Myasthenia research over the last 50 years – a personal perspective

Authors

DOI:

https://doi.org/10.17161/rrnmf.v4i3.19551

Keywords:

Myasthenia gravis, Acetylcholine receptor, Autoantibody, Muscle specific kinase, Thymus, Arthrogryposis, Fetal

Abstract

Myasthenia gravis (MG) research has, in many respects, been a trail blazer for the growing number of autoantibody-mediated disorders that affect the nervous system. The breakthroughs in MG understanding were made in the 1970s and even 50 years later, MG still remains a topic which scientists, clinicians and, most recently Pharma, return to as the most common and well-studied disorder.  Here, some of the main discoveries will be reviewed very briefly focusing on how the knowledge of the disease evolved during the first decades after the discovery of acetylcholine receptor antibodies.  It should be noted that this is a personal perspective and not a systematic or fully referenced review.

Metrics

Metrics Loading ...

Downloads

Download data is not yet available.

References

Willis T. De anima brutorum. 404–407. Oxonii Theatro Sheldoniano, Oxford (1672).

Erb W. Zur casuistik der bulbären lähmungen. Arch. Psychiatr. Nervenkr. 1879;9:336–350.

Goldflam S. Ueber einen scheinbar heilbaren bulbar paralytischen symptomen complex mit betheiligung der extremitäten. Dtsch. Z. Nervenheilkd. 1893;4:312–352.

Jolly F. Ueber Myasthenia gravis pseudoparalytica. Berl.Klin. Wochenschr. 1895; 32: 1–7.

Campbell H. & Bramwell E. Myasthenia gravis. Brain. 1900;23:277–336.

Weigert C. Pathologisch-anatomischer beiträg zur erb’schen krankheit (myasthenia gravis). Neurologisches Zentralblatt. 1901;20:597–601.

Buzzard EF. The clinical history and postmorten examination of five cases of myasthenia gravis. Brain. 1905;28:438–483.

Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet i. 1200-1201.

Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol. 2002 Oct;2(10):797-804. doi: 10.1038/nri916. PMID: 12360217.

Keesey JC. Myasthenia Gravis. An Illustrated History (Publishers Design Group, Roseville, California, 2002).

Nastuk WL, Plescia OJ, Osserman KE. Changes in serum complement activity in patients with myasthenia gravis. Proc. Soc. Exp. Biol. Med. 1960;105,177–184. doi: 10.3181/00379727-105-26050. PMID: 13727889.

Strauss AJL, Seegal BC, Hsu KC, Burkholder PM, Nastuk WL, Osserman KE. Immunofluorescence demonstration of muscle binding, complement fixing serum globulin fraction in myasthenia gravis. Proc. Soc. Exp. Biol. Med. 1960;105:184–191.

Roitt IM, Doniach D, Campbell R, Hudson RV. Auto-antibodies in Hashimoto’s disease (lymphoadenoid goiter). Lancet. 1956 ii:820–821. doi: 10.1016/s0140-6736(56)92249-8. PMID: 13368530.

Simpson JA. Myasthenia gravis, a new hypothesis. Scott. Med J. 1960;5:419–436.

Fatt P, Katz B. Spontaneous subthreshold activity at motor nerve endings. J. Physiol. (Lond.) 1952;117:109–128. PMID: 14946732; PMCID: PMC1392564.

Elmqvist D, Hofmann W. Kugelberg J & Quastel D. An electrophysiological investigation of neuromuscular transmission in myasthenia gravis. J. Physiol. (Lond.) 1964;174:417–434. Doi: 10.1113/jphysiol.1964.sp007495. PMID: 14232401; PMCID: PMC1368938.

Chang C, Lee C. Isolation of neurotoxins from the venom of Bungarus multicinctus and their modes of neuromuscular blocking action. Arch Pharmacodyn. Ther. 1962;144:241–257.

Keesey J. How electric fish became sources of acetylcholine receptor. J Hist Neurosci. 2005 Jun;14(2):149-64. doi: 10.1080/096470490512599. PMID: 16019659.

Cuatrecasas P. Affinity chromatography. Annu. Rev. Biochem. 1971;40:259–278. doi: 10.1146/annurev.bi.40.070171.001355. PMID: 4399260.

Miledi R, Molinoff P, Potter LT. Isolation of cholinergic receptor protein of torpedo electric tissue. Nature. 1971;229:554-557. doi: 10.1038/229554a0. PMID: 4925349.

Olsen RW, Meunier JC, Changeux JP. Progress in the purification of cholinergic receptor protein from Electrophorus electricus by affinity chromatography. FEBS Lett.1972;28:96-100. doi: 10.1016/0014-5793(72)80686-0. PMID: 4646881.

Vincent A. New support for autoimmune basis of myasthenia-gravis. Nature. 1975;256:10-11.

Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science 1973;182,293–295. Doi: 10.1126/science.182.4109.293. PMID: 4742736.

Patrick J Lindstrom J. Autoimmune response to acetylcholine receptor. Science 1973;180,871–872. Doi: 10.1126/science.180.4088.871. PMID: 4706680.

Almon RR, Andrew CG, Appel SH. Serum globulin in myasthenia gravis: inhibition of α-bungarotoxin binding to acetylcholine receptors. Science 1974;186 55–57. Doi: 10.1126/science.186.4158.55. PMID: 4421998.

Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates and diagnostic value. Neurology 1976;26,1054–1059. Doi: 10.1212/wnl.26.11.1054. PMID: 988512.

Toyka KV, Drachman DB, Pestronk A, Kao I. Myasthenia gravis: passive transfer from man to mouse. Science. 1975;190:397–399. doi: 10.1126/science.1179220. PMID: 1179220.

Matell G, Bergstrom K, Franksson C, Hammarstrom L, Lefvert AK, Moller E, et al. Effects of Some Immunosuppressive Procedures on Myasthenia-Gravis. Ann Ny Acad Sci. 1976;274:659-76. doi: 10.1111/j.1749-6632.1976.tb47724.x. PMID: 183592.

Pinching A, Peters DK, Newsom-Davis J. Remission of myasthenia gravis following plasma exchange. Lancet. 1976: ii,1373–1376. doi: 10.1016/s0140-6736(76)91917-6. PMID: 63848.

Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG. Function of circulating antibody to acetylcholine receptor in myasthenia gravis investigated by plasma exchange. Neurology. 1978;28:266–272. doi: 10.1212/wnl.28.3.266. PMID: 564482.

Vincent A. Immunology of acetylcholine receptors in relation to myasthenia gravis. Physiol Rev. 1980 Jul;60(3):756-824. doi: 10.1152/physrev.1980.60.3.756. PMID: 6248907.

Vincent A, Newsom Davis J. Acetylcholine-receptor antibody characteristics in myasthenia-gravis. I. Patients with generalized myasthenia or disease restricted to ocular muscles. Clin Exp Immunol. 1982;49:257-265. PMID: 6813004; PMCID: PMC1536506.

Tzartos SJ, Seybold ME, Lindstrom JM. Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies. Proc. Natl. Acad. Sci. U.S.A. 1982;79,188–192. doi: 10.1073/pnas.79.1.188. PMID: 6948300; PMCID: PMC345688.

Tzartos SJ, Barkas T, Cung MT, Mamalaki A, Marraud M, Orlewski P, et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol Rev. 1998;163:89-120. doi: 10.1111/j.1600-065x.1998.tb01190.x. PMID: 9700504.

Whiting PJ, Vincent A, Newsom-Davis J. Myasthenia-Gravis: Monoclonal antihuman acetylcholine-receptor antibodies used to analyze antibody specificities and responses to treatment. Neurology. 1986;36:612-617. doi: 10.1212/wnl.36.5.612. PMID: 3703260.

Jacobson L, Beeson D, Tzartos S, Vincent A. Monoclonal antibodies raised against human acetylcholine receptor bind to all five subunits of the fetal isoform. J Neuroimmunol. 1999;98:112-120. doi: 10.1016/s0165-5728(99)00086-7. PMID: 10430044.

Engel AG, Lambert EH, Howard FM. 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;52,267–280. PMID: 870771.

Sahashi K, Engel AG, Lambert EH, Howard FMJr. Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis. J. Neuropathol. Exp. Neurol. 1980; 39,160–172. doi: 10.1097/00005072-198003000-00005. PMID: 7373347.

Howard JF Jr, Nowak RJ, Wolfe GI, Freimer ML, Vu TH, Hinton JL, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: Results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. JAMA Neurol. 2020 May 1;77(5):582-592. doi: 10.1001/jamaneurol.2019.5125. PMID: 32065623; PMCID: PMC7042797.

Obaid AH, Zografou C, Vadysirisack DD, Munro-Sheldon B, Fichtner ML, Roy B, et al. Heterogeneity of acetylcholine receptor autoantibody-mediated complement activity in patients with myasthenia gravis. Neurol Neuroimmunol Neuroinflamm. 2022 Apr 26;9(4):e1169. doi: 10.1212/NXI.0000000000001169. Erratum in: Neurol Neuroimmunol Neuroinflamm. 2022 Aug 3;9(5): PMID: 35473886; PMCID: PMC9128035.

Drachman DB, Angus CW, Adams RN, Michelson JD, Hoffman GJ. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N. Engl. J. Med. 1978;298,1116–1122. doi: 10.1056/NEJM197805182982004. PMID: 643030.

Rose N, Holdermann S, Callegari I, Kim H, Fruh I, Kappos L, et al. Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities. Acta Neuropathol. 2022 Nov;144(5):1005-1025. doi: 10.1007/s00401-022-02493-6. Epub 2022 Sep 8. PMID: 36074148; PMCID: PMC9547806.

Riemersma S, Vincent A, Beeson D, Newland C, Hawke S, Vernet-der Garabedian B, et al. Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine-receptor function. J. Clin. Invest. 1996; 98,2358–2363. doi: 10.1016/s0140-6736(95)92652-6. PMID: 7603140.

Jacobson L, Polizzi A, Morriss-Kay GM, Vincent A. An animal model of antibody-mediated neurodevelopmental disease: arythrogryposis multiplex congenita caused by antibodies to fetal acetylcholine receptor. J. Clin. Invest. 1999;103,1031–1038. doi: 10.1172/JCI5943. PMID: 10194476; PMCID: PMC408264.

Oskoui M, Jacobson L, Chung WK, Haddad J, Vincent A, Kaufmann P, et al. Fetal acetylcholine receptor inactivation syndrome and maternal myasthenia gravis. Neurology. 2008;71:2010-2012. doi: 10.1212/01.wnl.0000336929.38733.7a. PMID: 19064884; PMCID: PMC2676977.

Allen NM, O’Rahelly M, Eymard B, Chouchane M, Hahn A, Kearns G et al. The emerging spectrum of fetal acetylcholine receptor antibody-associated disorders (FARAD). Forthcoming Brain. 2023.

Pirskanen R. Genetic associations between myasthenia gravis and the HL-A system. J. Neurol. Neurosurg. Psychiatry. 1976;39, 23–33. doi: 10.1136/jnnp.39.1.23. PMID: 1255208; PMCID: PMC492209.

Compston DA, Vincent A, Newsom-Davis J, Batchelor JR. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain. 1980;103,579–601. doi: 10.1093/brain/103.3.579. PMID: 6968236.

Sauerbruch H, Schumacher CH, Roth P. Thymektomie bei einem fall von morbus basedowi mit myastheine. Mitteil. Grenzgeb. Med. Chir. 1913;25,746–765.

Blalock A, Mason MF, Morgan HJ, Riven SS. Myasthenia gravis and tumors of the thymic region. Report of a case in which the tumor was removed. Ann. Surg. 1939;110,544–559. doi: 10.1097/00000658-193910000-00005. PMID: 17857470; PMCID: PMC1391425.

Scadding GK, Vincent A, Newsom-Davis J, Henry K. Acetylcholine receptor antibody synthesis by thymic lymphocytes: correlation with thymic histology. Neurology 1981;31:935–943. doi: 10.1212/wnl.31.8.935. PMID: 6973710.

Kao I, Drachman DB. Thymic muscle cells bear acetylcholine receptors: possible relation to myasthenia gravis. Science. 1977;195:74-75. doi: 10.1126/science.831257. PMID: 831257.

Vincent A, Newsom-Davis J, Newton P, Beck N. Acetylcholine-receptor antibody and clinical-response to thymectomy in myasthenia-gravis. Neurology. 1983;33:1276-1282. doi: 10.1212/wnl.33.10.1276. PMID: 6684222.

Kuks J, Oosterhuis HJ, Limburg PC, The TH. Anti-acetylcholine receptor antibodies decrease after thymectomy in patients with myasthenia gravis. Clinical correlations. J. Autoimmun. 1991;4,197–211. doi: 10.1016/0896-8411(91)90018-8. PMID: 1883480.

Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55,7–15 (2000). doi: 10.1212/wnl.55.1.7. PMID: 10891896.

Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, et al. Randomized trial of thymectomy in myasthenia gravis. New Engl J Med. 2016;375:511-522. PMID: 27509100; PMCID: PMC5189669.

Müller-Hermelink HK, Wilisch A, Schultz A, Marx A. Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma.

Arch Histol Cytol. 1997;60:9-28. doi: 10.1679/aohc.60.9. PMID: 9161686.

Aarli JA, Stefansson K, Marton LS, Wollmann RL. Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin. Clin. Exp. Immunol. 1990;82, 284–288. doi: 10.1111/j.1365-2249.1990.tb05440.x. PMID: 2242609; PMCID: PMC1535140.

Mygland A, Rysnes OB, Matre R, Volpe P, Aarli JA, Gilhus NE. Ryanodine receptor autoantibodies in myasthenia gravis patients with a thymoma. Ann. Neurol. 1992;32, 589–591. doi: 10.1002/ana.410320419. PMID: 1333745.

Buckley C, Newsom-Davis J, Willcox N, Vincent A. Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence? Neurology. 2001;57,1579–1582. doi: 10.1212/wnl.57.9.1579. PMID: 11706095.

Salmon AM, Bruand C, Cardona A, Changeux J, Berrih-Aknin S. An acetylcholine receptor α-subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis. J. Clin. Invest. 1998;101,2340–2350. doi: 10.1172/JCI1615. PMID: 9616205; PMCID: PMC508823.

Buckley C, Dueck D, Newsom-Davis J, Vincent A, Willcox N. Mature, long-lived CD4 and CD8 T cells are generated by thymoma in myasthenia gravis. Ann. Neurol. 2001;50, 64–73. doi: 10.1002/ana.1017. PMID: 11456312.

Noda M, Takahashi H, Tanabe T, Toyosato M, Furutani Y, Hirose T, et al. Primary structure of α-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence. Nature. 1982;299,793–797. doi: 10.1038/299793a0. PMID: 6182472.

Beeson D, Brydson M, Betty M, Jeremiah S, Povey S, Vincent A, Newsom-Davis J. Primary structure of the human muscle acetylcholine receptor. cDNA cloning of the γ and ε subunits. Eur. J. Biochem. 1993;215,229–238. doi: 10.1111/j.1432-1033.1993.tb18027.x. PMID: 7688301.

Hohlfeld R, Toyka KV, Heininger K, Grosse-Wilde H, Kalies I. Autoimmune human T lymphocytes specific for acetylcholine receptor. Nature. 1984;310,244–246. doi: 10.1038/310244a0. PMID: 6611507.

Ong B, Willcox N, Wordsworth P, Beeson D, Vincent A, Altmann D, et al. Critical role for the Val/Gly86 HLA-DR beta dimorphism in autoantigen presentation to human T cells. Proc. Natl. Acad. Sci. U.S.A. 1991;88:7343-7347. doi: 10.1073/pnas.88.16.7343. PMID: 1714600; PMCID: PMC52291.

Melms A, Schalke BC, Kirchner T, Müller-Hermelink HK, Albert E, Wekerle HJ. Thymus in myasthenia gravis. Isolation of T-lymphocyte lines specific for the nicotinic acetylcholine receptor from thymuses of myasthenic patients. J. Clin. Invest. 1988;81:902-908. PMID: 2449461 doi: 10.1172/JCI113401. PMID: 2449461; PMCID: PMC442543.

Protti MP, Manfredi AA, Horton RM, Bellone M, Conti-Tronconi BM. Myasthenia gravis: recognition of a human autoantigen at the molecular level. Immunol. Today. 1993;14, 363–368. doi: 10.1016/0167-5699(93)90237-F. PMID: 8363727.

Willcox N, Baggi F, Batocchi AP, Beeson D, Harcourt G, Hawke S, et al. Approaches for studying the pathogenic T cells in autoimmune patients. Ann. Ny. Acad. Sci. 1993;681:219-37. doi: 10.1111/j.1749-6632.1993.tb22888.x. PMID: 8357164.

Hill M, Beeson D, Moss P, Jacobson L, Bond A, Corlett L, et al. Early-onset myasthenia gravis: A recurring T-cell epitope in the adult-specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a. Ann Neurol. 1999;45:224-231. doi: 10.1002/1531-8249(199902)45:2<224::aid-ana13>3.0.co;2-b. PMID: 9989625.

Nicolle MW, Nag B, Sharma SD, Willcox N, Vincent A, Ferguson DJP, et al. Specific tolerance to an acetylcholine receptor epitope induced in-vitro in myasthenia gravis CD4+ lymphocytes by soluble major histocompatibility complex class II-peptide complexes. J. Clin. Invest. 1994;93(4):1361-1369. doi: 10.1172/JCI117112. PMID: 7512979; PMCID: PMC294148.

Jerne NK. The generative grammar of the immune system. Nobel lecture, 8 December (1984). Biosci. Rep. 1985;5,439–451. doi: 10.1007/BF01116941. PMID: 3899210.

Dwyer DS, Bradley RJ, Urquhart CK, Kearney JF. Naturally occurring anti-idiotypic antibodies in myasthenia gravis patients. Nature. 1983;301,611–614. doi: 10.1038/301611a0. PMID: 6402708.

Schwimmbeck PL, Dryberg PL, Dyrberg T, Drachman DB, Oldstone MB. Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor α-subunit that has biologic activity and reacts immunochemically with herpes simplex virus. J. Clin. Invest. 1989;84,1174–1180. doi: 10.1016/0090-1229(90)90090-d. PMID: 1688524.

Stefansson K, Dieperink ME, Richman DP, Gomez CM, Marton LS. Sharing of antigenic determinants between the nicotinic acetylcholine receptor and proteins in Escherichia coli, Proteus vulgaris and Klebsiella pneumoniae. Possible role in the pathogenesis of myasthenia gravis. N. Engl. J. Med.1985;312,221–225. doi: 10.1056/NEJM198501243120407. PMID: 2578213.

Vincent AC. Are Spontaneous Anti-Idiotypic Antibodies against anti-acetylcholine receptor antibodies present in myasthenia-gravis. J. Autoimmun. 1988;1:131-42. doi: 10.1016/0896-8411(88)90021-2. PMID: 3252806.

Aoki T, Drachman DB, Asher DM, Gibbs CJ Jr, Bahmanyar S, Wolinsky JS. Attempts to implicate viruses in myasthenia gravis. Neurology. 1985; 35,185–192. doi: 10.1212/wnl.35.2.185. PMID: 2982113.

Klavinskis LS, Willcox N, Oxford JS, Newsom-Davis J. Attempted isolation of viruses from myasthenia-gravis thymus. J. Neuroimmunol. 1986;11:287-99. Doi: 10.1212/wnl.35.9.1381. PMID: 2991819.

Vincent, Willcox N, Hill M, Curnow J, MacLennan C, Beeson D. Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis. Immunol. Rev. 1998;164,157–168. doi: 10.1111/j.1600-065x.1998.tb01217.x. PMID: 9795773.

Mossman S, Vincent A, Newsom-Davis J. Myasthenia gravis without acetylcholine-receptor antibody: a distinct disease entity. Lancet. 1986;i,116–119. doi: 10.1016/s0140-6736(86)92259-2. PMID: 2417076.

Evoli, A. Batocchi AP, Lo Monaco M, Servidei S, Padua L, Majolini L, Tonali P. Clinical heterogeneity of seronegative myasthenia gravis. Neuromuscul. Disord. 1996; 6, 155–161. doi: 10.1016/0960-8966(96)00009-0. PMID: 8784802

Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, et al. IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain. 2008;131:1940-1952. doi: 10.1093/brain/awn092. Epub 2008 May 31. PMID: 18515870; PMCID: PMC2442426.

DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, Smith C, DiStefano PS, Glass DJ, Burden SJ, Yancopoulos GD. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell. 1996 May 17;85(4):501-12. doi: 10.1016/s0092-8674(00)81251-9. PMID: 8653786.

Kim N, Stiegler AL, Cameron TO, Hallock PT, Gomez AM, Huang JH, Hubbard SR, Dustin ML, Burden SJ. Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell. 2008 Oct 17;135(2):334-42. doi: 10.1016/j.cell.2008.10.002. Epub 2008 Oct 9. PMID: 18848351; PMCID: PMC2933840.

Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat. Med. 2001;7:365-368. doi: 10.1038/85520. PMID: 11231638.

McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann. Neurol. 2004;55:580-584. doi: 10.1002/ana.20061. PMID: 15048899.

Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003;126:2304-2311. doi: 10.1093/brain/awg223. Epub 2003 Jun 23. PMID: 12821509.

Leite MI, Strobel P, Jones M, Micklem K, Moritz R, Gold R, et al. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann. Neurol. 2005;57:444-448. doi: 10.1002/ana.20386. PMID: 15732104.

Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Rey A, Blesa R, et al. Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients.

Neuroimmunol. 2008;201-202:90-94. PMID: 18653247. doi: 10.1016/j.jneuroim.2008.04.039. Epub 2008 Jul 23. PMID: 18653247.

Stathopoulos P, Kumar A, Nowak RJ, O'Connor KC. Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis. JCI Insight. 2017 Sep 7;2(17):e94263. doi: 10.1172/jci.insight.94263. PMID: 28878127; PMCID: PMC5621905.

Huijbers MG, Zhang W, Klooster R, Niks EH, Friese MB, Straasheijm KR, Thijssen PE, Vrolijk H, Plomp JJ, Vogels P, Losen M, Van der Maarel SM, Burden SJ, Verschuuren JJ. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc. Natl. Acad. Sci. U.S.A. 2013 Dec 17;110(51):20783-8. doi: 10.1073/pnas.1313944110. Epub 2013 Dec 2. PMID: 24297891; PMCID: PMC3870730.

Koneczny I, Cossins J, Waters P, Beeson D, Vincent A. MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. PLoS One. 2013 Nov 7;8(11):e80695. doi: 10.1371/journal.pone.0080695. PMID: 24244707; PMCID: PMC3820634.

Huijbers MG, Vergoossen DL, Fillié-Grijpma YE, van Es IE, Koning MT, Slot LM, Veelken H, Plomp JJ, van der Maarel SM, Verschuuren JJ. MuSK myasthenia gravis monoclonal antibodies: Valency dictates pathogenicity. Neurol. Neuroimmunol. Neuroinflamm. 2019 Feb 21;6(3):e547. doi: 10.1212/NXI.0000000000000547. PMID: 30882021; PMCID: PMC6410930.

Takata K, Stathopoulos P, Cao M, Mané-Damas M, Fichtner ML, Benotti ES, Jacobson L, Waters P, Irani SR, Martinez-Martinez P, Beeson D, Losen M, Vincent A, Nowak RJ, O'Connor KC. Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients. JCI Insight. 2019 Jun 20;4(12):e127167. doi: 10.1172/jci.insight.127167. PMID: 31217355; PMCID: PMC6629167.

Koneczny I, Tzartos J, Mané-Damas M, Yilmaz V, Huijbers MG, Lazaridis K, Höftberger R, Tüzün E, Martinez-Martinez P, Tzartos S, Leypoldt F. IgG4 autoantibodies in organ-specific autoimmunopathies: Reviewing class switching, antibody-producing cells, and specific immunotherapies. Front. Immunol. 2022 Mar 24;13:834342. doi: 10.3389/fimmu.2022.834342. PMID: 35401530; PMCID: PMC8986991.

Hesselmans LF, Jennekens FG, Van den Oord CJ, Veldman H, Vincent A. Development of innervation of skeletal muscle fibers in man: relation to acetylcholine receptors. Anat. Rec. 1993 Jul;236(3):553-62. doi: 10.1002/ar.1092360315. PMID: 8363059.

Downloads

Published

2023-08-29

Issue

Section

MGFA International Conference Proceedings

How to Cite

Vincent, A. (2023). Myasthenia research over the last 50 years – a personal perspective. RRNMF Neuromuscular Journal, 4(3). https://doi.org/10.17161/rrnmf.v4i3.19551