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. 1980 Jul;43(7):568–576. doi: 10.1136/jnnp.43.7.568

Experimental autoimmune myasthenia gravis.

J Lindstrom
PMCID: PMC490624  PMID: 6249892

Abstract

Injection of animals with purified acetylcholine receptor in complete Freund's adjuvant causes development of antibodies which crossreact with receptors in muscle. The crossreacting antibodies impair neuromuscular transmission. Animals with experimental autoimmune myasthenia gravis (EAMG) are excellent models for studying the complex mechanisms by which the autoimmune response to receptor in myasthenia gravis causes muscle weakness. This review first briefly describes the discovery of EAMG. Then, to provide the necessary perspective, receptor structure and function and properties of anti-receptor antibodies are discussed, followed by a brief review of the pathological mechanisms in EAMG.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aharonov A., Kalderon N., Silman I., Fuchs S. Preparation and immunochemical characterization of a water-soluble acetylcholine receptor fraction from the electric organ tissue of the electric eel. Immunochemistry. 1975 Sep;12(9):765–771. doi: 10.1016/0019-2791(75)90227-x. [DOI] [PubMed] [Google Scholar]
  2. Appel S. H., Anwyl R., McAdams M. W., Elias S. Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins. Proc Natl Acad Sci U S A. 1977 May;74(5):2130–2134. doi: 10.1073/pnas.74.5.2130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berti F., Clementi F., Conti-Tronconi B., Folco G. C. A cholinoceptor antiserum: its pharmacological properties. Br J Pharmacol. 1976 May;57(1):17–22. doi: 10.1111/j.1476-5381.1976.tb07651.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bevan S., Heinemann S., Lennon V. A., Lindstrom J. Reduced muscle acetylcholine sensitivity in rats immunised with acetylcholine receptor. Nature. 1976 Apr 1;260(5550):438–439. doi: 10.1038/260438a0. [DOI] [PubMed] [Google Scholar]
  5. Brockes J. P., Hall Z. W. Acetylcholine receptors in normal and denervated rat diaphragm muscle. II. Comparison of junctional and extrajunctional receptors. Biochemistry. 1975 May 20;14(10):2100–2106. doi: 10.1021/bi00681a009. [DOI] [PubMed] [Google Scholar]
  6. Chang H. W., Bock E. Molecular forms of acetylcholine receptor. Effects of calcium ions and a sulfhydryl reagent on the occurrence of oligomers. Biochemistry. 1977 Oct 4;16(20):4513–4520. doi: 10.1021/bi00639a028. [DOI] [PubMed] [Google Scholar]
  7. Changeux J. P., Meunier J. C., Huchet M. Studies on the cholinergic receptor protein of Electrophorus electricus. I. An assay in vitro for the cholinergic receptor site and solubilization of the receptor protein from electric tissue. Mol Pharmacol. 1971 Sep;7(5):538–553. [PubMed] [Google Scholar]
  8. Christadoss P., Lennon V. A., David C. Genetic control of experimental autoimmune myasthenia gravis in mice. I. Lymphocyte proliferative response to acetylcholine receptors is under H-2-linked Ir gene control. J Immunol. 1979 Dec;123(6):2540–2543. [PubMed] [Google Scholar]
  9. Claudio T., Raftery M. A. Immunological comparison of acetylcholine receptors and their subunits from species of electric ray. Arch Biochem Biophys. 1977 Jun;181(2):484–489. doi: 10.1016/0003-9861(77)90254-5. [DOI] [PubMed] [Google Scholar]
  10. Drachman D. B., Angus C. W., Adams R. N., Kao I. Effect of myasthenic patients' immunoglobulin on acetylcholine receptor turnover: selectivity of degradation process. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3422–3426. doi: 10.1073/pnas.75.7.3422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Drachman D. B., Angus C. W., Adams R. N., Michelson J. D., Hoffman G. J. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116–1122. doi: 10.1056/NEJM197805182982004. [DOI] [PubMed] [Google Scholar]
  12. Engel A. G., Lindstrom J. M., Lambert E. H., Lennon V. A. Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and in its experimental autoimmune model. Neurology. 1977 Apr;27(4):307–315. doi: 10.1212/wnl.27.4.307. [DOI] [PubMed] [Google Scholar]
  13. Engel A. G., Sakakibara H., Sahashi K., Lindstrom J. M., Lambert E. H., Lennon V. A. Passively transferred experimental autoimmune myasthenia gravis. Sequential and quantitative study of the motor end-plate fine structure and ultrastructural localization of immune complexes (IgG and C3), and of the acetylcholine receptor. Neurology. 1979 Feb;29(2):179–188. doi: 10.1212/wnl.29.2.179. [DOI] [PubMed] [Google Scholar]
  14. Engel A. G., Tsujihata M., Lambert E. H., Lindstrom J. M., Lennon V. A. Experimental autoimmune myasthenia gravis: a sequential and quantitative study of the neuromuscular junction ultrastructure and electrophysiologic correlations. J Neuropathol Exp Neurol. 1976 Sep-Oct;35(5):569–587. doi: 10.1097/00005072-197609000-00008. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Fambrough D. M. Control of acetylcholine receptors in skeletal muscle. Physiol Rev. 1979 Jan;59(1):165–227. doi: 10.1152/physrev.1979.59.1.165. [DOI] [PubMed] [Google Scholar]
  17. Fambrough D. M., Devreotes P. N., Card D. J., Gardner J., Tepperman K. Metabolism of acetylcholine receptors in skeletal muscle. Natl Cancer Inst Monogr. 1978 May;(48):277–294. [PubMed] [Google Scholar]
  18. Fertuck H. C., Salpeter M. M. Localization of acetylcholine receptor by 125I-labeled alpha-bungarotoxin binding at mouse motor endplates. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1376–1378. doi: 10.1073/pnas.71.4.1376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Froehner S. C., Rafto S. Comparison of the subunits of Torpedo californica acetylcholine receptor by peptide mapping. Biochemistry. 1979 Jan 23;18(2):301–307. doi: 10.1021/bi00569a011. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Fulpius B. W., Zurn A. D., Granato D. A., Leder R. M. Acetylcholine receptor and myasthenia gravis. Ann N Y Acad Sci. 1976;274:116–129. doi: 10.1111/j.1749-6632.1976.tb47680.x. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Green D. P., Miledi R., Vincent A. Neuromuscular transmission after immunization against acetylcholine receptors. Proc R Soc Lond B Biol Sci. 1975 Apr 29;189(1094):57–68. doi: 10.1098/rspb.1975.0041. [DOI] [PubMed] [Google Scholar]
  24. Hall Z. W., Reiness C. G. Electrical stimulation of denervated muscles reduces incorporation of methionine into the ACh receptor. Nature. 1977 Aug 18;268(5621):655–657. doi: 10.1038/268655a0. [DOI] [PubMed] [Google Scholar]
  25. Hamilton S. L., McLaughlin M., Karlin A. Disulfide bond cross-linked dimer in acetylcholine receptor from Torpedo californica. Biochem Biophys Res Commun. 1977 Dec 7;79(3):692–699. doi: 10.1016/0006-291x(77)91167-6. [DOI] [PubMed] [Google Scholar]
  26. Heilbronn E., Mattsson C., Thornell L. E., Sjöström M., Stålberg E., Hilton-Brown P., Elmqvist D. Experimental myasthenia in rabbits: biochemical, immunological, electrophysiological, and morphological aspects. Ann N Y Acad Sci. 1976;274:337–353. doi: 10.1111/j.1749-6632.1976.tb47696.x. [DOI] [PubMed] [Google Scholar]
  27. Heinemann S., Bevan S., Kullberg R., Lindstrom J., Rice J. Modulation of acetylcholine receptor by antibody against the receptor. Proc Natl Acad Sci U S A. 1977 Jul;74(7):3090–3094. doi: 10.1073/pnas.74.7.3090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Heinemann S., Merlie J., Lindstrom J. Modulation of acetylcholine receptor in rat diaphragm by anti-receptor sera. Nature. 1978 Jul 6;274(5666):65–68. doi: 10.1038/274065a0. [DOI] [PubMed] [Google Scholar]
  29. Heuser J. E., Reese T. S., Dennis M. J., Jan Y., Jan L., Evans L. Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J Cell Biol. 1979 May;81(2):275–300. doi: 10.1083/jcb.81.2.275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kao I., Drachman D. B. Myasthenic immunoglobulin accelerates acetylcholine receptor degradation. Science. 1977 Apr 29;196(4289):527–529. doi: 10.1126/science.850793. [DOI] [PubMed] [Google Scholar]
  31. Keesey J., Lindstrom J., Cokely H. Anti-acetylcholine receptor antibody in neonatal myasthenia gravis. N Engl J Med. 1977 Jan 6;296(1):55–55. doi: 10.1056/NEJM197701062960125. [DOI] [PubMed] [Google Scholar]
  32. Kiefer H., Lindstrom J., Lennox E. S., Singer S. J. Photo-affinity labeling of specific acetylcholine-binding sites on membranes. Proc Natl Acad Sci U S A. 1970 Dec;67(4):1688–1694. doi: 10.1073/pnas.67.4.1688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lambert E. H., Lindstrom J. M., Lennon V. A. End-plate potentials in experimental autoimmune myasthenia gravis in rats. Ann N Y Acad Sci. 1976;274:300–318. doi: 10.1111/j.1749-6632.1976.tb47694.x. [DOI] [PubMed] [Google Scholar]
  34. Lee C. Y., Tseng L. F., Chiu T. H. Influence of denervation on localization of neurotoxins from clapid venoms in rat diaphragm. Nature. 1967 Sep 9;215(5106):1177–1178. doi: 10.1038/2151177a0. [DOI] [PubMed] [Google Scholar]
  35. Lennon V. A., Lindstrom J. M., Seybold M. E. Experimental autoimmune myasthenia gravis: cellular and humoral immune responses. Ann N Y Acad Sci. 1976;274:283–299. doi: 10.1111/j.1749-6632.1976.tb47693.x. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Lennon V. A., Seybold M. E., Lindstrom J. M., Cochrane C., Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med. 1978 Apr 1;147(4):973–983. doi: 10.1084/jem.147.4.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lindstrom J. M., Einarson B. L., Lennon V. A., Seybold M. E. 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 Sep 1;144(3):726–738. doi: 10.1084/jem.144.3.726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lindstrom J. M., Engel A. G., Seybold M. E., Lennon V. A., Lambert E. H. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies. J Exp Med. 1976 Sep 1;144(3):739–753. doi: 10.1084/jem.144.3.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Lindstrom J. M., Lambert E. H. Content of acetylcholine receptor and antibodies bound to receptor in myasthenia gravis, experimental autoimmune myasthenia gravis, and Eaton-Lambert syndrome. Neurology. 1978 Feb;28(2):130–138. doi: 10.1212/wnl.28.2.130. [DOI] [PubMed] [Google Scholar]
  41. Lindstrom J. M., Lennon V. A., Seybold M. E., Whittingham S. Experimental autoimmune myasthenia gravis and myasthenia gravis: biochemical and immunochemical aspects. Ann N Y Acad Sci. 1976;274:254–274. doi: 10.1111/j.1749-6632.1976.tb47691.x. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Lindstrom J. An assay for antibodies to human acetylcholine receptor in serum from patients with myasthenia gravis. Clin Immunol Immunopathol. 1977 Jan;7(1):36–43. doi: 10.1016/0090-1229(77)90027-7. [DOI] [PubMed] [Google Scholar]
  44. Lindstrom J., Campbell M., Nave B. Specificities of antibodies to acetylcholine receptors. Muscle Nerve. 1978 Mar-Apr;1(2):140–145. doi: 10.1002/mus.880010206. [DOI] [PubMed] [Google Scholar]
  45. Lindstrom J., Einarson B. Antigenic modulation and receptor loss in experimental autoimmune myasthenia gravis. Muscle Nerve. 1979 May-Jun;2(3):173–179. doi: 10.1002/mus.880020304. [DOI] [PubMed] [Google Scholar]
  46. Lindstrom J., Einarson B., Merlie J. Immunization of rats with polypeptide chains from torpedo acetylcholine receptor causes an autoimmune response to receptors in rat muscle. Proc Natl Acad Sci U S A. 1978 Feb;75(2):769–773. doi: 10.1073/pnas.75.2.769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Lindstrom J. Immunological studies of acetylcholine receptors. J Supramol Struct. 1976;4(3):389–403. doi: 10.1002/jss.400040310. [DOI] [PubMed] [Google Scholar]
  48. Lindstrom J., Merlie J., Yogeeswaran G. Biochemical properties of acteylcholine receptor subunits from Torpedo californica. Biochemistry. 1979 Oct 16;18(21):4465–4470. doi: 10.1021/bi00588a003. [DOI] [PubMed] [Google Scholar]
  49. Lindstrom J., Walter B., Einarson B. Immunochemical similarities between subunits of acetylcholine receptors from Torpedo, Electrophorus, and mammalian muscle. Biochemistry. 1979 Oct 16;18(21):4470–4480. doi: 10.1021/bi00588a004. [DOI] [PubMed] [Google Scholar]
  50. Merlie J. P., Heinemann S., Einarson B., Lindstrom J. M. Degradation of acetylcholine receptor in diaphragms of rats with experimental autoimmune myasthenia gravis. J Biol Chem. 1979 Jul 25;254(14):6328–6332. [PubMed] [Google Scholar]
  51. Merlie J. P., Heinemann S., Lindstrom J. M. Acetylcholine receptor degradation in adult rat diaphragms in organ culture and the effect of anti-acetylcholine receptor antibodies. J Biol Chem. 1979 Jul 25;254(14):6320–6327. [PubMed] [Google Scholar]
  52. Nastuk W. L., Niemi W. D., Alexander J. T., Chang H. W., Nastuk M. A. Myasthenia in frogs immunized against cholinergic-receptor protein. Am J Physiol. 1979 Jan;236(1):C53–C57. doi: 10.1152/ajpcell.1979.236.1.C53. [DOI] [PubMed] [Google Scholar]
  53. Nathanson N. M., Hall Z. W. Subunit structure and peptide mapping of junctional and extrajunctional acetylcholine receptors from rat muscle. Biochemistry. 1979 Jul 24;18(15):3392–3401. doi: 10.1021/bi00582a028. [DOI] [PubMed] [Google Scholar]
  54. Patrick J., Heinemann S. F., Lindstrom J., Schubert D., Steinbach J. H. Appearance of acetylcholine receptors during differentiation of a myogenic cell line. Proc Natl Acad Sci U S A. 1972 Oct;69(10):2762–2766. doi: 10.1073/pnas.69.10.2762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. 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]
  56. Patrick J., Lindstrom J., Culp B., McMillan J. Studies on purified eel acetylcholine receptor and anti-acetylcholine receptor antibody. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3334–3338. doi: 10.1073/pnas.70.12.3334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Penn A. S., Chang H. W., Lovelace R. E., Niemi W., Miranda A. Antibodies to acetylcholine receptors in rabbits: immunochemical and electrophysiological studies. Ann N Y Acad Sci. 1976;274:354–376. doi: 10.1111/j.1749-6632.1976.tb47697.x. [DOI] [PubMed] [Google Scholar]
  58. Prives J., Hoffman L., Tarrab-Hazdai R., Fuchs S., Amsterdam A. Ligand induced changes in stability and distribution of acetylcholine receptors on surface membranes of muscle cells. Life Sci. 1979 Apr 30;24(18):1713–1718. doi: 10.1016/0024-3205(79)90257-1. [DOI] [PubMed] [Google Scholar]
  59. Reiness C. G., Hogan P. G., Marshall J. M., Hall Z. W. Factors influencing degradation of extrajunctional acetylcholine receptors in skeletal muscle. Prog Clin Biol Res. 1977;15:207–215. [PubMed] [Google Scholar]
  60. Reiness C. G., Weinberg C. B., Hall Z. W. Antibody to acetylcholine receptor increases degradation of junctional and extrajunctional receptors in adult muscle. Nature. 1978 Jul 6;274(5666):68–70. doi: 10.1038/274068a0. [DOI] [PubMed] [Google Scholar]
  61. Reynolds J. A., Karlin A. Molecular weight in detergent solution of acetylcholine receptor from Torpedo californica. Biochemistry. 1978 May 30;17(11):2035–2038. doi: 10.1021/bi00604a001. [DOI] [PubMed] [Google Scholar]
  62. Satyamurti S., Drachman D. B., Slone F. Blockade of acetylcholine receptors: a model of myasthenia gravis. Science. 1975 Mar 14;187(4180):955–957. doi: 10.1126/science.1145181. [DOI] [PubMed] [Google Scholar]
  63. Seybold M. E., Lambert E. H., Lennon V. A., Lindstrom J. M. Experimental autoimmune myasthenia: clinical, neurophysiologic, and pharmacologic aspects. Ann N Y Acad Sci. 1976;274:275–282. doi: 10.1111/j.1749-6632.1976.tb47692.x. [DOI] [PubMed] [Google Scholar]
  64. Sobel A., Heidmann T., Hofler J., Changeux J. P. Distinct protein components from Torpedo marmorata membranes carry the acetylcholine receptor site and the binding site for local anesthetics and histrionicotoxin. Proc Natl Acad Sci U S A. 1978 Jan;75(1):510–514. doi: 10.1073/pnas.75.1.510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. 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]
  66. 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]
  67. Tarrab-Hazdi R., Aharonov A., Abramsky O., Yaar I., Fuchs S. Passive transfer of experimental autoimmune myasthenia by lymph node cells in inbred guinea pigs. J Exp Med. 1975 Sep 1;142(3):785–789. doi: 10.1084/jem.142.3.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Tzartos S. J., Lindstrom J. M. Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits. Proc Natl Acad Sci U S A. 1980 Feb;77(2):755–759. doi: 10.1073/pnas.77.2.755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Vandlen R. L., Wu W. C., Eisenach J. C., Raftery M. A. Studies of the composition of purified Torpedo californica acetylcholine receptor and of its subunits. Biochemistry. 1979 May 15;18(10):1845–1854. doi: 10.1021/bi00577a001. [DOI] [PubMed] [Google Scholar]
  70. Weinberg C. B., Hall Z. W. Antibodies from patients with myasthenia gravis recognize determinants unique to extrajunctional acetylcholine receptors. Proc Natl Acad Sci U S A. 1979 Jan;76(1):504–508. doi: 10.1073/pnas.76.1.504. [DOI] [PMC free article] [PubMed] [Google Scholar]

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