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Show /. Clio. Neuro-ophthalmol. 1: 63-66, 1981. Editorial Myasthenia Gravis Acetylcholine Receptor Antibodies and Beyond RONALD M. BURDE, M.D. Myasthenia gravis is characterized by weakness and fatigability of skeletal muscle. Diplopia and ptosis are the presenting symptoms in half the cases, and if the disease remains isolated to the extraocular muscles for 18 months, Grobl has concluded that there is a small likelihood of systemic involvement. The ocular findings are summarized in Table 1. The pathogenesis of myasthenia gravis has remained e~igm~tic until recently. In 1964, Elmqvist and assoCiates- reported a decrease in the amplitude of miniature endplate potentials, which occur at the myoneural junctions of patients with myasthenia gravis. The cause of the reduction of the amplitude of the miniature endplate potentials remained speculative until 1973, when Fambrough and co-workers,3 using labeled 1125 a-bungarotoxin, demonstrated a quantitative decrease in the number of acetylcholine receptors at the myoneural junction in patients with myasthenia gravis. In 1974, Almon and associates4 demonstrated the presence of a circulating globulin in patients with myasthenia gravis that blocked the binding of 1125 _ labeled a-bungarotoxin to acetylcholine receptors extracted from denervated rat muscle. Appel and co-workers5 extended this work, demonstrating antibodies against acetylcholine receptors in 70% of patients with myasthenia gravis. Lindstrom and associates6 have demonstrated significant antibody titers in 90% of patients with myasthenia gravis. A recent paper by Oda and co-workers7 suggests that the discrepancy noted in the reporting of percentages of patients with myasthenia gravis having acetylcholine receptor antibodies is due to whether human or rat acetylcholine receptors are used to determine the titers. Although Bender and associates8 demonstrated that serum of myasthenia gravis patients could block the binding of 1125 a-bungarotoxin to acetylcholine receptors of normal human muscle, it was not until the report of Toyka and co-workers9 in 1977, demonstrating that the From the Departments of Ophthalmology and Neurology, Washington University School of Medicine, SI. louis, Missouri. March 1981 passive transfer of IgG from patients with myasthenia gravis to mice produced a typical myasthenia syndrome, that the direct connection between the presence of antibody and the clinical state was established. A similar mechanism has been demonstrated in the transient myasthenic syndrome of the neonate. 10. II It has been established subsequently that the presence of antibody to acetylcholine receptors increases the rate of degradation of acetylcholine receptors. 12 - 14 Titers of antibodies against human acetylcholine receptors determined at anyone time during the disease process have not correlated with the severity of the disease, nor do they appear to have prognostic value. '5 This is surprising in view of the numerous reports of the parallel decreases in patient weakness and antibody titers as a result of therapy with immunosuppressive drugs, thoracic duct drainage, or plasmapheresis. 16 - 20 De Crousaz and Fulpiusl6 have demonstrated a fall in antiacetylcholine receptor titers during myasthenic crisis, reflecting an enhanced uptake of anti-acetylcholine receptor antibodies at the motor endplate. Similarly, Elias and Appefl have shown that there is a change in the binding affinity of acetylcholine receptors in patients with myasthenia gravis probably reflecting membrane alteration, which contributes to the pathogenesis of myasthenia gravis. Further evidence that autoimmune mechanisms are involved includes the association of myasthenia gravis with other autoimmune diseases such as systemic lupus erythematosus, thyroid disease, etc./2 the r-eculiar segregation of certain HL-A antigens;'" 2. -25 as well as the finding of a similar segregation of Gm haplotypes (Gm I. ~. 21_heavy_ chain component of IgG) especially in those patients with thymoma. 19 In addition, the fact that the thymectoml6 and immunosuppressive therapl7 have beneficial effects in more than 70% of patients with myasthenia gravis24 has been supportive of this notion. Experimental myasthenia gravis, as mentioned previously, has been produced in rabbits and in primates as well28 by injecting purified acetylcholine receptors. T-helper cells have been shown to be required for the development of the 63 Editorial: Myasthenia Gravis disease 29,30 and T-cells sensitized to receptor are demons, trable before onset of symptoms.29 The disease can be transferred with sensitized lymph node cells,29, 31 TABLE I. Ocular Findings in Myasthenia Gravis I. lid signs and phenomena A. Ptosis B. Lid retraction I. contralateral eye (see-saw ptosis) 2. after sustained upgaze 3. associated with thyroid orbitopathy C. Cogan's lid twitch sign D. "Peak sign"-weakness of orbicularis muscle II. Extraocular Muscle Involvement A. Diplopia> medical rectus B. Pseudointemuclear ophthalmoplegia C. Endpoint nystagmus D. "Quiver" movements on initiation of saccades in patients with limited range. E. Decreased versions and vergences with limitation of ocular rotations THYMUS It is clear that antibodies are produced by Blymphocytes against acetylcholine receptors, but what is the link between the thymus (seat of the cellular immune response) abnormalities and the development of myasthenia gravis? In 1971, Shore and associates32 demonstrated two factors in the serum of patients with early onset myasthenia gravis, which shed some light on the interaction of immunologic mechanisms in these patients. The first factor was an IgG antibody, which prevented the normal production of a given subset of T-suppressor cells to an appropriate antigenic stimulus. The effect of this antibody could be blocked by the use of d -tubocurarine. This finding suggested that the IgG antibody might well have anticholine receptor activity. The second, or non-lgG, factor had an action similar to thymosin, an extract obtained from thymic epithelium, or extracts from calf thymus which induce T-cell maturation in normal bone marrow. Thymectomy has been shown to produce a disappearance of the bone marrow-inducing factor but not of the IgG antibody component. In 1976, Engle and associates33 demonstrated that thymic epithelial cells contained acetylcholine Lymphocyt e (T) AChR-like surface antigen Epithelium AChR Thymosin Periphery Lymphocyte (T) AChR receptor Thymosin ell (in excess) 1 T-cell maturation with increased production T_SUPPCO"Oj ~:', . (:')1-h01POC ,oIl" B-Cells Antiacetylcholine receptor antibodies ~---------------------- -JL-__--+ Myoneural Junction (clinical syndrome) (AChR = acetylcholine receptors) Figure 1. Proposed scheme of the initiating event in myasthenia gravis, 64 Journal of Clinical Neuro-ophthalmology receptor. More recently, Dalakas and co-workers,:w using indirect immunofluorescent techniques, have demonstrated thymosin 0'1 in thymic epithelial cells of normal as well as myasthenic patients. The finding of epithelial binding was markedly more prominent in patients with myasthenia gravis, especially those with thymomas. Previous reports have suggested that the immunologic cross-reactivity between acetylcholine receptors and thymus could be due to the presence of thymic myoid cells which develop striated muscle fibers under selective culture conditions.3S · ~16 In addition, it has now been shown that thymic lymphocytes bear a surface anti§!!n which cross-reacts with acetylcholine receptor. ' The initiating event in myasthenia gravis remains enigmatic. The presence of inducing agent has been postulated;34 it causes the thymic epithelial cell to become hypersecretory and prevents recognition of acetylcholine receptor as self. Hypersecretion of thymosin would produce an increase in the number of T-helper lymphocytes presumably sensitized against acetylcholine receptors. Such lymphocytes would stimulate B-lymphocytes to produce specific antibodies against acetylcholine rec.eptors. These antibodies would bind to the acetylcholine receptors at the myoneural junction producing the typical clinical picture and to the surface of a given T-cell population preventing the transformation to or production of suppressor T-cells which could act to inhibit the production of these autoantibodies (Fig. 1). Such a scenario would partially explain the beneficial effect of thymectomy in patients of any age by removing the presence of the immune potentiating factor thymosin.32 . 33 Once the sequence has been initiated and failure of self-recognition has taken place, the process could continue without the continued reinforcement of thymic factors. Why the extraocular muscles are then preferentially involved in so many cases remains unknown. References 1. Grob, D.: Course and management of myasthenia gravis. f. Am. Med. Assoc. 153: 529-532, 1953. 2. Elmqvist, D., Hofmann, W.W., Kugelberg, J., and Quastel, D.M.].: An electrophysiological investigation of neuromuscular transmission in myasthenia gravis. f. Physio/. 174: 417-434, 1964. 3. Fambrough, D.M., Drachman, D.B., and Satyamurti, S.: Neuromuscular junction in myasthenia gravis. Decreased acetylcholine receptors. Science 182: 293295, 1973. 4. Almon, RR, Andrew, CG., and Appel, S.H.: Serum globulin in myasthenia gravis: Inhibition of alphabungarotoxin binding to acetylcholine receptors. Science 186: 55-57, 1974. 5. Appel, S.H., Almon, R.R., and Levy, N.: Acetylcholine receptor antibodies in myasthenia gravis. N. Engl. f. Med. 293: 760-761, 1975. March 1981 Burde 6. Lindstrom, J.M., Seybold, M.E., Lennon, V.A., Whittingham, S., and Duane, D.O.: Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 26: 1054-1059, 1976. 7. Oda, K., Goto, I., Kuroiwa, Y., Onoue, K., and Ito, Y.: Myasthenia gravis: Antibodies to acetylcholine receptor with human and rat antigens. Neurology 30: 543-546, 1980. 8. Bender, A.N., Ringel, S.P., Engel, W.K., Daniels, M.P., and Vogel, Z.: Myasthenia gravis: A serum factor blocking acetylcholine receptors of the human neuromuscular junction. Lancet 1: 607-609, 1975. 9. Toyka, K.V., Drachman, D.B., Griffin, D.E., Pestronk, A, Winkelstein, J.A., Fischbeck, K.H., Jr., and Kao, I.: Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N. Engl. f. Med. 296: 125-131, 1977. 10. Nako, K., Nishitani, H., Suzuki, M., Ohta, M., and Hayashi, K.: Anti-acetylcholine receptor IgG in neonatal myasthenia gravis. N. Engl. f. Med. 297: 169, 1977. 11. Keesey, J., Lindstrom, J., Cokely, H., and Herrmann, C, Jr.: Anti-acetylcholine receptor antibody in neonatal myasthenia gravis. N. Engl. f. Med. 296: 55, 1977. 12. Kao, I. and Drachman, D.B.: Myasthenic immunoglobulin accelerates acetylcholine receptor degradation. Science 196: 527-529, 1977. 13. Appel, S.H., Anwyl, R., McAdams, M. W., and Elias, S.: Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins. Proc. Nat/. Acad. Sci. USA 74: 2130-2134, 1977. 14. Drachman, D.B., Angus, CW., Adams, R.N., Michelson, J.D., and Hoffman, G.J.: Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N. Engl. f. Med. 298: 1116-1122, 1978. 15. Lindstrom, J.M., Lennon, V.A, Seybold, M.E., and Whittingham, S.: Experimental autoimmune myasthenia and myasthenia gravis: Biochemical and immunochemical aspects. Ann. N. Y. Acad. Sci. 274: 254-274, 1976. 16. de Crousaz, G. and Fulpius, B.W.: Increased uptake of acetylcholine receptor antibody at motor endplate in myasthenic exacerbation. Lancet 1: 47, 1978. 17. Newsom-Davis, J., Vincent, A, Wilson, S.G., Ward, CD., Pinching, AJ., and Hawkey, C: Plasmapheresis for myasthenia gravis. N. Engl. f. Med. 298: 456, 1978. 18. Editorial: Plasmapheresis. Br. Med. f. 1: 1011-1012, 1978. 19. Behan, P.O., Shakir, R.A., Simpson, J.A, Burnett, A.K., Allan, T.L., and Haase, G.: Plasma-exchange combined with immunosuppressive therapy in myasthenia gravis. Lancet 2: 438-440, 1979. 20. Newsom-Davis, J., Pinching, AJ., Vincent, A., and Wilson, S.G.: Function of circulating antibody to acetylcholine receptor in myasthenia gravis: Investigation by plasma exchange. Neurology 28: 266272,1978. 21. Elias, S.B. and Appel, S.H.: Acetylcholine receptor in myasthenia gravis: Increased affinity for a-bungarotoxin. Ann. Neuro/. 4: 250-252, 1978. 65 Editorial: Myasthenia Gravis 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Simpson, j.A: Myasthenia gravis as an autoimmune disease: Clinical aspects. Ann. N. Y. Acad. Sci. 135: 506-516, 1966. Behan, P.O., Simpson, J.A, and Dick, H.: Immune response genes in myastheni<t gravis. Lancet 11: 1033, 1973. Feltkamp, T.E.W., Van Den Berg-Loonen, P.M., Nijenhuis, L.E., Engelfriet, CP., Van Rossum, AL., Van Loghem, J.J., and Oosterhuis, H.J.G.H.: Myasthenia gravis, autoantibodies, and HL-A antigens. Sr. Med.]. 1: 131-133,1974. Fritze, D., Herrmann, C, Jr., Naeim, F., Smith, G.5., and Walford, R.L.: HL-A antigens in myasthenia gravis. Lancet 1: 240-242, 1974. Drachman, D.B.: Myasthenia gravis (second of two parts). N. Engl. ]. Med. 298: 186-193, 1978. Mann, J.D., Johns, T.R., Campa, J.F., and Muller, W.H.: Long-term prednisone followed by thymectomy in myasthenia gravis. Ann. N. Y. Acad. Sci. 274: 608-622, jQ76. Tarrab-Hazdai, R., Aharonov, A., Silman, I., Fuchs, S., and Abramsky, 0.: Experimental autoimmune myasthenia induced in monkeys by purified acetylcholine receptor. Nature 256: 128-130, 1975. Lennon, V.A, Lindstrom, J.M., and Seybold, M.E.: Experimental autoimmune myasthenia gravis: Cellular and humoral immune responses. Ann. N. Y. Acad. Sci. 274: 283-299, 1976. Lennon, V.A: Myasthenia gravis: A prototype immunopharmacological disease. In International Symposium on Organ-Specific Autoimmunity, P.A. Miescher, Ed., Schwabe and Company, Basel, 1980. Tarrab-Hazdai, R., Aharonov, A, Abramsky, 0., Yaar, I., and Fuchs, S.: Passive transfer of experimental autoimmune myasthenia by lymph node cells in inbred guinea pigs. }. Exp. Med. 142: 785789, 1975. 32. Shore, A, Limatibul, 5., Dosch, H.-M., and Gelfand, E.W.: Identification of two serum components regulating the expression of T-Iymphocyte function in childhood myasthenia gravis. N. Engl. }. Med. 201: 625-629, 1979. 33. Engel, W.K., Trotter, J.L., McFarlin, D.E., and McIntosh, CL.: Thymic epithelial cell contains acetylcholine receptor. Lancet 2: 1310-1311, 1977. 34. Dalakas, M.C, Engel, W.K., McClure, J.E., and Goldstein, A.L.: Thymosin at in myasthenia gravis. N. Engl. }. Med. 302: 1092, 1980. 35. WekerJe, H., Paterson, B., Ketelsen, U.P., and Feldman, M.: Striated muscle fibres differentiated in monolayer cultures of adult thymus reticulum. Nature 256: 493-494, 1975. 36. Kao, I. and Drachman, D.B.: Thymic muscle cells bear acetylcholine receptor: Possible relation to myasthenia gravis. Science 195: 74-75, 1977. 37. Fuchs, S., Schmidt-Hopfeld, I., Tridente, G., and Tarrab-Hazdai, R.: Thymic lymphocytes bear a surface antigen which cross-reacts with acetylcholine receptor. Nature 287: 162-164, 1980. Acknowledgment This work was supported in part by a grant from Research To Prevent Blindness, Inc., New York, New York (Department of Ophthalmology). Write for reprints to: Ronald M. Burde, M.D., Department of Ophthalmology-Box 8096, Washington UniversIty School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. 66 Journal of Clinical Neuro-ophthalmology |