1749-6632.1987.tb51279.x. [DOI] [PubMed] [Google Scholar]
  28. Oosterhuis H. J., Kuks J. B. Myasthenia gravis and myasthenic syndromes. Curr Opin Neurol Neurosurg. 1992 Oct;5(5):638–644. [PubMed] [Google Scholar]
  29. Pachner A. R., Kantor F. S. Nerve stimulation test in murine experimental autoimmune myasthenia gravis. Ann Neurol. 1982 Jan;11(1):48–52. doi: 10.1002/ana.410110109. [DOI] [PubMed] [Google Scholar]
  30. Patrick J., Lindstrom J. Autoimmune response to acetylcholine receptor. Science. 1973 May 25;180(4088):871–872. doi: 10.1126/science.180.4088.871. [DOI] [PubMed] [Google Scholar]
  31. Penn A. S., Jacques J. J. Cells from mice exposed chronically to D-penicillamine show proliferative responses to D-penicillamine-treated self (macrophage/dendritic cells): a graft-versus-host response? Ann N Y Acad Sci. 1993 Jun 21;681:319–322. doi: 10.1111/j.1749-6632.1993.tb22906.x. [DOI] [PubMed] [Google Scholar]
  32. Sanes J. R., Johnson Y. R., Kotzbauer P. T., Mudd J., Hanley T., Martinou J. C., Merlie J. P. Selective expression of an acetylcholine receptor-lacZ transgene in synaptic nuclei of adult muscle fibers. Development. 1991 Dec;113(4):1181–1191. doi: 10.1242/dev.113.4.1181. [DOI] [PubMed] [Google Scholar]
  33. Santa T., Engel A. G., Lambert E. H. Histometric study of neuromuscular junction ultrastructure. I. Myasthenia gravis. Neurology. 1972 Jan;22(1):71–82. doi: 10.1212/wnl.22.1.71. [DOI] [PubMed] [Google Scholar]
  34. Sarvetnick N., Liggitt D., Pitts S. L., Hansen S. E., Stewart T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell. 1988 Mar 11;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sarvetnick N., Shizuru J., Liggitt D., Martin L., McIntyre B., Gregory A., Parslow T., Stewart T. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 1990 Aug 30;346(6287):844–847. doi: 10.1038/346844a0. [DOI] [PubMed] [Google Scholar]
  36. Sarvetnick N., Shizuru J., Liggitt D., Stewart T. Inflammatory destruction of pancreatic beta cells in gamma-interferon transgenic mice. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 2):837–842. doi: 10.1101/sqb.1989.054.01.097. [DOI] [PubMed] [Google Scholar]
  37. Solimena M., Folli F., Aparisi R., Pozza G., De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med. 1990 May 31;322(22):1555–1560. doi: 10.1056/NEJM199005313222202. [DOI] [PubMed] [Google Scholar]
  38. Sommer N., Willcox N., Harcourt G. C., Newsom-Davis J. Myasthenic thymus and thymoma are selectively enriched in acetylcholine receptor-reactive T cells. Ann Neurol. 1990 Sep;28(3):312–319. doi: 10.1002/ana.410280303. [DOI] [PubMed] [Google Scholar]
  39. Sugiyama H., Benda P., Meunier J. C., Changeux J. P. Immunological characterisation of the cholinergic receptor protein from Electrophorus electricus. FEBS Lett. 1973 Sep 1;35(1):124–128. doi: 10.1016/0014-5793(73)80592-7. [DOI] [PubMed] [Google Scholar]
  40. Tarrab-Hazdai R., Aharonov A., Silman I., Fuchs S., Abramsky O. Experimental autoimmune myasthenia induced in monkeys by purified acetylcholine receptor. Nature. 1975 Jul 10;256(5513):128–130. doi: 10.1038/256128a0. [DOI] [PubMed] [Google Scholar]
  41. Vincent A., Newsom Davis J. Anti-acetylcholine receptor antibodies. J Neurol Neurosurg Psychiatry. 1980 Jul;43(7):590–600. doi: 10.1136/jnnp.43.7.590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wagner K. R., Cohen J. B., Huganir R. L. The 87K postsynaptic membrane protein from Torpedo is a protein-tyrosine kinase substrate homologous to dystrophin. Neuron. 1993 Mar;10(3):511–522. doi: 10.1016/0896-6273(93)90338-r. [DOI] [PubMed] [Google Scholar]
  43. Wogensen L., Huang X., Sarvetnick N. Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med. 1993 Jul 1;178(1):175–185. doi: 10.1084/jem.178.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]

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