Skip to main content
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1980 Jul;43(7):601–610. doi: 10.1136/jnnp.43.7.601

Mechanisms of acetylcholine receptor loss in myasthenia gravis.

D B Drachman, R N Adams, E F Stanley, A Pestronk
PMCID: PMC490627  PMID: 6249894

Abstract

The fundamental abnormality affecting the neuromuscular junctions of myasthenic patients is a reduction of available AChRs, due to an autoimmune attack directed against the receptors. Antibodies to AChR are present in most patients, and there is evidence that they have a predominant pathogenic role in the disease, aided by complement. The mechanism of antibody action involves acceleration of the rate of degradation of AChRs, attributable to cross-linking of the receptors. In addition, antibodies may block AChRs, and may participate in producing destructive changes, perhaps in conjunction with complement. The possibility that cell-mediated mechanisms may play a role in the autoimmune responses of some myasthenic patients remains to be explored. Although the target of the autoimmune attack in myasthenic patients is probably always the acetylcholine receptors, it is not yet clear which of these immune mechanisms are most important. It is likely that the relative role of each mechanism varies from patient to patient. One of the goals of future research will be to identify the relative importance of each of these mechanisms in the individual patient, and to tailor specific immunotherapeutic measures to the abnormalities found.

Full text

PDF
601

Selected References

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

  1. Abramsky O., Aharonov A., Webb C., Fuchs S. Cellular immune response to acetylcholine receptor-rich fraction, in patients with myasthenia gravis. Clin Exp Immunol. 1975 Jan;19(1):11–16. [PMC free article] [PubMed] [Google Scholar]
  2. Aharonov A., Abramsky O., Tarrab-Hazdai R., Fuchs S. Humoral antibodies to acetylcholine receptor in patients with myasthenia gravis. Lancet. 1975 Aug 23;2(7930):340–342. doi: 10.1016/s0140-6736(75)92779-8. [DOI] [PubMed] [Google Scholar]
  3. Albuquerque E. X., Lebeda F. J., Appel S. H., Almon R., Kauffman F. C., Mayer R. F., Narahashi T., Yeh J. Z. Effects of normal and myasthenic serum factors on innervated and chronically denervated mammalian muscles. Ann N Y Acad Sci. 1976;274:475–492. doi: 10.1111/j.1749-6632.1976.tb47709.x. [DOI] [PubMed] [Google Scholar]
  4. Albuquerque E. X., Rash J. E., Mayer R. F., Satterfield J. R. An electrophysiological and morphological study of the neuromuscular junction in patients with myasthenia gravis. Exp Neurol. 1976 Jun;51(3):536–563. doi: 10.1016/0014-4886(76)90179-5. [DOI] [PubMed] [Google Scholar]
  5. Almon R. R., Andrew C. G., Appel S. H. Serum globulin in myasthenia gravis: inhibition of alpha-bungarotoxin binding to acetylcholine receptors. Science. 1974 Oct 4;186(4158):55–57. doi: 10.1126/science.186.4158.55. [DOI] [PubMed] [Google Scholar]
  6. Appel S. H., Almon R. R., Levy N. Acetylcholine receptor antibodies in myasthenia gravis. N Engl J Med. 1975 Oct 9;293(15):760–761. doi: 10.1056/NEJM197510092931508. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Bender A. N., Ringel S. P., Engel W. K., Daniels M. P., Vogel Z. Myasthenia gravis: a serum factor blocking acetylcholine receptors of the human neuromuscular junction. Lancet. 1975 Mar 15;1(7907):607–609. doi: 10.1016/s0140-6736(75)91886-3. [DOI] [PubMed] [Google Scholar]
  9. Bergman R. A., Johns R. J. Ultrastructural alterations in muscle from patients with myasthenia gravis and Eaton-Lumbert syndrome. Ann N Y Acad Sci. 1971 Sep 15;183:88–122. doi: 10.1111/j.1749-6632.1971.tb30744.x. [DOI] [PubMed] [Google Scholar]
  10. Brockes J. P., Berg D. K., Hall Z. W. The biochemical properties and regulation of acetylcholine receptors in normal and denervated muscle. Cold Spring Harb Symp Quant Biol. 1976;40:253–262. doi: 10.1101/sqb.1976.040.01.026. [DOI] [PubMed] [Google Scholar]
  11. Chang C. C., Lee C. Y. Electrophysiological study of neuromuscular blocking action of cobra neurotoxin. Br J Pharmacol Chemother. 1966 Nov;28(2):172–181. doi: 10.1111/j.1476-5381.1966.tb01883.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cull-Candy S. G., Miledi R., Trautmann A. End-plate currents and acetylcholine noise at normal and myasthenic human end-plates. J Physiol. 1979 Feb;287:247–265. doi: 10.1113/jphysiol.1979.sp012657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Devreotes P. N., Fambrough D. M. Acetylcholine receptor turnover in membranes of developing muscle fibers. J Cell Biol. 1975 May;65(2):335–358. doi: 10.1083/jcb.65.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Drachman D. B., Kao I., Pestronk A., Toyka K. V. Myasthenia gravis as a receptor disorder. Ann N Y Acad Sci. 1976;274:226–234. doi: 10.1111/j.1749-6632.1976.tb47688.x. [DOI] [PubMed] [Google Scholar]
  17. Drachman D. B. Myasthenia gravis (first of two parts). N Engl J Med. 1978 Jan 19;298(3):136–142. doi: 10.1056/NEJM197801192980305. [DOI] [PubMed] [Google Scholar]
  18. ELMQVIST D., HOFMANN W. W., KUGELBERG J., QUASTEL D. M. AN ELECTROPHYSIOLOGICAL INVESTIGATION OF NEUROMUSCULAR TRANSMISSION IN MYASTHENIA GRAVIS. J Physiol. 1964 Nov;174:417–434. doi: 10.1113/jphysiol.1964.sp007495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Engel A. G., Lambert E. H., Howard F. M. Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis: ultrastructural and light microscopic localization and electrophysiologic correlations. Mayo Clin Proc. 1977 May;52(5):267–280. [PubMed] [Google Scholar]
  20. Engel W. K., Warmolts J. R. Myasthenia gravis: a new hypothesis of the pathogenesis and a new form of treatment. Ann N Y Acad Sci. 1971 Sep 15;183:72–87. doi: 10.1111/j.1749-6632.1971.tb30743.x. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. GROB D., HARVEY A. M., JOHNS R. J. Studies in neuromuscular function. IV. Stimulating and depressant effects of acetylcholine and choline in patients with myasthenia gravis, and their relationship to the defect in neuromuscular transmission. Bull Johns Hopkins Hosp. 1956 Sep;99(3):153–181. [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Ito Y., Miledi R., Vincent A., Newsom-Davis J. Acetylcholine receptors and end-plate electrophysiology in myasthenia gravis. Brain. 1978 Jun;101(2):345–368. doi: 10.1093/brain/101.2.345. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Lee C. Y. Chemistry and pharmacology of polypeptide toxins in snake venoms. Annu Rev Pharmacol. 1972;12:265–286. doi: 10.1146/annurev.pa.12.040172.001405. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Lindstrom J. Immunological studies of acetylcholine receptors. J Supramol Struct. 1976;4(3):389–403. doi: 10.1002/jss.400040310. [DOI] [PubMed] [Google Scholar]
  30. Mittag T., Kornfeld P., Tormay A., Woo C. Detection of anti-acetylcholine receptor factors in serum and thymus from patients with myasthenia gravis. N Engl J Med. 1976 Mar 25;294(13):691–694. doi: 10.1056/NEJM197603252941303. [DOI] [PubMed] [Google Scholar]
  31. NASTUK W. L., PLESCIA O. J., OSSERMAN K. E. Changes in serum complement activity in patients with myasthenia gravis. Proc Soc Exp Biol Med. 1960 Oct;105:177–184. doi: 10.3181/00379727-105-26050. [DOI] [PubMed] [Google Scholar]
  32. Namba T., Brown S. B., Grob D. Neonatal myasthenia gravis: report of two cases and review of the literature. Pediatrics. 1970 Mar;45(3):488–504. [PubMed] [Google Scholar]
  33. 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]
  34. RUSSELL D. S. Histological changes in the striped muscles in myasthenia gravis. J Pathol Bacteriol. 1953 Apr;65(2):279–289. doi: 10.1002/path.1700650202. [DOI] [PubMed] [Google Scholar]
  35. Rash J. E., Albuquerque E. X., Hudson C. S., Mayer R. F., Satterfield J. R. Studies of human myasthenia gravis: electrophysiological and ultrastructural evidence compatible with antibody attachment to acetylcholine receptor complex. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4584–4588. doi: 10.1073/pnas.73.12.4584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Richman D. P., Patrick J., Arnason B. G. Cellular immunity in myasthenia gravis. Response to purified acetylcholine receptor and autologous thymocytes. N Engl J Med. 1976 Mar 25;294(13):694–698. doi: 10.1056/NEJM197603252941304. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Stanley E. F., Drachman D. B. Effect of myasthenic immunoglobulin on acetylcholine receptors of intact mammalian neuromuscular junctions. Science. 1978 Jun 16;200(4347):1285–1287. doi: 10.1126/science.663610. [DOI] [PubMed] [Google Scholar]
  40. Toyka K. V., Brachman D. B., Pestronk A., Kao I. Myasthenia gravis: passive transfer from man to mouse. Science. 1975 Oct 24;190(4212):397–399. doi: 10.1126/science.1179220. [DOI] [PubMed] [Google Scholar]
  41. Toyka K. V., Drachman D. B., Griffin D. E., Pestronk A., Winkelstein J. A., Fishbeck K. H., Kao I. Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N Engl J Med. 1977 Jan 20;296(3):125–131. doi: 10.1056/NEJM197701202960301. [DOI] [PubMed] [Google Scholar]
  42. Winkelstein J. A., Smith M. R., Shin H. S. The role of C3 as an opsonin in the early stages of infection. Proc Soc Exp Biol Med. 1975 Jun;149(2):397–401. doi: 10.3181/00379727-149-38815. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES