PDF herunterladen
Semin Neurol 2018; 38(03): 344-354
DOI: 10.1055/s-0038-1660500
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pathogenic Mechanisms and Clinical Correlations in Autoimmune Myasthenic Syndromes

Hakan Cetin
1   Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
2   Department of Neurology, Medical University of Vienna, Vienna, Austria
,
Angela Vincent
1   Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
16. Juli 2018 (online)

    Lizenzen und Reprints

Abstract

Autoimmune myasthenic syndromes are antibody-mediated disorders of the neuromuscular junction. Common antigenic targets are the acetylcholine receptor or muscle specific kinase (MuSK) in myasthenia gravis (MG) and the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. There is evidence that antibodies directed against other antigens such as low-density lipoprotein receptor-related protein 4 (LRP4) are also involved in MG. The mechanisms by which various antibodies exert their pathogenic effect depend on the IgG subclass and also the epitope location on the antigens. These mechanisms are partly heterogeneous and include antigen degradation, complement activation, direct functional blocking, or disruption of protein–protein interactions. The neuromuscular junction is characterized by a structural and functional plasticity that is able to compensate for some of the neuromuscular junction defects. Here, we discuss the underlying pathogenic mechanisms of the different autoantibodies and correlate them with phenotypic features. The understanding of these elements should help guide the clinical management of patients with autoimmune myasthenic syndromes.

Keywords

neuromuscular junction - acetylcholine receptor - myasthenia gravis - Lambert-Eaton myasthenic syndrome
 

  • References

  • 1 Slater CR, Lyons PR, Walls TJ, Fawcett PR, Young C. Structure and function of neuromuscular junctions in the vastus lateralis of man. A motor point biopsy study of two groups of patients. Brain 1992; 115 (Pt 2): 451-478
    CrossrefPubMedGoogle Scholar
  • 2 Matthews-Bellinger JA, Salpeter MM. Fine structural distribution of acetylcholine receptors at developing mouse neuromuscular junctions. J Neurosci 1983; 3 (03) 644-657
    CrossrefPubMedGoogle Scholar
  • 3 Huh KH, Fuhrer C. Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses. Mol Neurobiol 2002; 25 (01) 79-112
    CrossrefPubMedGoogle Scholar
  • 4 Hoch W, Ferns M, Campanelli JT, Hall ZW, Scheller RH. Developmental regulation of highly active alternatively spliced forms of agrin. Neuron 1993; 11 (03) 479-490
    CrossrefPubMedGoogle Scholar
  • 5 Zong Y, Jin R. Structural mechanisms of the agrin-LRP4-MuSK signaling pathway in neuromuscular junction differentiation. Cell Mol Life Sci 2013; 70 (17) 3077-3088
    CrossrefPubMedGoogle Scholar
  • 6 Wallace BG, Qu Z, Huganir RL. Agrin induces phosphorylation of the nicotinic acetylcholine receptor. Neuron 1991; 6 (06) 869-878
    CrossrefPubMedGoogle Scholar
  • 7 Friese MB, Blagden CS, Burden SJ. Synaptic differentiation is defective in mice lacking acetylcholine receptor beta-subunit tyrosine phosphorylation. Development 2007; 134 (23) 4167-4176
    CrossrefPubMedGoogle Scholar
  • 8 Zuber B, Unwin N. Structure and superorganization of acetylcholine receptor-rapsyn complexes. Proc Natl Acad Sci U S A 2013; 110 (26) 10622-10627
    CrossrefPubMedGoogle Scholar
  • 9 Gillespie SK, Balasubramanian S, Fung ET, Huganir RL. Rapsyn clusters and activates the synapse-specific receptor tyrosine kinase MuSK. Neuron 1996; 16 (05) 953-962
    CrossrefPubMedGoogle Scholar
  • 10 Chen F, Qian L, Yang ZH. , et al. Rapsyn interaction with calpain stabilizes AChR clusters at the neuromuscular junction. Neuron 2007; 55 (02) 247-260
    CrossrefPubMedGoogle Scholar
  • 11 Engel AG, Lambert EH, Santa T. Study of long-term anticholinesterase therapy. Effects on neuromuscular transmission and on motor end-plate fine structure. Neurology 1973; 23 (12) 1273-1281
    CrossrefPubMedGoogle Scholar
  • 12 Chang CC, Chen TF, Chuang ST. Influence of chronic neostigmine treatment on the number of acetylcholine receptors and the release of acetylcholine from the rat diaphragm. J Physiol 1973; 230 (03) 613-618
    CrossrefPubMedGoogle Scholar
  • 13 Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol 2015; 14 (10) 1023-1036
    CrossrefPubMedGoogle Scholar
  • 14 Matsui N, Nakane S, Nakagawa Y. , et al. Increasing incidence of elderly onset patients with myasthenia gravis in a local area of Japan. J Neurol Neurosurg Psychiatry 2009; 80 (10) 1168-1171
    CrossrefPubMedGoogle Scholar
  • 15 de Meel RH, Lipka AF, van Zwet EW, Niks EH, Verschuuren JJ. Prognostic factors for exacerbations and emergency treatments in myasthenia gravis. J Neuroimmunol 2015; 282: 123-125
    CrossrefPubMedGoogle Scholar
  • 16 Jaretzki III A, Barohn RJ, Ernstoff RM. , et al; Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Myasthenia gravis: recommendations for clinical research standards. Neurology 2000; 55 (01) 16-23
    CrossrefPubMedGoogle Scholar
  • 17 Sharshar T, Chevret S, Mazighi M. , et al. Validity and reliability of two muscle strength scores commonly used as endpoints in assessing treatment of myasthenia gravis. J Neurol 2000; 247 (04) 286-290
    CrossrefPubMedGoogle Scholar
  • 18 Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985; 48 (12) 1246-1252
    CrossrefPubMedGoogle Scholar
  • 19 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 (11) 1054-1059
    CrossrefPubMedGoogle Scholar
  • 20 Kawanami S, Tsuji R, Oda K. Enzyme-linked immunosorbent assay for antibody against the nicotinic acetylcholine receptor in human myasthenia gravis. Ann Neurol 1984; 15 (02) 195-200
    CrossrefPubMedGoogle Scholar
  • 21 Leite MI, Waters P, Vincent A. Diagnostic use of autoantibodies in myasthenia gravis. Autoimmunity 2010; 43 (5-6): 371-379
    CrossrefPubMedGoogle Scholar
  • 22 Zisimopoulou P, Brenner T, Trakas N, Tzartos SJ. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens. Autoimmun Rev 2013; 12 (09) 924-930
    CrossrefPubMedGoogle Scholar
  • 23 Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2002; 2 (10) 797-804
    CrossrefPubMedGoogle Scholar
  • 24 Tzartos SJ, Barkas T, Cung MT. , et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol Rev 1998; 163: 89-120
    CrossrefPubMedGoogle Scholar
  • 25 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 (01) 188-192
    CrossrefPubMedGoogle Scholar
  • 26 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 (20) 1116-1122
    CrossrefPubMedGoogle Scholar
  • 27 Burges J, Wray DW, Pizzighella S, Hall Z, Vincent A. A myasthenia gravis plasma immunoglobulin reduces miniature endplate potentials at human endplates in vitro. Muscle Nerve 1990; 13 (05) 407-413
    CrossrefPubMedGoogle Scholar
  • 28 Bufler J, Kahlert S, Tzartos S, Toyka KV, Maelicke A, Franke C. Activation and blockade of mouse muscle nicotinic channels by antibodies directed against the binding site of the acetylcholine receptor. J Physiol 1996; 492 (Pt 1): 107-114
    CrossrefPubMedGoogle Scholar
  • 29 Lang B, Richardson G, Rees J, Vincent A, Newsom-Davis J. Plasma from myasthenia gravis patients reduces acetylcholine receptor agonist-induced Na+ flux into TE671 cell line. J Neuroimmunol 1988; 19 (1-2): 141-148
    CrossrefPubMedGoogle Scholar
  • 30 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 (13) 769-775
    CrossrefPubMedGoogle Scholar
  • 31 Lennon VA, Griesmann GE. Evidence against acetylcholine receptor having a main immunogenic region as target for autoantibodies in myasthenia gravis. Neurology 1989; 39 (08) 1069-1076
    CrossrefPubMedGoogle Scholar
  • 32 Vernet-der Garabedian B, Morel E, Bach JF. Heterogeneity of antibodies directed against the alpha-bungarotoxin binding site on human acetylcholine receptor and severity of myasthenia gravis. J Neuroimmunol 1986; 12 (01) 65-74
    CrossrefPubMedGoogle Scholar
  • 33 Vincent A, Newland C, Brueton L. , et al. Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen. Lancet 1995; 346 (8966): 24-25
    CrossrefPubMedGoogle Scholar
  • 34 Riemersma S, Vincent A, Beeson D. , et al. Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine receptor function. J Clin Invest 1996; 98 (10) 2358-2363
    CrossrefPubMedGoogle Scholar
  • 35 Ruff RL, Lennon VA. How myasthenia gravis alters the safety factor for neuromuscular transmission. J Neuroimmunol 2008; ;201-202: 13-20
    PubMedGoogle Scholar
  • 36 Verschuuren JJ, Huijbers MG, Plomp JJ. , et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev 2013; 12 (09) 918-923
    CrossrefPubMedGoogle Scholar
  • 37 Guyon T, Levasseur P, Truffault F, Cottin C, Gaud C, Berrih-Aknin S. Regulation of acetylcholine receptor alpha subunit variants in human myasthenia gravis. Quantification of steady-state levels of messenger RNA in muscle biopsy using the polymerase chain reaction. J Clin Invest 1994; 94 (01) 16-24
    CrossrefPubMedGoogle Scholar
  • 38 Guyon T, Wakkach A, Poea S. , et al. Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss. J Clin Invest 1998; 102 (01) 249-263
    CrossrefPubMedGoogle Scholar
  • 39 Asher O, Kues WA, Witzemann V, Tzartos SJ, Fuchs S, Souroujon MC. Increased gene expression of acetylcholine receptor and myogenic factors in passively transferred experimental autoimmune myasthenia gravis. J Immunol 1993; 151 (11) 6442-6450
    PubMedGoogle Scholar
  • 40 Molenaar PC, Newsom-Davis J, Polak RL, Vincent A. Choline acetyltransferase in skeletal muscle from patients with myasthenia gravis. J Neurochem 1981; 37 (05) 1081-1088
    CrossrefPubMedGoogle Scholar
  • 41 Molenaar PC, Polak RL, Miledi R, Alema S, Vincent A, Newsom-Davis J. Acetylcholine in intercostal muscle from myasthenia gravis patients and in rat diaphragm after blockade of acetylcholine receptors. Prog Brain Res 1979; 49: 449-458
    PubMedGoogle Scholar
  • 42 Cull-Candy SG, Miledi R, Trautmann A, Uchitel OD. On the release of transmitter at normal, myasthenia gravis and myasthenic syndrome affected human end-plates. J Physiol 1980; 299: 621-638
    CrossrefPubMedGoogle Scholar
  • 43 Plomp JJ, Van Kempen GT, De Baets MB, Graus YM, Kuks JB, Molenaar PC. Acetylcholine release in myasthenia gravis: regulation at single end-plate level. Ann Neurol 1995; 37 (05) 627-636
    CrossrefPubMedGoogle Scholar
  • 44 Miledi R, Molenaar PC, Polak RL. Alpha-Bungarotoxin enhances transmitter “released” at the neuromuscular junction. Nature 1978; 272 (5654): 641-643
    CrossrefPubMedGoogle Scholar
  • 45 Yumoto N, Kim N, Burden SJ. Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses. Nature 2012; 489 (7416): 438-442
    CrossrefPubMedGoogle Scholar
  • 46 Wu H, Lu Y, Shen C. , et al. Distinct roles of muscle and motoneuron LRP4 in neuromuscular junction formation. Neuron 2012; 75 (01) 94-107
    CrossrefPubMedGoogle Scholar
  • 47 Berrih-Aknin S, Le Panse R. Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun 2014; 52: 90-100
    CrossrefPubMedGoogle Scholar
  • 48 Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Ströbel P. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 2013; 12 (09) 875-884
    CrossrefPubMedGoogle Scholar
  • 49 Hohlfeld R, Toyka KV, Heininger K, Grosse-Wilde H, Kalies I. Autoimmune human T lymphocytes specific for acetylcholine receptor. Nature 1984; 310 (5974): 244-246
    CrossrefPubMedGoogle Scholar
  • 50 Willcox N, Leite MI, Kadota Y. , et al. Autoimmunizing mechanisms in thymoma and thymus. Ann N Y Acad Sci 2008; 1132: 163-173
    CrossrefPubMedGoogle Scholar
  • 51 Leprince C, Cohen-Kaminsky S, Berrih-Aknin S. , et al. Thymic B cells from myasthenia gravis patients are activated B cells. Phenotypic and functional analysis. J Immunol 1990; 145 (07) 2115-2122
    PubMedGoogle Scholar
  • 52 Fujii Y, Hashimoto J, Monden Y, Ito T, Nakahara K, Kawashima Y. Specific activation of lymphocytes against acetylcholine receptor in the thymus in myasthenia gravis. J Immunol 1986; 136 (03) 887-891
    PubMedGoogle Scholar
  • 53 Vincent A, Jacobson L, Shillito P. Response to human acetylcholine receptor alpha 138-199: determinant spreading initiates autoimmunity to self-antigen in rabbits. Immunol Lett 1994; 39 (03) 269-275
    CrossrefPubMedGoogle Scholar
  • 54 Maclennan CA, Vincent A, Marx A. , et al. Preferential expression of AChR epsilon-subunit in thymomas from patients with myasthenia gravis. J Neuroimmunol 2008; ;201–202: 28-32
    PubMedGoogle Scholar
  • 55 Balandina A, Lécart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 2005; 105 (02) 735-741
    CrossrefPubMedGoogle Scholar
  • 56 Zhang Y, Wang HB, Chi LJ, Wang WZ. The role of FoxP3+CD4+CD25hi Tregs in the pathogenesis of myasthenia gravis. Immunol Lett 2009; 122 (01) 52-57
    CrossrefPubMedGoogle Scholar
  • 57 Filosso PL, Galassi C, Ruffini E. , et al. Thymoma and the increased risk of developing extrathymic malignancies: a multicentre study. Eur J Cardiothorac Surg 2013; 44 (02) 219-224 , discussion 224
    CrossrefPubMedGoogle Scholar
  • 58 Mao ZF, Mo XA, Qin C, Lai YR, Hackett ML. Incidence of thymoma in myasthenia gravis: a systematic review. J Clin Neurol 2012; 8 (03) 161-169
    CrossrefPubMedGoogle Scholar
  • 59 Marx A, Willcox N, Leite MI. , et al. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity 2010; 43 (5-6): 413-427
    CrossrefPubMedGoogle Scholar
  • 60 Szczudlik P, Szyluk B, Lipowska M. , et al. Antititin antibody in early- and late-onset myasthenia gravis. Acta Neurol Scand 2014; 130 (04) 229-233
    CrossrefPubMedGoogle Scholar
  • 61 Romi F, Skeie GO, Gilhus NE, Aarli JA. Striational antibodies in myasthenia gravis: reactivity and possible clinical significance. Arch Neurol 2005; 62 (03) 442-446
    CrossrefPubMedGoogle Scholar
  • 62 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 (09) 1579-1582
    CrossrefPubMedGoogle Scholar
  • 63 Zach H, Cetin H, Hilger E. , et al. The effect of early prednisolone treatment on the generalization rate in ocular myasthenia gravis. Eur J Neurol 2013; 20 (04) 708-713
    CrossrefPubMedGoogle Scholar
  • 64 Sanders DB, Wolfe GI, Benatar M. , et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology 2016; 87 (04) 419-425
    CrossrefPubMedGoogle Scholar
  • 65 Wolfe GI, Kaminski HJ, Aban IB. , et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med 2016; 375 (06) 511-522 (corrected in N Engl J Med 2017;376(21):2097)
    CrossrefPubMedGoogle Scholar
  • 66 Vincent A, Newsom Davis J. Anti-acetylcholine receptor antibodies. J Neurol Neurosurg Psychiatry 1980; 43 (07) 590-600
    CrossrefPubMedGoogle Scholar
  • 67 Takeo G, Motomura M, Mats H. , et al. Effect of myasthenic IgG on degradation of junctional acetylcholine receptor. Muscle Nerve 1993; 16 (08) 840-848
    CrossrefPubMedGoogle Scholar
  • 68 Roses AD, Olanow CW, McAdams MW, Lane RJ. No direct correlation between serum antiacetylcholine receptor antibody levels and clinical state of individual patients with myasthenia gravis. Neurology 1981; 31 (02) 220-224
    CrossrefPubMedGoogle Scholar
  • 69 Masuda T, Motomura M, Utsugisawa K. , et al. Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis. J Neurol Neurosurg Psychiatry 2012; 83 (09) 935-940
    CrossrefPubMedGoogle Scholar
  • 70 Newsom-Davis J, Wilson SG, Vincent A, Ward CD. Long-term effects of repeated plasma exchange in myasthenia gravis. Lancet 1979; 1 (8114): 464-468
    PubMedGoogle Scholar
  • 71 Heldal AT, Eide GE, Romi F, Owe JF, Gilhus NE. Repeated acetylcholine receptor antibody-concentrations and association to clinical myasthenia gravis development. PLoS One 2014; 9 (12) e114060
    CrossrefPubMedGoogle Scholar
  • 72 Vincent A, Newsom-Davis J, Newton P, Beck N. Acetylcholine receptor antibody and clinical response to thymectomy in myasthenia gravis. Neurology 1983; 33 (10) 1276-1282
    CrossrefPubMedGoogle Scholar
  • 73 Leite MI, Jacob S, Viegas S. , et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008; 131 (Pt 7): 1940-1952
    CrossrefPubMedGoogle Scholar
  • 74 Devic P, Petiot P, Simonet T. , et al. Antibodies to clustered acetylcholine receptor: expanding the phenotype. Eur J Neurol 2014; 21 (01) 130-134
    CrossrefPubMedGoogle Scholar
  • 75 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 (08) 994-1001
    PubMedGoogle Scholar
  • 76 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 (06) 642-649
    CrossrefPubMedGoogle Scholar
  • 77 Rodriguez Cruz PM, Huda S, López-Ruiz P, Vincent A. Use of cell-based assays in myasthenia gravis and other antibody-mediated diseases. Exp Neurol 2015; 270: 66-71
    CrossrefPubMedGoogle Scholar
  • 78 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 (03) 365-368
    CrossrefPubMedGoogle Scholar
  • 79 Huda S, Waters P, Woodhall M. , et al. IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG. Neurol Neuroimmunol Neuroinflamm 2017; 4 (04) e357
    CrossrefPubMedGoogle Scholar
  • 80 Huijbers MG, Querol LA, Niks EH. , et al. The expanding field of IgG4-mediated neurological autoimmune disorders. Eur J Neurol 2015; 22 (08) 1151-1161
    CrossrefPubMedGoogle Scholar
  • 81 Koneczny I, Stevens JA, De Rosa A. , et al. IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients. J Autoimmun 2017; 77: 104-115
    CrossrefPubMedGoogle Scholar
  • 82 Zhang W, Coldefy AS, Hubbard SR, Burden SJ. Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK). J Biol Chem 2011; 286 (47) 40624-40630
    CrossrefPubMedGoogle Scholar
  • 83 Huijbers MG, Zhang W, Klooster R. , et al. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc Natl Acad Sci U S A 2013; 110 (51) 20783-20788
    CrossrefPubMedGoogle Scholar
  • 84 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; 8 (11) e80695
    CrossrefPubMedGoogle Scholar
  • 85 Kawakami Y, Ito M, Hirayama M. , et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77 (20) 1819-1826
    CrossrefPubMedGoogle Scholar
  • 86 Cole RN, Reddel SW, Gervásio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol 2008; 63 (06) 782-789
    CrossrefPubMedGoogle Scholar
  • 87 Cole RN, Ghazanfari N, Ngo ST, Gervásio OL, Reddel SW, Phillips WD. Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice. J Physiol 2010; 588 (Pt 17): 3217-3229
    CrossrefPubMedGoogle Scholar
  • 88 Shiraishi H, Motomura M, Yoshimura T. , et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 2005; 57 (02) 289-293
    CrossrefPubMedGoogle Scholar
  • 89 Klooster R, Plomp JJ, Huijbers MG. , et al. Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 2012; 135 (Pt 4): 1081-1101
    CrossrefPubMedGoogle Scholar
  • 90 Mori S, Yamada S, Kubo S. , et al. Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis. J Neuroimmunol 2012; 244 (1-2): 1-7
    CrossrefPubMedGoogle Scholar
  • 91 Morsch M, Reddel SW, Ghazanfari N, Toyka KV, Phillips WD. Muscle specific kinase autoantibodies cause synaptic failure through progressive wastage of postsynaptic acetylcholine receptors. Exp Neurol 2012; 237 (02) 286-295
    CrossrefPubMedGoogle Scholar
  • 92 Viegas S, Jacobson L, Waters P. , et al. Passive and active immunization models of MuSK-Ab positive myasthenia: electrophysiological evidence for pre and postsynaptic defects. Exp Neurol 2012; 234 (02) 506-512
    CrossrefPubMedGoogle Scholar
  • 93 Evoli A, Tonali PA, Padua L. , et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003; 126 (Pt 10): 2304-2311
    CrossrefPubMedGoogle Scholar
  • 94 Farrugia ME, Robson MD, Clover L. , et al. MRI and clinical studies of facial and bulbar muscle involvement in MuSK antibody-associated myasthenia gravis. Brain 2006; 129 (Pt 6): 1481-1492
    CrossrefPubMedGoogle Scholar
  • 95 Hatanaka Y, Hemmi S, Morgan MB. , et al. Nonresponsiveness to anticholinesterase agents in patients with MuSK-antibody-positive MG. Neurology 2005; 65 (09) 1508-1509
    PubMedGoogle Scholar
  • 96 Morsch M, Reddel SW, Ghazanfari N, Toyka KV, Phillips WD. Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody. J Physiol 2013; 591 (10) 2747-2762
    CrossrefPubMedGoogle Scholar
  • 97 Lauriola L, Ranelletti F, Maggiano N. , et al. Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology 2005; 64 (03) 536-538
    CrossrefPubMedGoogle Scholar
  • 98 Díaz-Manera J, Martínez-Hernández E, Querol L. , et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology 2012; 78 (03) 189-193
    CrossrefPubMedGoogle Scholar
  • 99 Niks EH, van Leeuwen Y, Leite MI. , et al. Clinical fluctuations in MuSK myasthenia gravis are related to antigen-specific IgG4 instead of IgG1. J Neuroimmunol 2008; 195 (1-2): 151-156
    CrossrefPubMedGoogle Scholar
  • 100 Huijbers MG, Vink AF, Niks EH. , et al. Longitudinal epitope mapping in MuSK myasthenia gravis: implications for disease severity. J Neuroimmunol 2016; 291: 82-88
    CrossrefPubMedGoogle Scholar
  • 101 Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011; 69 (02) 418-422
    CrossrefPubMedGoogle Scholar
  • 102 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 (04) 445-451
    CrossrefPubMedGoogle Scholar
  • 103 Pevzner A, Schoser B, Peters K. , et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 2012; 259 (03) 427-435
    CrossrefPubMedGoogle Scholar
  • 104 Shen C, Lu Y, Zhang B. , et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest 2013; 123 (12) 5190-5202
    CrossrefPubMedGoogle Scholar
  • 105 Zisimopoulou P, Evangelakou P, Tzartos J. , et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun 2014; 52: 139-145
    CrossrefPubMedGoogle Scholar
  • 106 Tzartos JS, Zisimopoulou P, Rentzos M. , et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol 2014; 1 (02) 80-87
    CrossrefPubMedGoogle Scholar
  • 107 Rivner MH, Liu S, Quarles B. , et al. Agrin and low-density lipoprotein-related receptor protein 4 antibodies in amyotrophic lateral sclerosis patients. Muscle Nerve 2017; 55 (03) 430-432
    CrossrefPubMedGoogle Scholar
  • 108 Gasperi C, Melms A, Schoser B. , et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology 2014; 82 (22) 1976-1983
    CrossrefPubMedGoogle Scholar
  • 109 Zhang B, Shen C, Bealmear B. , et al. Autoantibodies to agrin in myasthenia gravis patients. PLoS One 2014; 9 (03) e91816
    CrossrefPubMedGoogle Scholar
  • 110 Cossins J, Belaya K, Zoltowska K. , et al. The search for new antigenic targets in myasthenia gravis. Ann N Y Acad Sci 2012; 1275: 123-128
    CrossrefPubMedGoogle Scholar
  • 111 Zoltowska Katarzyna M, Belaya K, Leite M, Patrick W, Vincent A, Beeson D. Collagen Q–a potential target for autoantibodies in myasthenia gravis. J Neurol Sci 2015; 348 (1-2): 241-244
    CrossrefPubMedGoogle Scholar
  • 112 Yellen G. The voltage-gated potassium channels and their relatives. Nature 2002; 419 (6902): 35-42
    CrossrefPubMedGoogle Scholar
  • 113 Suzuki S, Baba A, Kaida K. , et al. Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies. Eur J Neurol 2014; 21 (02) 223-230
    CrossrefPubMedGoogle Scholar
  • 114 Romi F, Suzuki S, Suzuki N, Petzold A, Plant GT, Gilhus NE. Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis. J Neurol 2012; 259 (07) 1312-1316
    CrossrefPubMedGoogle Scholar
  • 115 Suzuki S, Satoh T, Yasuoka H. , et al. Novel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis. J Neuroimmunol 2005; 170 (1-2): 141-149
    CrossrefPubMedGoogle Scholar
  • 116 Madhavan R, Gong ZL, Ma JJ, Chan AW, Peng HB. The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction. PLoS One 2009; 4 (12) e8478
    CrossrefPubMedGoogle Scholar
  • 117 Gallardo E, Martínez-Hernández E, Titulaer MJ. , et al. Cortactin autoantibodies in myasthenia gravis. Autoimmun Rev 2014; 13 (10) 1003-1007
    CrossrefPubMedGoogle Scholar
  • 118 Cortés-Vicente E, Gallardo E, Martínez MA. , et al. Clinical characteristics of patients with double-seronegative myasthenia gravis and antibodies to cortactin. JAMA Neurol 2016; 73 (09) 1099-1104
    CrossrefPubMedGoogle Scholar
  • 119 Motomura M, Johnston I, Lang B, Vincent A, Newsom-Davis J. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1995; 58 (01) 85-87
    CrossrefPubMedGoogle Scholar
  • 120 Lennon VA, Kryzer TJ, Griesmann GE. , et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 1995; 332 (22) 1467-1474
    CrossrefPubMedGoogle Scholar
  • 121 Titulaer MJ, Maddison P, Sont JK. , et al. Clinical Dutch-English Lambert-Eaton Myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS. J Clin Oncol 2011; 29 (07) 902-908
    CrossrefPubMedGoogle Scholar
  • 122 Komai K, Iwasa K, Takamori M. Calcium channel peptide can cause an autoimmune-mediated model of Lambert-Eaton myasthenic syndrome in rats. J Neurol Sci 1999; 166 (02) 126-130
    CrossrefPubMedGoogle Scholar
  • 123 Kim YI. Passive transfer of the Lambert-Eaton myasthenic syndrome: neuromuscular transmission in mice injected with plasma. Muscle Nerve 1985; 8 (02) 162-172
    CrossrefPubMedGoogle Scholar
  • 124 Prior C, Lang B, Wray D, Newsom-Davis J. Action of Lambert-Eaton myasthenic syndrome IgG at mouse motor nerve terminals. Ann Neurol 1985; 17 (06) 587-592
    CrossrefPubMedGoogle Scholar
  • 125 Fukunaga H, Engel AG, Lang B, Newsom-Davis J, Vincent A. Passive transfer of Lambert-Eaton myasthenic syndrome with IgG from man to mouse depletes the presynaptic membrane active zones. Proc Natl Acad Sci U S A 1983; 80 (24) 7636-7640
    CrossrefPubMedGoogle Scholar
  • 126 Peers C, Johnston I, Lang B, Wray D. Cross-linking of presynaptic calcium channels: a mechanism of action for Lambert-Eaton myasthenic syndrome antibodies at the mouse neuromuscular junction. Neurosci Lett 1993; 153 (01) 45-48
    CrossrefPubMedGoogle Scholar
  • 127 Lambert EH, Lennon VA. Selected IgG rapidly induces Lambert-Eaton myasthenic syndrome in mice: complement independence and EMG abnormalities. Muscle Nerve 1988; 11 (11) 1133-1145
    CrossrefPubMedGoogle Scholar
  • 128 Kim YI, Neher E. IgG from patients with Lambert-Eaton syndrome blocks voltage-dependent calcium channels. Science 1988; 239 (4838): 405-408
    CrossrefPubMedGoogle Scholar
  • 129 Viglione MP, O'Shaughnessy TJ, Kim YI. Inhibition of calcium currents and exocytosis by Lambert-Eaton syndrome antibodies in human lung cancer cells. J Physiol 1995; 488 (Pt 2): 303-317
    CrossrefPubMedGoogle Scholar
  • 130 Takamori M, Iwasa K, Komai K. Antibodies to synthetic peptides of the alpha1A subunit of the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. Neurology 1997; 48 (05) 1261-1265
    CrossrefPubMedGoogle Scholar
  • 131 Parsons KT, Kwok WW. Linear B-cell epitopes in Lambert-Eaton myasthenic syndrome defined by cell-free synthetic peptide binding. J Neuroimmunol 2002; 126 (1-2): 190-195
    CrossrefPubMedGoogle Scholar
  • 132 Pellkofer HL, Armbruster L, Krumbholz M. , et al. Lambert-Eaton myasthenic syndrome differential reactivity of tumor versus non-tumor patients to subunits of the voltage-gated calcium channel. J Neuroimmunol 2008; 204 (1-2): 136-139
    CrossrefPubMedGoogle Scholar
  • 133 Verschuuren JJ, Dalmau J, Tunkel R. , et al. Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic syndrome. Neurology 1998; 50 (02) 475-479
    CrossrefPubMedGoogle Scholar
  • 134 Nakao YK, Motomura M, Fukudome T. , et al. Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients. Neurology 2002; 59 (11) 1773-1775
    CrossrefPubMedGoogle Scholar
  • 135 Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol 2011; 10 (12) 1098-1107
    CrossrefPubMedGoogle Scholar
  • 136 Titulaer MJ, Klooster R, Potman M. , et al. SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J Clin Oncol 2009; 27 (26) 4260-4267
    CrossrefPubMedGoogle Scholar
  • 137 Sabater L, Titulaer M, Saiz A, Verschuuren J, Güre AO, Graus F. SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology 2008; 70 (12) 924-928
    CrossrefPubMedGoogle Scholar
  • 138 Hatanaka Y, Oh SJ. Ten-second exercise is superior to 30-second exercise for post-exercise facilitation in diagnosing Lambert-Eaton myasthenic syndrome. Muscle Nerve 2008; 37 (05) 572-575
    CrossrefPubMedGoogle Scholar
  • 139 Oh SJ, Kurokawa K, Claussen GC, Ryan Jr HF. Electrophysiological diagnostic criteria of Lambert-Eaton myasthenic syndrome. Muscle Nerve 2005; 32 (04) 515-520
    CrossrefPubMedGoogle Scholar
  • 140 Waterman SA, Lang B, Newsom-Davis J. Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol 1997; 42 (02) 147-156
    CrossrefPubMedGoogle Scholar
  • 141 Waterman SA. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. Clin Auton Res 2001; 11 (03) 145-154
    CrossrefPubMedGoogle Scholar
  • 142 Lipka AF, Verschuuren JJ, Titulaer MJ. SOX1 antibodies in Lambert-Eaton myasthenic syndrome and screening for small cell lung carcinoma. Ann N Y Acad Sci 2012; 1275: 70-77
    CrossrefPubMedGoogle Scholar
  • 143 Maddison P, Lang B, Mills K, Newsom-Davis J. Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer. J Neurol Neurosurg Psychiatry 2001; 70 (02) 212-217
    CrossrefPubMedGoogle Scholar