Pathogenesis of myasthenia gravis
- Shawn J Bird, MD
Shawn J Bird, MD
- Professor of Neurology
- University of Pennsylvania School of Medicine
- Section Editors
- Jeremy M Shefner, MD, PhD
Jeremy M Shefner, MD, PhD
- Section Editor — Neuromuscular Disease
- Professor and Chair of Neurology, Barrow Neurological Institute
- Professor of Neurology, University of Arizona, Phoenix
- Clinical Professor of Neurology, Creighton University
- Ira N Targoff, MD
Ira N Targoff, MD
- Section Editor — Muscle Disease
- Professor of Medicine, Section of Rheumatology
- University of Oklahoma Health Sciences Center
Myasthenia gravis is an autoimmune disorder characterized by weakness and fatigability of skeletal muscles. Muscle weakness due to dysfunction of the neuromuscular junction (myasthenia) may be an acquired disorder. The vast majority of patients who develop myasthenia in adolescence or adulthood have autoantibodies that play a pathogenetically important role by attacking the acetylcholine receptor (AChR), fixing complement, and reducing the number of AChRs over time. These autoantibodies are thought to originate in hyperplastic germinal centers in the thymus where myoid cells expressing AChR are clustered. Such antibody-mediated disease is referred to as myasthenia gravis.
Similar weakness can also result from mutation of components of the neuromuscular junction, resulting in a group of disorders collectively referred to as "congenital myasthenia." This type of myasthenia is often appreciated at birth. Congenital myasthenia and weakness in newborns that is due to transplacental passage of antibodies from a pregnant woman with myasthenia gravis are presented separately. (See "Neuromuscular junction disorders in newborns and infants".)
The pathogenesis of myasthenia gravis is discussed in this topic review. Other aspects of this disorder are discussed separately. (See "Clinical manifestations of myasthenia gravis" and "Diagnosis of myasthenia gravis" and "Treatment of myasthenia gravis".)
Myasthenia gravis is a condition that fulfills all the major criteria for a disorder mediated by autoantibodies against the acetylcholine receptor (AChR) [1,2]:
●The autoantibodies are present in 80 to 90 percent of affected patients
- Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330:1797.
- Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2002; 2:797.
- Drachman DB, Adams RN, Josifek LF, Self SG. Functional activities of autoantibodies to acetylcholine receptors and the clinical severity of myasthenia gravis. N Engl J Med 1982; 307:769.
- Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006; 116:2843.
- Karlin A, Akabas MH. Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 1995; 15:1231.
- Vincent A, Whiting PJ, Schluep M, et al. Antibody heterogeneity and specificity in myasthenia gravis. Ann N Y Acad Sci 1987; 505:106.
- Nielsen FC, Rødgaard A, Djurup R, et al. A triple antibody assay for the quantitation of plasma IgG subclass antibodies to acetylcholine receptors in patients with myasthenia gravis. J Immunol Methods 1985; 83:249.
- Hoch W, McConville J, Helms S, et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001; 7:365.
- Vincent A, McConville J, Farrugia ME, et al. Antibodies in myasthenia gravis and related disorders. Ann N Y Acad Sci 2003; 998:324.
- McConville J, Farrugia ME, Beeson D, et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004; 55:580.
- Liyanage Y, Hoch W, Beeson D, Vincent A. The agrin/muscle-specific kinase pathway: new targets for autoimmune and genetic disorders at the neuromuscular junction. Muscle Nerve 2002; 25:4.
- Ohta K, Shigemoto K, Kubo S, et al. MuSK antibodies in AChR Ab-seropositive MG vs AChR Ab-seronegative MG. Neurology 2004; 62:2132.
- Yeh JH, Chen WH, Chiu HC, Vincent A. Low frequency of MuSK antibody in generalized seronegative myasthenia gravis among Chinese. Neurology 2004; 62:2131.
- Rødgaard A, Nielsen FC, Djurup R, et al. Acetylcholine receptor antibody in myasthenia gravis: predominance of IgG subclasses 1 and 3. Clin Exp Immunol 1987; 67:82.
- Leite MI, Jacob S, Viegas S, et al. IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain 2008; 131:1940.
- Ghazanfari N, Fernandez KJ, Murata Y, et al. Muscle specific kinase: organiser of synaptic membrane domains. Int J Biochem Cell Biol 2011; 43:295.
- Bergamin E, Hallock PT, Burden SJ, Hubbard SR. The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell 2010; 39:100.
- Okada K, Inoue A, Okada M, et al. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 2006; 312:1802.
- Cartaud A, Strochlic L, Guerra M, et al. MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. J Cell Biol 2004; 165:505.
- Peng HB, Xie H, Rossi SG, Rotundo RL. Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. J Cell Biol 1999; 145:911.
- Shigemoto K, Kubo S, Maruyama N, et al. Induction of myasthenia by immunization against muscle-specific kinase. J Clin Invest 2006; 116:1016.
- Richman DP, Nishi K, Morell SW, et al. Acute severe animal model of anti-muscle-specific kinase myasthenia: combined postsynaptic and presynaptic changes. Arch Neurol 2012; 69:453.
- Cole RN, Reddel SW, Gervásio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol 2008; 63:782.
- Selcen D, Fukuda T, Shen XM, Engel AG. Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology 2004; 62:1945.
- Shiraishi H, Motomura M, Yoshimura T, et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 2005; 57:289.
- Niks EH, Kuks JB, Wokke JH, et al. Pre- and postsynaptic neuromuscular junction abnormalities in musk myasthenia. Muscle Nerve 2010; 42:283.
- Kawakami Y, Ito M, Hirayama M, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77:1819.
- Sigoillot SM, Bourgeois F, Lambergeon M, et al. ColQ controls postsynaptic differentiation at the neuromuscular junction. J Neurosci 2010; 30:13.
- Sanders DB, El-Salem K, Massey JM, et al. Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003; 60:1978.
- Chan KH, Lachance DH, Harper CM, Lennon VA. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve 2007; 36:651.
- Sanders DB, Andrews PI, Howard Jr JF, Massey JM. Seronegative myasthenia gravis. Neurology 1997; 48:S40.
- Deymeer F, Gungor-Tuncer O, Yilmaz V, et al. Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis. Neurology 2007; 68:609.
- Jacob S, Viegas S, Leite MI, et al. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol 2012; 69:994.
- Rodríguez Cruz PM, Al-Hajjar M, Huda S, et al. Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis. JAMA Neurol 2015; 72:642.
- Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011; 69:418.
- Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 2012; 259:427.
- Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol 2012; 69:445.
- Madhavan R, Gong ZL, Ma JJ, et al. The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction. PLoS One 2009; 4:e8478.
- Cortés-Vicente E, Gallardo E, Martínez MÁ, et al. Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin. JAMA Neurol 2016; 73:1099.
- Ohta M, Ohta K, Itoh N, et al. Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis. Clin Chim Acta 1990; 187:255.
- Nauert JB, Klauck TM, Langeberg LK, Scott JD. Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr Biol 1997; 7:52.
- Agius MA, Zhu S, Kirvan CA, et al. Rapsyn antibodies in myasthenia gravis. Ann N Y Acad Sci 1998; 841:516.
- Yi Q, Pirskanen R, Lefvert AK. Human muscle acetylcholine receptor reactive T and B lymphocytes in the peripheral blood of patients with myasthenia gravis. J Neuroimmunol 1993; 42:215.
- Jambou F, Zhang W, Menestrier M, et al. Circulating regulatory anti-T cell receptor antibodies in patients with myasthenia gravis. J Clin Invest 2003; 112:265.
- Willcox N, Leite MI, Kadota Y, et al. Autoimmunizing mechanisms in thymoma and thymus. Ann N Y Acad Sci 2008; 1132:163.
- Leite MI, Jones M, Ströbel P, et al. Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Am J Pathol 2007; 171:893.
- Hohlfeld R, Wekerle H. Reflections on the "intrathymic pathogenesis" of myasthenia gravis. J Neuroimmunol 2008; 201-202:21.
- Tolosa E, Li W, Yasuda Y, et al. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J Clin Invest 2003; 112:517.
- Carlsson B, Wallin J, Pirskanen R, et al. Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis. Immunogenetics 1990; 31:285.
- Niks EH, Kuks JB, Roep BO, et al. Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5. Neurology 2006; 66:1772.
- Cavalcante P, Serafini B, Rosicarelli B, et al. Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol 2010; 67:726.
- Wilisch A, Gutsche S, Hoffacker V, et al. Association of acetylcholine receptor alpha-subunit gene expression in mixed thymoma with myasthenia gravis. Neurology 1999; 52:1460.
- Voltz RD, Albrich WC, Nägele A, et al. Paraneoplastic myasthenia gravis: detection of anti-MGT30 (titin) antibodies predicts thymic epithelial tumor. Neurology 1997; 49:1454.
- Gautel M, Lakey A, Barlow DP, et al. Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin. Neurology 1993; 43:1581.
- Romi F, Gilhus NE, Varhaug JE, et al. Disease severity and outcome in thymoma myasthenia gravis: a long-term observation study. Eur J Neurol 2003; 10:701.
- Yamamoto AM, Gajdos P, Eymard B, et al. Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients. Arch Neurol 2001; 58:885.
- Romi F, Gilhus NE, Varhaug JE, et al. Thymectomy and antimuscle antibodies in nonthymomatous myasthenia gravis. Ann N Y Acad Sci 2003; 998:481.
- Meraouna A, Cizeron-Clairac G, Panse RL, et al. The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. Blood 2006; 108:432.
- Berrih-Aknin S, Ruhlmann N, Bismuth J, et al. CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia. Ann Neurol 2009; 66:521.
- Luckman SP, Skeie GO, Helgeland G, Gilhus NE. Morphological effects of myasthenia gravis patient sera on human muscle cells. Muscle Nerve 2006; 33:93.