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Semin Neurol 2004; 24(1): 21-30
DOI: 10.1055/s-2004-829585
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Pathophysiology of Myasthenia Gravis

Benjamin W. Hughes1 , Maria Luisa Moro De Casillas1 , Henry J. Kaminski1 , 2
  • 1Department of Neurology, Case Western Reserve University, Louis Stokes Cleveland DVA Medical Center, University Hospitals of Cleveland, Cleveland, Ohio
  • 2Department of Neurosciences, Case Western Reserve University, Louis Stokes Cleveland DVA Medical Center, University Hospitals of Cleveland, Cleveland, Ohio
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Publication History

Publication Date:
01 July 2004 (online)

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Myasthenia gravis (MG) is arguably the best understood autoimmune disease, and its study has also led to fundamental appreciation of mechanisms of neuromuscular transmission. MG is caused by antibodies against the acetylcholine receptor (AChR), which produce a compromise in the end-plate potential, reducing the safety factor for effective synaptic transmission. It is clear that AChR antibody destruction of the postsynaptic surface is dependent on complement activation. A muscle-specific kinase has been recently found to be an antigenic target in MG patients without antibodies against the AChR. Autoantibody production in MG is a T-cell-dependent process, but how a breakdown in tolerance occurs is not known. In MG there is an interesting differential involvement of muscle groups, in particular, the extraocular muscles. This article reviews normal neuromuscular transmission, mechanisms of the autoimmune process of MG, and differential susceptibility of eye muscles to MG.

KEYWORDS

Myasthenia gravis - neuromuscular transmission - acetylcholine receptor - neuromuscular junction

REFERENCES

  • 1 Engel A G. Anatomy and molecular architecture of the neuromuscular junction. In: Engel AG Myasthenia Gravis and Myasthenic Disorders. Oxford; Oxford University Press 1999: 3-39
    Google Scholar
  • 2 Sanes J R, Lichtman J W. Induction, assembly, maturation and maintenance of a postsynaptic apparatus.  Nat Rev Neurosci. 2001;  2 791-805
    CrossrefPubMedGoogle Scholar
  • 3 Boonyapisit K, Kaminski H J, Ruff R L. The molecular basis of neuromuscular transmission disorders.  Am J Med. 1999;  106 97-113
    CrossrefPubMedGoogle Scholar
  • 4 Ruff R L. Neurophysiology of the neuromuscular junction: overview.  Ann N Y Acad Sci. 2003;  998 1-10
    CrossrefPubMedGoogle Scholar
  • 5 Kaminski H J. Myasthenia Gravis and Related Disorders. Totowa, NJ; Humana Press 2003: 1-396
    Google Scholar
  • 6 Stanley E F. Presynaptic calcium channels and the transmitter release mechanism.  Ann N Y Acad Sci. 1993;  681 368-372
    PubMedGoogle Scholar
  • 7 Poage R E, Meriney S D. Presynaptic calcium influx, neurotransmitter release, and neuromuscular disease.  Physiol Behav. 2002;  77 507-512
    CrossrefPubMedGoogle Scholar
  • 8 Fon E A, Edwards R H. Molecular mechanisms of neurotransmitter release.  Muscle Nerve. 2001;  24 581-601
    PubMedGoogle Scholar
  • 9 Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis.  Physiol Rev. 2000;  80 717-766
    PubMedGoogle Scholar
  • 10 Abbas L. Synapse formation: let's stick together.  Curr Biol. 2003;  13 R25-R27
    CrossrefPubMedGoogle Scholar
  • 11 Arber S, Burden S J, Harris A J. Patterning of skeletal muscle.  Curr Opin Neurobiol. 2002;  12 100-103
    CrossrefPubMedGoogle Scholar
  • 12 McMahan U J, Sanes J R, Marshall L M. Cholinesterase is associated with the basal lamina at the neuromuscular junction.  Nature. 1978;  271 172-174
    PubMedGoogle Scholar
  • 13 Smit A B, Syed N I, Schaap D et al.. A glia-derived acetylcholine-binding protein that modulates synaptic transmission.  Nature. 2001;  411 261-268
    CrossrefPubMedGoogle Scholar
  • 14 Brejc K, van Dijk W J, Klaassen R V et al.. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.  Nature. 2001;  411 269-276
    CrossrefPubMedGoogle Scholar
  • 15 Wood S J, Slater C R. Safety factor at the neuromuscular junction.  Prog Neurobiol. 2001;  64 393-429
    CrossrefPubMedGoogle Scholar
  • 16 Vincent A. The neuromuscular junction and neuromuscular transmission. In: Karpati G, Hilton-Jones D, Griggs RC Disorders of Voluntary Muscle. Cambridge; Cambridge University Press 2001: 142-167
    Google Scholar
  • 17 Sieb J P, Dorfler P, Tzartos S et al.. Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency.  Neurology. 1998;  50 54-61
    PubMedGoogle Scholar
  • 18 Gautam M, Noakes P G, Mudd J et al.. Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice.  Nature. 1995;  377 232-236
    CrossrefPubMedGoogle Scholar
  • 19 Burke G, Cossins J, Maxwell S et al.. Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes.  Neurology. 2003;  61 826-828
    CrossrefPubMedGoogle Scholar
  • 20 Merlie J P, Sanes J R. Concentration of acetylcholine receptor mRNA in synaptic regions of adult muscle fibers.  Nature. 1985;  317 66-68
    CrossrefPubMedGoogle Scholar
  • 21 Brenman J E, Chao D S, Gee S H et al.. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains.  Cell. 1996;  84 757-767
    CrossrefPubMedGoogle Scholar
  • 22 Kusner L L, Kaminski H J. Nitric oxide synthase is concentrated at the skeletal muscle endplate.  Brain Res. 1996;  730 238-242
    PubMedGoogle Scholar
  • 23 Wang T, Xie Z, Lu B. Nitric oxide mediates activity dependent synaptic suppression at developing neuromuscular synapses.  Nature. 1995;  374 262-266
    CrossrefPubMedGoogle Scholar
  • 24 Kaminski H J, Ruff R L. Insights into possible skeletal muscle nicotinic acetylcholine receptor (AChR) changes in some congenital myasthenias from physiological studies, point mutations, subunit substitutions of the AChR.  Ann N Y Acad Sci. 1993;  681 435-450
    PubMedGoogle Scholar
  • 25 Lindstrom J. Acetylcholine receptors and myasthenia.  Muscle Nerve. 2000;  23 453-477
    PubMedGoogle Scholar
  • 26 Lindstrom J. Acetylcholine receptor structure. In: Kaminski HJ Myasthenia Gravis and Related Disorders. Totowa, NJ; Humana Press 2003: 15-52
    Google Scholar
  • 27 Unwin N. Projection structure of the nicotinic acetylcholine receptor: distinct conformations of the α subunits.  J Mol Biol. 1996;  257 586-596
    CrossrefPubMedGoogle Scholar
  • 28 Unwin N, Toyoshima C, Kubalek E. Arrangement of the acetylcholine receptor subunits in the resting and desensitized states, determined by cryoelectron microscopy of crystallized torpedo postsynaptic membranes.  J Cell Biol. 1988;  107 1123-1138
    CrossrefPubMedGoogle Scholar
  • 29 Brehm P, Henderson L. Regulation of acetylcholine receptor channel function during development of skeletal muscle.  Dev Biol. 1988;  129 1-11
    CrossrefPubMedGoogle Scholar
  • 30 Kaminski H J, Kusner L L, Block C H. Expression of acetylcholine receptor isoforms at extraocular muscle endplates.  Invest Ophthalmol Vis Sci. 1996;  37 345-351
    PubMedGoogle Scholar
  • 31 MacLennan C, Beeson D, Buijs A-M, Vincent A, Newsom-Davis J. Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis.  Ann Neurol. 1997;  41 423-431
    CrossrefPubMedGoogle Scholar
  • 32 Engel A G, Ohno K, Bouzat C, Sine S M, Griggs R C. End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit.  Ann Neurol. 1996;  40 810-817
    CrossrefPubMedGoogle Scholar
  • 33 Ruegg M A, Bixby J L. Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction.  Trends Neurosci. 1998;  21 22-27
    CrossrefPubMedGoogle Scholar
  • 34 Wallace B G. Agrin-induced specializations contain cytoplasmic, membrane, and extracellular matrix-associated components of the postsynaptic apparatus.  J Neurosci. 1989;  9 1294-1302
    PubMedGoogle Scholar
  • 35 Wallace B G, Qu Z, Huganir R L. Agrin induces phosphorylation of the nicotinic acetylcholine receptor.  Neuron. 1991;  6 869-878
    CrossrefPubMedGoogle Scholar
  • 36 Wallace B G. The mechanism of agrin-induced acetylcholine receptor aggregation.  Philos Trans R Soc Lond B Biol Sci. 1991;  331 273-280
    PubMedGoogle Scholar
  • 37 Gautam M, Noakes P G, Moscoso L et al.. Defective neuromuscular synaptogenesis in agrin-deficient mutant mice.  Cell. 1996;  85 525-535
    CrossrefPubMedGoogle Scholar
  • 38 Glass D J, Bowen D C, Stitt T N et al.. Agrin acts via a MuSK receptor complex.  Cell. 1996;  85 513-523
    CrossrefPubMedGoogle Scholar
  • 39 Wallace B. scFvs get down to basics: how MuSK makes synapses.  Nat Biotechnol. 1997;  15 721-722
    CrossrefPubMedGoogle Scholar
  • 40 Wickelgren I. Synapse-making molecules revealed.  Science. 1996;  272 1100
    CrossrefPubMedGoogle Scholar
  • 41 Lindstrom J M, Seybold M D, Lennon V A, Whittingham S, Duane D D. Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value.  Neurology. 1976;  26 1054-1059
    CrossrefPubMedGoogle Scholar
  • 42 Engel A G, Lambert E H, Howard F M. Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis. Ultrastructure and light microscopic localization and electrophysiological correlations.  Mayo Clin Proc. 1977;  52 267-280
    PubMedGoogle Scholar
  • 43 Toyka K V, Drachman D B, Griffin D E, Pestronk D. Myasthenia gravis study of humoral immune mechanisms by transfer to mice.  N Engl J Med. 1977;  296 125-131
    CrossrefPubMedGoogle Scholar
  • 44 Pinching A J, Peters D K, Newsom-Davis J. Remission of myasthenia gravis following plasma exchange.  Lancet. 1976;  2 1373-1376
    PubMedGoogle Scholar
  • 45 Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor.  Science. 1973;  180 871-872
    PubMedGoogle Scholar
  • 46 Conti-Fine B M, Kaminski H J. Autoimmune neuromuscular transmission disorders: myasthenia gravis and Lambert-Eaton myasthenic syndrome.  Continuum. 2001;  7 56-93
    PubMedGoogle Scholar
  • 47 Conti-Fine B, Bellone M, Howard J J, Protti M. Myasthenia Gravis: The Immunobiology of an Autoimmune Disease. Georgetown, TX; Neuroscience Intelligence, Unit: R.G. Landes 1997
    Google Scholar
  • 48 Drachman D, 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 USA. 1978;  75 3422-3426
    PubMedGoogle Scholar
  • 49 Sahashi K, Engel A G, Lambert E H, Howard Jr F M. 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
    PubMedGoogle Scholar
  • 50 Nakano S, Engel A G. Myasthenia gravis: quantitative immunocytochemical analysis of inflammatory cells and detection of complement membrane attack complex at the end-plate in 30 patients.  Neurology. 1993;  43 1167-1172
    CrossrefPubMedGoogle Scholar
  • 51 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;  147 973-983
    CrossrefPubMedGoogle Scholar
  • 52 Corey A L, Richman D P, Agius M A, Wollmann R L. Refractoriness to a second episode of experimental myasthenia gravis. Correlation with AChR concentration and morphologic appearance of the postsynaptic membrane.  J Immunol. 1987;  138 3269-3275
    PubMedGoogle Scholar
  • 53 Corey A L, Richman D P, Shuman C A, Gomez C M, Arnason B G. Use of monoclonal antiacetylcholine receptor antibodies to investigate the macrophage inflammation of acute experimental myasthenia gravis: refractoriness to a second episode of acute disease.  Neurology. 1985;  35 1455-1460
    PubMedGoogle Scholar
  • 54 Biesecker G, Gomez C M. Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with fab antibody to complement C5.  J Immunol. 1989;  142 2654-2659
    PubMedGoogle Scholar
  • 55 Tuzun E, Scott B G, Goluszko E, Higgs S, Christadoss P. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis.  J Immunol. 2003;  171 3847-3854
    PubMedGoogle Scholar
  • 56 Miwa T, Song W C. Membrane complement regulatory proteins: insight from animal studies and relevance to human diseases.  Int Immunopharmacol. 2001;  1 445-459
    PubMedGoogle Scholar
  • 57 Walport M J. Complement.  N Engl J Med. 2001;  344 1058-1066
    CrossrefPubMedGoogle Scholar
  • 58 Lin F, Kaminski H, Conti-Fine B, Wang W, Richmonds C, Medof M. Enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection.  J Clin Invest. 2002;  110 1269-1274
    CrossrefPubMedGoogle Scholar
  • 59 Tzartos S, Seybold M, Lindstrom J. Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies.  Proc Natl Acad Sci USA. 1982;  79 188-192
    PubMedGoogle Scholar
  • 60 Manfredi A A, Protti M P, Bellone M, Moiola L, Conti-Tronconi B M. Molecular anatomy of an autoantigen: T and B epitopes on the nicotinic acetylcholine receptor in myasthenia gravis.  J Lab Clin Med. 1992;  120 13-21
    PubMedGoogle Scholar
  • 61 Gomez C M, Richman D P. Monoclonal anti-acetylcholine receptor antibodies with differing capacities to induce experimental autoimmune myasthenia gravis.  J Immunol. 1985;  135 234-241
    PubMedGoogle Scholar
  • 62 Strauss A JL, Seegal J C, Hsu J C, Burkholder P M, Nastuk W, Ossermann K E. Immunofluoresence demonstration of a muscle binding, complement fixing serum globulin fraction in myasthenia gravis.  Proc Soc Exp Biol Med. 1960;  105 177-184
    PubMedGoogle Scholar
  • 63 Aarli J A, Stefanson K, Marton L SG, Wollman R L. Patients with myasthenia gravis and thymoma have in their sera IgG antibodies against titin.  Clin Exp Immunol. 1990;  82 284-288
    PubMedGoogle Scholar
  • 64 Skeie G O, Mygland Å, Aarli J A, Gilhus N E. Titin antibodies in patients with late onset myasthenia gravis: clinical correlations.  Autoimmunity. 1995;  20 99-104
    PubMedGoogle Scholar
  • 65 Skeie G O, Lunde P K, Sejersted O M, Mygland A, Aarli J A, Gilhus N E. Myasthenia gravis sera containing antiryanodine receptor antibodies inhibit binding of [3H]-ryanodine to sarcoplasmic reticulum.  Muscle Nerve. 1998;  21 329-335
    PubMedGoogle Scholar
  • 66 Mygland Å, Vincent A, Newsom-Davis J et al.. Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia.  Arch Neurol. 2000;  57 527-531
    CrossrefPubMedGoogle Scholar
  • 67 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
    CrossrefPubMedGoogle Scholar
  • 68 Evoli A, Tonali P A, Padua L et al.. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis.  Brain. 2003;  126 2304-2311
    CrossrefPubMedGoogle Scholar
  • 69 Vincent A, Bowen J, Newsom-Davis J, McConville J. Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets.  Lancet Neurol. 2003;  2 99-106
    CrossrefPubMedGoogle Scholar
  • 70 Yang B, McIntosh K R, Drachman D B. How subtle differences in MHC class II affect the severity of experimental myasthenia gravis.  Clin Immunol Immunopathol. 1998;  86 45-58
    CrossrefPubMedGoogle Scholar
  • 71 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
    PubMedGoogle Scholar
  • 72 Limburg P C, The T C, Hummel-Teppel E, Oosterhuis H. Anti-acetylcholine receptor antibodies in myasthenia gravis. I. Relation to clinical parameters in 250 patients.  J Neurol Sci. 1983;  58 357-370
    CrossrefPubMedGoogle Scholar
  • 73 Compston D AS, Vincent A, Newsom-Davis J, Batchelor J R. Clinical, pathological, HLA antigen, and immunological evidence for disease heterogeneity in myasthenia gravis.  Brain. 1980;  103 579-601
    CrossrefPubMedGoogle Scholar
  • 74 Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis.  Lancet. 2001;  357 2122-2128
    CrossrefPubMedGoogle Scholar
  • 75 Yi Q, Lefvert A K. Idiotype- and anti-idiotype-reactive T lymphocytes in myasthenia gravis. Evidence for the involvement of different subpopulations of T helper lymphocytes.  J Immunol. 1994;  153 3353-3359
    PubMedGoogle Scholar
  • 76 Link J, Navikas V, Yu M, Fredrikson S, Osterman P O, Link H. Augmented interferon-gamma, interleukin-4 and transforming growth factor-beta mRNA expression in blood mononuclear cells in myasthenia gravis.  J Neuroimmunol. 1994;  51 185-192
    CrossrefPubMedGoogle Scholar
  • 77 Hohlfeld R, Wekerle H. The thymus in myasthenia gravis.  Neurol Clin. 1994;  12 331-342
    PubMedGoogle Scholar
  • 78 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;  28 312-319
    CrossrefPubMedGoogle Scholar
  • 79 Schonbeck S, Padberg F, Hohlfeld R, Wekerle H. Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice.  J Clin Invest. 1992;  90 245-250
    PubMedGoogle Scholar
  • 80 Zheng Y, Wheatley L M, Liu T, Levinson A I. Acetylcholine receptor alpha subunit mRNA expression in human thymus: augmented expression in myasthenia gravis and upregulation by interferon-gamma.  Clin Immunol. 1999;  91 170-177
    CrossrefPubMedGoogle Scholar
  • 81 Kaminski H J, Fenstermaker R A, Abdul-Karim F W, Clayman J, Ruff R L. Acetylcholine receptor subunit gene expression in thymic tissue.  Muscle Nerve. 1993;  16 1332-1337
    PubMedGoogle Scholar
  • 82 Navaneetham D, Penn A S, Howard J FJ, Conti-Fine B M. Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the delta subunit.  Muscle Nerve. 2001;  24 203-210
    PubMedGoogle Scholar
  • 83 Gronseth G S, Barohn R J. 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
    CrossrefPubMedGoogle Scholar
  • 84 Grob D, Arsura E L, Brunner N G, Namba T. The course of myasthenia gravis and therapies affecting outcome.  Ann N Y Acad Sci. 1987;  505 472-499
    CrossrefPubMedGoogle Scholar
  • 85 Kaminski H J, Li Z, Richmonds C, Ruff R L, Kusner L. Susceptibility of ocular tissues to autoimmune diseases.  Ann N Y Acad Sci. 2003;  998 362-374
    CrossrefPubMedGoogle Scholar
  • 86 Ubogu E E, Kaminski H J. Preferential involvement of extraocular muscle by myasthenia gravis.  Neuroophthalmology. 2001;  25 219-228
    PubMedGoogle Scholar
  • 87 Leigh R J, Zee D S. The Neurology of Eye Movements. Contemporary Neurology Series. Philadelphia; F.A. Davis 1999: 561
    Google Scholar
  • 88 Porter J D. Extraocular muscle: cellular adaptations for a diverse functional repertoire.  Ann N Y Acad Sci. 2002;  956 7-16
    PubMedGoogle Scholar
  • 89 Ruff R L. Na current density at and away from end plates on rat fast- and slow-twitch skeletal muscle fibers.  Am J Physiol. 1992;  262 C229-C234
    PubMedGoogle Scholar
  • 90 Ruff R L, Lennon V. End-plate voltage-gated sodium channels are lost in clinical and experimental myasthenia gravis.  Ann Neurol. 1998;  43 370-379
    CrossrefPubMedGoogle Scholar
  • 91 Khanna S, Richmonds C, Kaminski H, Porter J. Molecular organization of the extraocular muscle neuromuscular junction: partial conservation of and divergence from skeletal muscle prototype.  Invest Ophthalmol Vis Sci. 2003;  44 1918-1926
    CrossrefPubMedGoogle Scholar
  • 92 Wang Z, Diethelm-Okita B, Okita D, Kaminski H, Howard J, Conti-Fine B. T-cell recognition of muscle acetylcholine receptor in ocular myasthenia gravis.  J Neuroimmunol. 2000;  108 29-39
    CrossrefPubMedGoogle Scholar
  • 93 Porter J D, Khanna S, Kaminski H J et al.. Extraocular muscle is defined by a fundamentally distinct gene expression profile.  Proc Natl Acad Sci USA. 2001;  98 12062-12067
    CrossrefPubMedGoogle Scholar

Henry J KaminskiM.D. 

Department of Neurology, University Hospitals of Cleveland

11100 Euclid Avenue, Cleveland, OH 44106