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Research Article

Antibody effector mechanisms in myasthenia gravis—Pathogenesis at the neuromuscular junction

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Pages 353-370 | Received 10 Dec 2009, Accepted 14 Dec 2009, Published online: 12 Apr 2010

References

  • 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.
  • 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 3: 365–368.
  • Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, Marino M, Bartoccioni E. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003; 126 Pt 10: 2304–2311.
  • Kong XC, Barzaghi P, Ruegg MA. Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference. EMBO Rep. 2004; 5 2: 183–188.
  • Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity. 2010; 43 5: 428–435.
  • Vrolix K, Fraussen J, Molenaar PC, Losen M, Somers V, Stinissen P, De Baets MH, Martínez-Martínez P. The auto-antigen repertoire in myasthenia gravis. Autoimmunity. 2010; 43 5: 380–400.
  • Marx A, Willcox N, Leite MI, Chuang W, Schalke B, Nix W, Ströbel P. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity. 2010; 43 5: 413–427.
  • Shiono H, Wong YL, Matthews I, Liu JL, Zhang W, Sims G, Meager A, Beeson D, Vincent A, Willcox N. Spontaneous production of anti-IFN-alpha and anti-IL-12 autoantibodies by thymoma cells from myasthenia gravis patients suggests autoimmunization in the tumor. Int Immunol. 2003; 15 8: 903–913.
  • Le Panse R, Bismuth J, Cizeron-Clairac G, Weiss JM, Cufi P, Dartevelle P, Kerlero de Rosbo N, Berrih-Aknin S. Thymic remodeling associated with hyperplasia in myasthenia gravis. Autoimmunity. 2010; 43 5: 401–412.
  • Leite MI, Strobel P, Jones M, Micklem K, Moritz R, Gold R, Niks EH, Berrih-Aknin S, Scaravilli F, Canelhas A, and others. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol. 2005; 57 3: 444–448.
  • Romi F, Skeie GO, Gilhus NE, Aarli JA. Striational antibodies in myasthenia gravis: Reactivity and possible clinical significance. Arch Neurol. 2005; 62 3: 442–446.
  • Vincent A, Leite MI. Neuromuscular junction autoimmune disease: Muscle specific kinase antibodies and treatments for myasthenia gravis. Curr Opin Neurol. 2005; 18 5: 519–525.
  • Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, Beeson D, Willcox N, Vincent A. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain. 2008; 131 Pt 7: 1940–1952.
  • Leite MI, Waters P, Vincent A. Diagnostic use of auto-antibodies in myasthenia gravis. Autoimmunity. 2010; 43 5: 371–379.
  • Changeux JP, Devillers-Thiery A, Chemouilli P. Acetylcholine receptor: An allosteric protein. Science. 1984; 225 4668: 1335–1345.
  • Katz B, Miledi R. Further observations on the distribution of actylcholine-reactive sites in skeletal muscle. J Physiol. 1964; 170:379–388.
  • Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog Neurobiol. 2001; 64 4: 393–429.
  • Schaeffer L, de Kerchove d'Exaerde A, Changeux JP. Targeting transcription to the neuromuscular synapse. Neuron. 2001; 31 1: 15–22.
  • Bevan S, Steinbach JH. The distribution of alpha-bungarotoxin binding sites of mammalian skeletal muscle developing in vivo. J Physiol. 1977; 267 1: 195–213.
  • Jessell TM, Siegel RE, Fischbach GD. Induction of acetylcholine receptors on cultured skeletal muscle by a factor extracted from brain and spinal cord. Proc Natl Acad Sci USA. 1979; 76 10: 5397–5401.
  • Goldman D, Staple J. Spatial and temporal expression of acetylcholine receptor RNAs in innervated and denervated rat soleus muscle. Neuron. 1989; 3 2: 219–228.
  • Gautam M, Noakes PG, Mudd J, Nichol M, Chu GC, Sanes JR, Merlie JP. Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature. 1995; 377 6546: 232–236.
  • Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, and others. Agrin acts via a MuSK receptor complex. Cell. 1996; 85 4: 513–523.
  • Moransard M, Borges LS, Willmann R, Marangi PA, Brenner HR, Ferns MJ, Fuhrer C. Agrin regulates rapsyn interaction with surface acetylcholine receptors, and this underlies cytoskeletal anchoring and clustering. J Biol Chem. 2003; 278 9: 7350–7359.
  • Cartaud A, Coutant S, Petrucci TC, Cartaud J. Evidence for in situ and in vitro association between beta-dystroglycan and the subsynaptic 43K rapsyn protein. Consequence for acetylcholine receptor clustering at the synapse. J Biol Chem. 1998; 273 18: 11321–11326.
  • Rybakova IN, Humston JL, Sonnemann KJ, Ervasti JM. Dystrophin and utrophin bind actin through distinct modes of contact. J Biol Chem. 2006; 281 15: 9996–10001.
  • Wang ZZ, Mathias A, Gautam M, Hall ZW. Metabolic stabilization of muscle nicotinic acetylcholine receptor by rapsyn. J Neurosci. 1999; 19 6: 1998–2007.
  • Phillips WD, Vladeta D, Han H, Noakes PG. Rapsyn and agrin slow the metabolic degradation of the acetylcholine receptor. Mol Cell Neurosci. 1997; 10 1–2: 16–26.
  • Drachman DB. Myasthenia gravis. N Engl J Med. 1994; 330 25: 1797–1810.
  • 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 5: 627–636.
  • 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.
  • Shiraishi H, Motomura M, Yoshimura T, Fukudome T, Fukuda T, Nakao Y, Tsujihata M, Vincent A, Eguchi K. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol. 2005; 57 2: 289–293.
  • Selcen D, Fukuda T, Shen XM, Engel AG. Are MuSK antibodies the primary cause of myasthenic symptoms?. Neurology. 2004; 62 11: 1945–1950.
  • McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol. 2004; 55 4: 580–584.
  • Kuwabara S, Nemoto Y, Misawa S, Takahashi H, Kawaguchi N, Hattori T. Anti-MuSK-positive myasthenia gravis: Neuromuscular transmission failure in facial and limb muscles. Acta Neurol Scand. 2007; 115 2: 126–128.
  • Stickler DE, Massey JM, Sanders DB. MuSK-antibody positive myasthenia gravis: Clinical and electrodiagnostic patterns. Clin Neurophysiol. 2005; 116 9: 2065–2068.
  • Farrugia ME, Kennett RP, Newsom-Davis J, Hilton-Jones D, Vincent A. Single-fiber electromyography in limb and facial muscles in muscle-specific kinase antibody and acetylcholine receptor antibody myasthenia gravis. Muscle Nerve. 2006; 33 4: 568–570.
  • Bruggemann M, Williams GT, Bindon CI, Clark MR, Walker MR, Jefferis R, Waldmann H, Neuberger MS. Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J Exp Med. 1987; 166 5: 1351–1361.
  • Dangl JL, Wensel TG, Morrison SL, Stryer L, Herzenberg LA, Oi VT. Segmental flexibility and complement fixation of genetically engineered chimeric human, rabbit and mouse antibodies. Embo J. 1988; 7 7: 1989–1994.
  • Tao MH, Canfield SM, Morrison SL. The differential ability of human IgG1 and IgG4 to activate complement is determined by the COOH-terminal sequence of the CH2 domain. J Exp Med. 1991; 173 4: 1025–1028.
  • Tan LK, Shopes RJ, Oi VT, Morrison SL. Influence of the hinge region on complement activation, C1q binding, and segmental flexibility in chimeric human immunoglobulins. Proc Natl Acad Sci USA. 1990; 87 1: 162–166.
  • Rodgaard A, Nielsen FC, Djurup R, Somnier F, Gammeltoft S. Acetylcholine receptor antibody in myasthenia gravis: Predominance of IgG subclasses 1 and 3. Clin Exp Immunol. 1987; 67 1: 82–88.
  • 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 2: 257–265.
  • Lefvert AK, Cuenoud S, Fulpius BW. Binding properties and subclass distribution of anti-acetylcholine receptor antibodies in myasthenia gravis. J Neuroimmunol. 1981; 1 1: 125–135.
  • Takeo G, Motomura M, Mats H, Ohishi K, Yoshimura T, Tsujihata M, Nagataki S. Effect of myasthenic IgG on degradation of junctional acetylcholine receptor. Muscle Nerve. 1993; 16 8: 840–848.
  • 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.
  • van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martinez-Martinez P, Vermeulen E, den Bleker TH, Wiegman L, Vink T, Aarden LA, and others. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007; 317 5844: 1554–1557.
  • Boneva N, Frenkian-Cuvelier M, Bidault J, Brenner T, Berrih-Aknin S. Major pathogenic effects of anti-MuSK antibodies in myasthenia gravis. J Neuroimmunol. 2006; 177 1–2: 119–131.
  • Schuurman J, Van Ree R, Perdok GJ, Van Doorn HR, Tan KY, Aalberse RC. Normal human immunoglobulin G4 is bispecific: It has two different antigen-combining sites. Immunology. 1999; 97 4: 693–698.
  • Petersen JG, Dorrington KJ. An in vitro system for studying the kinetics of interchain disulfide bond formation in immunoglobulin G. J Biol Chem. 1974; 249 17: 5633–5641.
  • Angal S, King DJ, Bodmer MW, Turner A, Lawson AD, Roberts G, Pedley B, Adair JR. A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody. Mol Immunol. 1993; 30 1: 105–108.
  • van der Zee JS, van Swieten P, Aalberse RC. Inhibition of complement activation by IgG4 antibodies. Clin Exp Immunol. 1986; 64 2: 415–422.
  • 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 2: 160–172.
  • 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.
  • Kao I, Drachman DB. Myasthenic immunoglobulin accelerates acetylcholine receptor degradation. Science. 1977; 196 4289: 527–529.
  • Stanley EF, Drachman DB. Effect of myasthenic immunoglobulin on acetylcholine receptors of intact mammalian neuromuscular junctions. Science. 1978; 200 4347: 1285–1287.
  • Pumplin DW, Drachman DB. Myasthenic patients’ IgG causes redistribution of acetylcholine receptors: Freeze-fracture studies. J Neurosci. 1983; 3 3: 576–584.
  • 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.
  • Howard FMJr, Lennon VA, Finley J, Matsumoto J, Elveback LR. Clinical correlations of antibodies that bind, block, or modulate human acetylcholine receptors in myasthenia gravis. Ann NY Acad Sci. 1987; 505:526–538.
  • Conti-Tronconi B, Tzartos S, Lindstrom J. Monoclonal antibodies as probes of acetylcholine receptor structure. 2. Binding to native receptor. Biochemistry. 1981; 20 8: 2181–2191.
  • Corey AL, Richman DP, Agius MA, Wollmann RL. Refractoriness to a second episode of experimental myasthenia gravis. Correlation with AChR concentration and morphologic appearance of the postsynaptic membrane. J Immunol. 1987; 138 10: 3269–3275.
  • Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. Ann N Y Acad Sci. 1987; 505:326–332.
  • Losen M, Martinez-Martinez P, Phernambucq M, Schuurman J, Parren PW, De Baets MH. Treatment of myasthenia gravis by preventing acetylcholine receptor modulation. Ann N Y Acad Sci. 2008; 1132:174–179.
  • Losen M, Stassen MH, Martinez-Martinez P, Machiels BM, Duimel H, Frederik P, Veldman H, Wokke JH, Spaans F, Vincent A, and others. Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis. Brain. 2005128(Pt 10: 2327–2337.
  • Lennon VA, Seybold ME, Lindstrom JM, Cochrane C, Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med. 1978; 147 4: 973–983.
  • Biesecker G, Gomez CM. Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6. J Immunol. 1989; 142 8: 2654–2659.
  • Piddlesden SJ, Jiang S, Levin JL, Vincent A, Morgan BP. Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis. J Neuroimmunol. 1996; 71 1–2: 173–177.
  • Christadoss P. C5 gene influences the development of murine myasthenia gravis. J Immunol. 1988; 140 8: 2589–2592.
  • Karachunski PI, Ostlie NS, Monfardini C, Conti-Fine BM. Absence of IFN-gamma or IL-12 has different effects on experimental myasthenia gravis in C57BL/6 mice. J Immunol. 2000; 164 10: 5236–5244.
  • 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 5: 267–280.
  • Mozrzymas JW, Lorenzon P, Riviera AP, Tedesco F, Ruzzier F. An electrophysiological study of the effects of myasthenia gravis sera and complement on rat isolated muscle fibres. J Neuroimmunol. 1993; 45 1–2: 155–162.
  • Martinez-Martinez P, Losen M, Duimel H, Frederik P, Spaans F, Molenaar P, Vincent A, De Baets MH. Overexpression of rapsyn in rat muscle increases acetylcholine receptor levels in chronic experimental autoimmune myasthenia gravis. Am J Pathol. 2007; 170 2: 644–657.
  • Gomez CM, Richman DP. Anti-acetylcholine receptor antibodies directed against the alpha-bungarotoxin binding site induce a unique form of experimental myasthenia. Proc Natl Acad Sci USA. 1983; 80 13: 4089–4093.
  • Whiting PJ, Vincent A, Newsom-Davis J. Acetylcholine receptor antibody characteristics in myasthenia gravis. Fractionation of alpha-bungarotoxin binding site antibodies and their relationship to IgG subclass. J Neuroimmunol. 1983; 5 1: 1–9.
  • Ito H, Yoshimura T, Satoh A, Takino H, Tsujihata M, Nagataki S. Immunohistochemical study of utrophin and dystrophin at the motor end-plate in myasthenia gravis. Acta Neuropathol. 1996; 92 1: 14–18.
  • Slater CR, Young C, Wood SJ, Bewick GS, Anderson LV, Baxter P, Fawcett PR, Roberts M, Jacobson L, Kuks J, and others. Utrophin abundance is reduced at neuromuscular junctions of patients with both inherited and acquired acetylcholine receptor deficiencies. Brain. 1997; 9 Pt 9: 1513–1531.
  • Engel AG, Sine SM. Current understanding of congenital myasthenic syndromes. Curr Opin Pharmacol. 2005; 5 3: 308–321.
  • Palace J, Beeson D. The congenital myasthenic syndromes. J Neuroimmunol. 2008; 201–202:2–5.
  • DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, and others. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell. 1996; 85 4: 501–512.
  • Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, and others. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006; 312 5781: 1802–1805.
  • Weatherbee SD, Anderson KV, Niswander LA. LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development. 2006; 133 24: 4993–5000.
  • Burke G, Cossins J, Maxwell S, Owens G, Vincent A, Robb S, Nicolle M, Hilton-Jones D, Newsom-Davis J, Palace J, and others. Rapsyn mutations in hereditary myasthenia: Distinct early- and late-onset phenotypes. Neurology. 2003; 61 6: 826–828.
  • Chevessier F, Faraut B, Ravel-Chapuis A, Richard P, Gaudon K, Bauche S, Prioleau C, Herbst R, Goillot E, Ioos C, and others. MUSK, a new target for mutations causing congenital myasthenic syndrome. Hum Mol Genet. 2004; 13 24: 3229–3240.
  • Beeson D, Higuchi O, Palace J, Cossins J, Spearman H, Maxwell S, Newsom-Davis J, Burke G, Fawcett P, Motomura M, and others. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006; 313 5795: 1975–1978.
  • Noakes PG, Gautam M, Mudd J, Sanes JR, Merlie JP. Aberrant differentiation of neuromuscular junctions in mice lacking s-laminin/laminin beta 2. Nature. 1995; 374 6519: 258–262.
  • Maselli RA, Ng JJ, Anderson JA, Cagney O, Arredondo J, Williams C, Wessel HB, Abdel-Hamid H, Wollmann RL. Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J Med Genet. 2009; 46 3: 203–208.
  • Martinez-Martinez P, Phernambucq M, Steinbusch L, Schaeffer L, Berrih-Aknin S, Duimel H, Frederik P, Molenaar P, De Baets MH, Losen M. Silencing rapsyn in vivo decreases acetylcholine receptors and augments sodium channels and secondary postsynaptic membrane folding. Neurobiol Dis. 2009; 35 1: 14–23.
  • Tanaka H, Ishiguro T, Eguchi C, Saito K, Ozawa E. Expression of a dystrophin-related protein associated with the skeletal muscle cell membrane. Histochemistry. 1991; 96 1: 1–5.
  • Tinsley JM, Blake DJ, Roche A, Fairbrother U, Riss J, Byth BC, Knight AE, Kendrick-Jones J, Suthers GK, Love DR, and others. Primary structure of dystrophin-related protein. Nature. 1992; 360 6404: 591–593.
  • Huard J, Fortier LP, Labrecque C, Dansereau G, Tremblay JP. Is dystrophin present in the nerve terminal at the neuromuscular junction? An immunohistochemical study of the heterozygote dystrophic (mdx) mouse. Synapse. 1991; 7 2: 135–140.
  • Bewick GS, Nicholson LV, Young C, O'Donnell E, Slater CR. Different distributions of dystrophin and related proteins at nerve-muscle junctions. Neuroreport. 1992; 3 10: 857–860.
  • Bewick GS, Young C, Slater CR. Spatial relationships of utrophin, dystrophin, beta-dystroglycan and beta-spectrin to acetylcholine receptor clusters during postnatal maturation of the rat neuromuscular junction. J Neurocytol. 1996; 25 7: 367–379.
  • Phillips WD, Noakes PG, Roberds SL, Campbell KP, Merlie JP. Clustering and immobilization of acetylcholine receptors by the 43-kD protein: A possible role for dystrophin-related protein. J Cell Biol. 1993; 123 3: 729–740.
  • Grady RM, Merlie JP, Sanes JR. Subtle neuromuscular defects in utrophin-deficient mice. J Cell Biol. 1997; 136 4: 871–882.
  • Deconinck AE, Potter AC, Tinsley JM, Wood SJ, Vater R, Young C, Metzinger L, Vincent A, Slater CR, Davies KE. Postsynaptic abnormalities at the neuromuscular junctions of utrophin-deficient mice. J Cell Biol. 1997; 136 4: 883–894.
  • Brockhausen J, Cole RN, Gervasio OL, Ngo ST, Noakes PG, Phillips WD. Neural agrin increases postsynaptic ACh receptor packing by elevating rapsyn protein at the mouse neuromuscular synapse. Dev Neurobiol. 2008; 68 9: 1153–1169.
  • 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; 135 2: 334–342.
  • Gervasio OL, Phillips WD. Increased ratio of rapsyn to ACh receptor stabilizes postsynaptic receptors at the mouse neuromuscular synapse. J Physiol. 2005; 562 Pt 3: 673–685.
  • Hesser BA, Henschel O, Witzemann V. Synapse disassembly and formation of new synapses in postnatal muscle upon conditional inactivation of MuSK. Mol Cell Neurosci. 2006; 31 3: 470–480.
  • Johnson EB, Hammer RE, Herz J. Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Hum Mol Genet. 2005; 14 22: 3523–3538.
  • Tian QB, Suzuki T, Yamauchi T, Sakagami H, Yoshimura Y, Miyazawa S, Nakayama K, Saitoh F, Zhang JP, Lu Y, and others. Interaction of LDL receptor-related protein 4 (LRP4) with postsynaptic scaffold proteins via its C-terminal PDZ domain-binding motif, and its regulation by Ca/calmodulin-dependent protein kinase II. Eur J Neurosci. 2006; 23 11: 2864–2876.
  • Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L. LRP4 serves as a coreceptor of agrin. Neuron. 2008; 60 2: 285–297.
  • Zhang Y, Yan Z, Farooq A, Liu X, Lu C, Zhou MM, He C. Molecular basis of distinct interactions between Dok1 PTB domain and tyrosine-phosphorylated EGF receptor. J Mol Biol. 2004; 343 4: 1147–1155.
  • Linnoila J, Wang Y, Yao Y, Wang ZZ. A mammalian homolog of Drosophila tumorous imaginal discs, Tid1, mediates agrin signaling at the neuromuscular junction. Neuron. 2008; 60 4: 625–641.
  • Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M. A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein. J Biol Chem. 2001; 276 16: 13087–13095.
  • Cheng H, Cenciarelli C, Tao M, Parks WP, Cheng-Mayer C. HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of Ikappa B kinase beta subunit. J Biol Chem. 2002; 277 23: 20605–20610.
  • Luo S, Zhang B, Dong XP, Tao Y, Ting A, Zhou Z, Meixiong J, Luo J, Chiu FC, Xiong WC, and others. HSP90 beta regulates rapsyn turnover and subsequent AChR cluster formation and maintenance. Neuron. 2008; 60 1: 97–110.
  • Song Y, Balice-Gordon R. New dogs in the dogma: Lrp4 and Tid1 in neuromuscular synapse formation. Neuron. 2008; 60 4: 526–528.
  • Yin X, Rozakis-Adcock M. Genomic organization and expression of the human tumorous imaginal disc (TID1) gene. Gene. 2001; 278 1-2: 201–210.
  • Catlett MG, Forsburg SL. Schizosaccharomyces pombe Rdh54 (TID1) acts with Rhp54 (RAD54) to repair meiotic double-strand breaks. Mol Biol Cell. 2003; 14 11: 4707–4720.
  • Tarunina M, Alger L, Chu G, Munger K, Gudkov A, Jat PS. functional genetic screen for genes involved in senescence: role of Tid1, a homologue of the Drosophila tumor suppressor l(2)tid, in senescence and cell survival. Mol Cell Biol. 2004; 24 24: 10792–10801.
  • Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S. hTid-1, a human DnaJ protein, modulates the interferon signaling pathway. J Biol Chem. 2001; 276 52: 49034–49042.
  • Toyka KV, Brachman DB, Pestronk A, Kao I. Myasthenia gravis: Passive transfer from man to mouse. Science. 1975; 190 4212: 397–399.
  • Shigemoto K, Kubo S, Maruyama N, Hato N, Yamada H, Jie C, Kobayashi N, Mominoki K, Abe Y, Ueda N, and others. Induction of myasthenia by immunization against muscle-specific kinase. J Clin Invest. 2006; 116 4: 1016–1024.
  • Jha S, Xu K, Maruta T, Oshima M, Mosier DR, Atassi MZ, Hoch W. Myasthenia gravis induced in mice by immunization with the recombinant extracellular domain of rat muscle-specific kinase (MuSK). J Neuroimmunol. 2006; 175 1-2: 107–117.
  • Cole RN, Reddel SW, Gervasio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol. 2008; 63 6: 782–789.
  • ter Beek WP, Martinez-Martinez P, Losen M, de Baets MH, Wintzen AR, Verschuuren JJ, Niks EH, van Duinen SG, Vincent A, Molenaar PC. The effect of plasma from muscle-specific tyrosine kinase myasthenia patients on regenerating endplates. Am J Pathol. 2009; 175 4: 1536–1544.
  • Souroujon MC, Brenner T, Fuchs S. Development of novel therapies for MG: Studies in animal models. Autoimmunity. 2010; 43 5: 446–460.
  • Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science. 1973; 180 88: 871–872.
  • Berman PW, Patrick J. Experimental myasthenia gravis. A murine system. J Exp Med. 1980; 151 1: 204–223.
  • Lennon VA, Lindstrom JM, Seybold ME. Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs. J Exp Med. 1975; 141 6: 1365–1375.
  • Tarrab-Hazdai R, Aharonov A, Silman I, Fuchs S, Abramsky O. Experimental autoimmune myasthenia induced in monkeys by purified acetylcholine receptor. Nature. 1975; 256 5513: 128–130.
  • Conti-Fine BM, Milani M, Wang W. CD4+T cells and cytokines in the pathogenesis of acquired myasthenia gravis. Ann N Y Acad Sci. 2008; 1132:193–209.
  • Balasa B, Deng C, Lee J, Bradley LM, Dalton DK, Christadoss P, Sarvetnick N. Interferon gamma (IFN-gamma) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J Exp Med. 1997; 186 3: 385–391.
  • Saoudi A, Bernard I, Hoedemaekers A, Cautain B, Martinez K, Druet P, De Baets M, Guery JC. Experimental autoimmune myasthenia gravis may occur in the context of a polarized Th1- or Th2-type immune response in rats. J Immunol. 1999; 162 12: 7189–7197.
  • Ostlie N, Milani M, Wang W, Okita D, Conti-Fine BM. Absence of IL-4 facilitates the development of chronic autoimmune myasthenia gravis in C57BL/6 mice. J Immunol. 2003; 170 1: 604–612.
  • Moiola L, Galbiati F, Martino G, Amadio S, Brambilla E, Comi G, Vincent A, Grimaldi LM, Adorini L. IL-12 is involved in the induction of experimental autoimmune myasthenia gravis, an antibody-mediated disease. Eur J Immunol. 1998; 28 8: 2487–2497.
  • Hoedemaekers AC, van Breda Vriesman PJ, De Baets MH. Myasthenia gravis as a prototype autoimmune receptor disease. Immunol Res. 1997; 16 4: 341–354.
  • Richman DP, Gomez CM, Berman PW, Burres SA, Fitch FW, Arnason BG. Monoclonal anti-acetylcholine receptor antibodies can cause experimental myasthenia. Nature. 1980; 286 5774: 738–739.
  • Tzartos SJ, Sophianos D, Efthimiadis A. Role of the main immunogenic region of acetylcholine receptor in myasthenia gravis. An Fab monoclonal antibody protects against antigenic modulation by human sera. J Immunol. 1985; 134 4: 2343–2349.
  • Balass M, Heldman Y, Cabilly S, Givol D, Katchalski-Katzir E, Fuchs S. Identification of a hexapeptide that mimics a conformation-dependent binding site of acetylcholine receptor by use of a phage-epitope library. Proc Natl Acad Sci USA. 1993; 90 22: 10638–10642.
  • Sterz R, Hohlfeld R, Rajki K, Kaul M, Heininger K, Peper K, Toyka KV. Effector mechanisms in myasthenia gravis: End-plate function after passive transfer of IgG, Fab, and F(ab’)2 hybrid molecules. Muscle Nerve. 1986; 9 4: 306–312.
  • Luo J, Taylor P, Losen M, de Baets MH, Shelton GD, Lindstrom J. Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity. J Neurosci. 2009; 29 44: 13898–13908.
  • Lagoumintzis G, Zisimopoulou P, Kordas G, Lazaridis K, Poulas K, Tzartos SJ. Recent approaches to the development of antigen-specific immunotherapies for myasthenia gravis. Autoimmunity. 2010; 43 5: 436–445.
  • Papanastasiou D, Poulas K, Kokla A, Tzartos SJ. Prevention of passively transferred experimental autoimmune myasthenia gravis by Fab fragments of monoclonal antibodies directed against the main immunogenic region of the acetylcholine receptor. J Neuroimmunol. 2000; 104 2: 124–132.
  • Toyka KV, Lowenadler B, Heininger K, Besinger UA, Birnberger KL, Fateh-Moghadam A, Heilbronn E. Passively transferred myasthenia gravis: Protection of mouse endplates by Fab fragments from human myasthenic IgG. J Neurol Neurosurg Psychiatry. 1980; 43 9: 836–842.
  • Graus YF, de Baets MH, Parren PW, Berrih-Aknin S, Wokke J, van Breda Vriesman PJ, Burton DR. Human anti-nicotinic acetylcholine receptor recombinant Fab fragments isolated from thymus-derived phage display libraries from myasthenia gravis patients reflect predominant specificities in serum and block the action of pathogenic serum antibodies. J Immunol. 1997; 158 4: 1919–1929.
  • Eymard B, Vernet-der Garabedian B, Berrih-Aknin S, Pannier C, Bach JF, Morel E. Anti-acetylcholine receptor antibodies in neonatal myasthenia gravis: Heterogeneity and pathogenic significance. J Autoimmun. 1991; 4 2: 185–195.
  • Morel E, Eymard B, Vernet-der Garabedian B, Pannier C, Dulac O, Bach JF. Neonatal myasthenia gravis: A new clinical and immunologic appraisal on 30 cases. Neurology. 1988; 38 1: 138–142.
  • Papazian O. Transient neonatal myasthenia gravis. J Child Neurol. 1992; 7 2: 135–141.
  • Vernet-der Garabedian B, Lacokova M, Eymard B, Morel E, Faltin M, Zajac J, Sadovsky O, Dommergues M, Tripon P, Bach JF. Association of neonatal myasthenia gravis with antibodies against the fetal acetylcholine receptor. J Clin Invest. 1994; 94 2: 555–559.
  • Shelton GD. Acquired myasthenia gravis: What we have learned from experimental and spontaneous animal models. Vet Immunol Immunopathol. 1999; 69 2–4: 239–249.
  • Shelton GD, Schule A, Kass PH. Risk factors for acquired myasthenia gravis in dogs: 1,154 cases (1991-1995). J Am Vet Med Assoc. 1997; 211 11: 1428–1431.
  • Lindstrom JM, Engel AG, Seybold ME, Lennon VA, Lambert EH. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies. J Exp Med. 1976; 144 3: 739–753.
  • Behin A, Mayer M, Kassis-Makhoul B, Jugie M, Espil-Taris C, Ferrer X, Chatenoud L, Laforet P, Eymard B. Severe neonatal myasthenia due to maternal anti-MuSK antibodies. Neuromuscul Disord. 2008; 18 6: 443–446.
  • Niks EH, Verrips A, Semmekrot BA, Prick MJ, Vincent A, van Tol MJ, Jol-van der Zijde CM, Verschuuren JJ. A transient neonatal myasthenic syndrome with anti-musk antibodies. Neurology. 2008; 70 14: 1215–1216.
  • Bazin H. Rat immunoglobulins. In: Bazin H, editor. Rat Hybridomas and Rat Monoclonal Antibodies. 1 st ed. Boca Raton: CRC Press; 1990. 5–42.
  • Zhang K. Accessibility control and machinery of immunoglobulin class switch recombination. J Leukoc Biol. 2003; 73 3: 323–332.
  • Saoudi A, Kuhn J, Huygen K, de Kozak Y, Velu T, Goldman M, Druet P, Bellon B. Role of the TH1-TH2 balance in the development of autoimmunity in rats. Transplant Proc. 1993; 25 5: 2824–2825.
  • Avery DT, Bryant VL, Ma CS, de Waal Malefyt R, Tangye SG. IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. J Immunol. 2008; 181 3: 1767–1779.
  • Zhang GX, Xiao BG, Yu LY, van der Meide PH, Link H. Interleukin 10 aggravates experimental autoimmune myasthenia gravis through inducing Th2 and B cell responses to AChR. J Neuroimmunol. 2001; 113 1: 10–18.
  • Kawano Y, Noma T. Role of interleukin-2 and interferon-gamma in inducing production of IgG subclasses in lymphocytes of human newborns. Immunology. 1996; 88 1: 40–48.
  • Kawano Y, Noma T, Yata J. Regulation of human IgG subclass production by cytokines. IFN-gamma and IL-6 act antagonistically in the induction of human IgG1 but additively in the induction of IgG2. J Immunol. 1994; 153 11: 4948–4958.
  • de Boer BA, Kruize YC, Rotmans PJ, Yazdanbakhsh M. Interleukin-12 suppresses immunoglobulin E production but enhances immunoglobulin G4 production by human peripheral blood mononuclear cells. Infect Immun. 1997; 65 3: 1122–1125.

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