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The main immunogenic region (MIR) of the nicotinic acetylcholine receptor and the anti-MIR antibodies

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Abstract

Myasthenia gravis (MG) is caused by autoantibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction. The anti-AChR antibodies are heterogeneous. However, a small region on the extracellular part of the AChR α subunit, called the main immunogenic region (MIR), seems to be the major target of the anti-AChR antibodies, but not of the specific T-cells, in experimental animals and possibly in MG patients. The major loop of the overlapping epitopes for all testable anti-MIR monoclonal antibodies (MAbs) was localized within residues 67–76 (WNPADYGGIK forTorpedo and WNPDDYGGVK for human AChR) of the α subunit. The N-terminal half of α67–76 is the most critical, Asn68 and Asp71 being indispensable for binding. Yet anti-MIR antibodies are functionally and structurally quite heterogeneous. Anti-MIR MAbs do not affect channel gating, but they are very potent in mediating acceleration of AChR degradation (antigenic modulation) in cell cultures and in transferring experimental MG in animals. Fab fragments of anti-MIR MAbs bound to the AChR prevent the majority of the MG patients' antibodies from binding to and causing loss of the AChR. Whether this inhibition means that most MG antibodies bind on the same small region or is a result of broad steric/allosteric effects is under current investigation.

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References

  • Appel S. H., Anwyl R., McAdams M. W., and Elias S. (1977) Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins.Proc. Natl. Acad. Sci. USA 74, 2130–2134.

    Article  PubMed  CAS  Google Scholar 

  • Aronheim A., Eshel Y., Mosckovitz R., and Gershoni J. M. (1988) Characterization of the binding of α-bungarotoxin to bacterially expressed cholinergic binding sites.J. Biol. Chem. 263, 9933–9937.

    PubMed  CAS  Google Scholar 

  • Barkas T., Gabriel J. M., Juillerat M., Kokla A., and Tzartos S. J. (1986) Localization of the main immunogenic region of the nicotinic acetylcholine receptor.FEBS. Lett. 196, 237–241.

    Article  PubMed  CAS  Google Scholar 

  • Barkas T., Gabriel J.-M., Mauron A., Hughes G. J., Roth B., Alliod C., Tzartos S. J., and Ballivet M. (1988) Fine localisation of the main immunogenic region of the nicotinic acetylcholine receptor to residues α61–76 of the α subunit.J. Biol. Chem. 263, 5916–5920.

    PubMed  CAS  Google Scholar 

  • Barkas T., Mauron A., Roth B., Alliod C., Tzartos S. J., and Ballivet M. (1987) Mapping the main immunogenic region and toxin binding site of the nicotinic acetylcholine receptor.Science 235, 77–80.

    Article  PubMed  CAS  Google Scholar 

  • Barnard E. A., Darlison M. G., and Seeburg P. (1987) Molecular biology of the GABA-A receptor: the receptor/channel superfamily.Trends Neurosci. 10, 502–509.

    Article  CAS  Google Scholar 

  • Bellone M., Tang F., Milius R., and Conti-Tronconi B. M. (1989) The main immunogenic region of the nicotinic acetylcholine receptor—identification of amino acid residues interacting with different antibodies.J. Immunol. 143, 3568–3579.

    PubMed  CAS  Google Scholar 

  • Bentley G. A., Boulot G., Riottot M. M., and Poljak R. J. (1990) Three-dimensional structure of an idiotope-anti-idiotope complex.Nature 348, 254–257.

    Article  PubMed  CAS  Google Scholar 

  • Blount P. and Merlie J. P. (1988) Native folding of an acetylcholine receptor α subunit expressed in the absence of other receptor subunits.J. Biol. Chem. 263, 1072–1080.

    PubMed  CAS  Google Scholar 

  • Brisson A. and Unwin P. (1985) Quaternary structure of the acetylcholine receptor.Nature 315, 474–477.

    Article  PubMed  CAS  Google Scholar 

  • Bucknall R. C. (1977) Myasthenia associated withd-penicillamine therapy in rheumatoid arthritis.Proc. R. Soc. Med. 70, (Suppl. 3), 114–117.

    PubMed  Google Scholar 

  • Cauley K., Agranoff B. W., and Goldman D. (1989) Identification of a novel nicotinic acetylcholine receptor structural subunit expressed in goldfish retina.J. Cell Biol. 108, 637–645.

    Article  PubMed  CAS  Google Scholar 

  • Changeux J. P. (1990) Functional architecture and dynamics of the nicotinic acetylcholine receptor: an allosteric ligand-gated ion channel.Fidia Research Foundation Neuroscience Award Lectures, vol. 4, Raven, New York, pp. 21–168.

    Google Scholar 

  • Charnet P., Labarca C., Leonard R. J., Vogelaar N. J., Czyzyk L., Gouin A., Davidson N., and Lester H. A. (1990) An open-channel blocker interacts with adjacent turns of alpha-helices in the nicotinic acetylcholine receptor.Neuron 4, 87–95.

    Article  PubMed  CAS  Google Scholar 

  • Chase B. A., Holliday J., Reese J. H., Chun L. L. Y., and Hawrot E. (1987) Monoclonal antibodies with defined specificities forTorpedo nicotinic acetylcholine receptor cross-react with Drosophila neural tissue.Neuroscience 21, 959–976.

    Article  PubMed  CAS  Google Scholar 

  • Claudio T. (1989) Molecular genetics of acetylcholine receptor-channels,Frontiers in Molecular Biology, Glover D. M. and Hames B. D., eds. IRL, Oxford, UK, pp. 63–142.

    Google Scholar 

  • Connor R. I., Lefvert A. K., Benes S. C., and Lang R. W. (1990) Incidence and reactivity patterns of skeletal and heart (SH) reactive autoantibodies in the sera of patients with myasthenia gravis.J. Neuroimmunol. 26, 147–157.

    Article  PubMed  CAS  Google Scholar 

  • Conroy W. G., Saedi M. S., and Lindstrom J. (1990) TE671 cells express an abundance of a partially mature acetylcholine receptor alpha subunit which has characteristics of an assembly intermediate.J. Biol. Chem. 265, 21642–21651.

    PubMed  CAS  Google Scholar 

  • Conti-Troncini B. M., Tang F., Diethelm B. M., Spencer S. R., Reinhardt-Maelicke S., and Maelicke A. (1990) Mapping of a cholinergic binding site by means of synthetic peptides, monoclonal antibodies, and α-bungarotoxin.Biochemistry 29, 6221–6230.

    Article  Google Scholar 

  • Conti-Tronconi B. M., Fels G., McLane K., Tang F., Bellone M., Kokla A., Tzartos S. J., Millius R., and Maelicke A. (1989) Use of synthetic peptides and high affinity protein ligands for structural studies of central and peripheral nicotinic receptors.Molecular Biology of Neuroreceptors and Ion Channels, Maelicke A., ed.,NATO ASI Series H, vol. 32, Springer-Verlag, Berlin, pp. 291–309.

    Google Scholar 

  • Conti-Tronconi B., Tzartos S. J., and Lindstrom J. (1981) Monoclonal antibodies as probes of acetylcholine receptor structure. II. Binding to native receptor.Biochemistry 20, 2181–2191.

    Article  PubMed  CAS  Google Scholar 

  • Cung M. T., Demange P., Marraud, M., Tsikaris V., Sakarellos C., Papadouli I., Kokla A., and Tzartos S. J. (1991b) Two-dimensional1H-NMR study of antigen-antibody interactions: binding of synthetic decapeptides to an anti-acetylcholine receptor monoclonal antibody.Biopolymers 31, 769–776.

    Article  PubMed  CAS  Google Scholar 

  • Cung M. T., Marraud M., Hadjidakis I., Bairaktari H., Sakarellos C., Kokla A., and Tzartos S. (1989) 2D-1H NMR study of a synthetic peptide containing the main immunogenic region of theTorpedo acetylcholine receptor.Biopolymers 28, 465–478.

    Article  PubMed  CAS  Google Scholar 

  • Cung M. T., Tsikaris V., Demange P., Papadouli I., Tzartos S. J., Sakarellos C., and Marraud M. (1991a) 2D-NMR and molecular dynamics analysis of theTorpedo californica acetylcholine receptor α67–76 fragment and of its [Ala76]-analogue.Peptide Res., in press.

  • Das M. K. and Lindstrom J. (1989) The main immunogenic region of the nicotinic acetylcholine receptor. Interaction of monoclonal antibodies with synthetic peptides.Biochem. Biophys. Res. Commun. 165, 865–871.

    Article  PubMed  CAS  Google Scholar 

  • Dau P. C., Yano C. S., and Ettinger S. J. (1979) Antibody to acetylcholine receptor in canine and human myasthenia gravis: differential crossreactivity with human and rabbit.Neurology 29, 1065–1068.

    PubMed  CAS  Google Scholar 

  • Dipaola M., Czajkowski C., and Karlin A. (1989) The sidedness of the COOH terminus of the acetylcholine receptor delta-subunit.J. Biol. Chem. 264, 15457–15463.

    PubMed  CAS  Google Scholar 

  • Drachman D., ed. (1987) Myasthenia gravis,Ann. NY Acad. Sci. 505, 1–914.

  • Drachman D. B., Adams R. N., Josifek L. F., and Self S. G. (1982) Functional activities of autoantibodies to acetylcholine receptors and the clinical severity of myasthenia gravis.N. Engl. J. Med. 307, 769–775.

    PubMed  CAS  Google Scholar 

  • Engel A. G. (1984) Myasthenia gravis and myasthenic syndromes.Ann. Neurol. 16, 519–533.

    Article  PubMed  CAS  Google Scholar 

  • Eymard B., De la Porte S., Pannier C., Berrih-Aknin S., Morel E., Fardeau M., Bach J. F., and Koenig J. (1988) Effect of myasthenic patient sera on the number and distribution of acetylcholine receptors in muscle and nerve-muscle cultures from rat. Correlations with clinical state.J. Neurol. Sci. 86, 41–59.

    Article  PubMed  CAS  Google Scholar 

  • Fambrough D. M., Drachman D. B., and Satiamurti S. (1973) Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors.Science 182, 293–295.

    Article  PubMed  CAS  Google Scholar 

  • Fels G., Plumer-Wilk R., Schreiber M., and Maelicke A. (1986) A monoclonal antibody interfering with binding and response of the acetylcholine receptor.J. Biol. Chem. 261, 15746–15754.

    PubMed  CAS  Google Scholar 

  • Froehner S. C. (1981) Identification of exposed and buried determinants of the membrane-bound acetylcholine receptor fromTorpedo californica Biochemistry 20, 4905–4915.

    Article  PubMed  CAS  Google Scholar 

  • Fujii Y. and Lindstrom J. (1988) Specificity of the T cell immune response to acetylcholine receptor in experimental autoimmune myasthenia gravis.J. Immunol. 140, 1830–1837.

    PubMed  CAS  Google Scholar 

  • Fujita N., Nelson N., Fox T. D., Claudio T., Lindstrom J., Riezman H., and Hess G. P. (1986) Biosynthesis of theTorpedo californica acetylcholine receptor α subunit in yeast.Science 231, 1284–1287.

    Article  PubMed  CAS  Google Scholar 

  • Gilhus N. E., Aarli J. A., and Matre R. (1983) Myasthenia gravis. Antibodies to skeletal muscle cell surface antigens.J. Neuroimmunol. 5, 239–249.

    Article  PubMed  CAS  Google Scholar 

  • Giraudat J., Dennis M., Heidmann T., Haumont P.-Y., Lederer F., and Changeux J.-P. (1987) Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: [3-H] chlorpromazine labels homologous residues in the β and δ chains.Biochemistry 26, 2410–2418.

    Article  PubMed  CAS  Google Scholar 

  • Gomez C. M. and Richman D. P. (1983) Anti-acetylcholine receptor antibodies directed against the α-bungarotoxin binding site induce a unique form of experimental myasthenia.Proc. Natl. Acad. Sci. USA 80, 4089–4093.

    Article  PubMed  CAS  Google Scholar 

  • Gotti C., Frigerio F., Bolognesi M., Longhi R., Racchetti G., and Clementi F. (1988) Nicotinic acetylcholine receptor: a structural model for α-subunit peptide 188–201, the putative binding site for cholinergic agents.FEBS Lett. 228, 118–122.

    Article  PubMed  CAS  Google Scholar 

  • Griesmann G. E., McCormick D. J., De Aizpurua H. J., and Lennon V. A. (1990) Alpha-Bungarotoxin binds to human acetylcholine receptor alpha-subunit peptide 185–199 in solution and solid phase but not to peptide 125–147 and peptide 389–409.J. Neurochem. 54, 1541–1547.

    Article  PubMed  CAS  Google Scholar 

  • Harvey A. L., Barkas T., Harrison R., and Lunt G. G. (1978) Inhibition of receptor function in cultured chick myotubes by antiserum to purifiedTorpedo acetylcholine receptor and myasthenic sera,The Biochemistry of Myasthenia Gravis and Muscular Dystrophy, Lunt G. G. and Marchbanks R. M., eds. Academic, London, pp. 167–175.

    Google Scholar 

  • Heidenreich F., Vincent A., Roberts A., and Newsom-Davis J. (1988a) Epitopes on human acetylcholine receptor defined by monoclonal antibodies and myasthenia gravis sera.Autoimmunity 1, 285–297.

    Article  PubMed  CAS  Google Scholar 

  • Heidenreich F., Vincent A., Willcox N., and Newsom-Davis J. (1988b) Anti-acetylcholine receptor antibody specificities in serum and in thymic cell culture supernatants from Myasthenia gravis patients.Neurology 38, 1784–1788.

    PubMed  CAS  Google Scholar 

  • Heinemann S., Bevan S., Kullberg R., Lindstrom J., and Rice J. (1977) Modulation of the acetylcholine receptor by anti-receptor antibodies.Proc. Natl. Acad. Sci. USA 74, 3090–3094.

    Article  PubMed  CAS  Google Scholar 

  • Henley J. M., Lindstrom J. M., and Oswald R. E. (1988) Interaction of monoclonal antibodies with α-bungarotoxin and (-)-nicotine binding sites in goldfish brain.J. Biol. Chem. 263, 9686–9691.

    PubMed  CAS  Google Scholar 

  • Higgins L. S., and Berg D. K. (1987) Immunological identification of a nicotinic acetylcholine receptor on bovine chromaffin cells.J. Neurosci. 7, 1792–1798.

    PubMed  CAS  Google Scholar 

  • Hohlfeld R. (1990) Myasthenia gravis and thymoma. Paraneoplastic failure of neuromuscular transmission.Lab. Invest. 62, 241–243.

    PubMed  CAS  Google Scholar 

  • Hohlfeld R., Toyka K., Tzartos S. J., Carson W., and Conti-Tronconi B. (1987) Human T helper lymphocytes in myasthenia gravis recognize the nicotinic receptor α-subunit.Proc. Natl. Acad. Sci. USA 84, 5379–5383.

    Article  PubMed  CAS  Google Scholar 

  • Hucho F., Oberthur W., and Lottspeich F. (1986) The ion channel of the nicotinic acetylcholine receptor is formed by the homologous helices M II of the receptor subunits.FEBS Lett. 205, 137–142.

    Article  PubMed  CAS  Google Scholar 

  • Imoto K., Busch C., Sakmann B., Mishina M., Konno T., Nakai J., Bujo H., Mori Y., Fukuda K., and Numa S. (1988) Rings of negatively charged aminoacids determine the acetylcholine receptor channel conductance.Nature 335, 645–648.

    Article  PubMed  CAS  Google Scholar 

  • Jacob M. H. and Berg D. K. (1988) The distribution of acetylcholine receptors in chick ciliary ganglion neurons following disruption of ganglionic connections.J. Neurosci. 8, 3838–3849.

    PubMed  CAS  Google Scholar 

  • Kao P. N. and Karlin A. (1986) Acetylcholine receptor binding site contains a disulfide crosslink between adjacent half-cystinyl residues.J. Biol. Chem. 261, 8085–8088.

    PubMed  CAS  Google Scholar 

  • Karlin A., Kao P. N., and Dipaola M. (1986) Molecular pharmacology of the nicotinic acetylcholine receptor.Trends Pharmacol. Sci. 7, 304–308.

    Article  CAS  Google Scholar 

  • Keesey J., Lindstrom J., Cokey H., and Hermann C. (1977) Anti-acetylcholine receptor antibody in neonatal myasthenia gravis.N. Engl. J. Med. 296, 55.

    PubMed  CAS  Google Scholar 

  • Killen J., Hochschwender S., and Lindstrom J. (1985) The main immunogenic region of acetylcholine receptors does not provoke the formation of antibodies to a predominant idiotype.J. Neuroimmunol. 9, 229–241.

    Article  PubMed  CAS  Google Scholar 

  • Kirchner T., Tzartos S., Hoppe F., Schalke B., Wekerle H., and Muller-Hermelink H. K. (1988) Pathogenesis of myasthenia gravis. Acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors.Am. J. Pathol. 130, 268–279.

    PubMed  CAS  Google Scholar 

  • Kordossi A. A. and Tzartos S. J. (1987) Conformation of cytoplasmic segments of acetylcholine receptor α and β subunits probed by monoclonal antibodies. Sensitivity of the antibody competition approach.EMBO J. 6, 1605–1610.

    PubMed  CAS  Google Scholar 

  • Kordossi A. A. and Tzartos S. J. (1989) Monoclonal antibodies against the main immunogenic region of the acetylcholine receptor. Mapping on the intact molecule.J. Neuroimmunol. 23, 35–40.

    Article  PubMed  CAS  Google Scholar 

  • Kubalek E., Ralston S., Lindstrom J., and Unwin N. (1987) Location of subunits within the acetylcholine receptor by electron image analysis of tubular crystals fromTorpedo marmorata.J. Cell Biol. 105, 9–18.

    Article  PubMed  CAS  Google Scholar 

  • Laver W. G., Air G. M., Webster R. G., and Smith-Gill S. J. (1990) Epitopes on protein antigens—misconceptions and realities.Cell 61, 553–556.

    Article  PubMed  CAS  Google Scholar 

  • Lefvert A. K., Pirskanen R., and Svanborg E. (1985) Anti-idiotypic antibodies, acetylcholine receptor antibodies and disturbed neuromuscular function in healthy relatives to patients with myasthenia gravis.J. Neuroimmunol. 9, 41–53.

    Article  PubMed  CAS  Google Scholar 

  • Lennon V. A. and Griesmann G. E. (1989) Evidence against acetylcholine receptor having amain immunogenic region as target for autoantibodies in myasthenia gravis.Neurology 39, 1069–1076.

    PubMed  CAS  Google Scholar 

  • Lennon V. A. and Lambert E. H. (1980) Myasthenia gravis induced by monoclonal antibodies to acetylcholine receptors.Nature 285, 238–240.

    Article  PubMed  CAS  Google Scholar 

  • Lennon V. A. and Lambert E. H. (1981) Monoclonal autoantibodies to acetylcholine receptors: evidence for a dominant idiotype and requirement of complement for pathogenicity.Ann. NY Acad. Sci. 377, 77–96.

    Article  PubMed  CAS  Google Scholar 

  • Lindstrom J. M., Engel A. G., Seybold M. E., Lennon V. A., and Lambert E. H. (1976a) Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine receptor antibodies.J. Exp. Med. 144, 739–753.

    Article  PubMed  CAS  Google Scholar 

  • Lindstrom J. M., Lennon V. A., Seybold M. E., and Whittingham S. (1976c) Experimental autoimmune myasthenia gravis and myasthenia gravis: biochemical and immunochemical aspects.Ann. NY Acad. Sci. 274, 254–274.

    Article  PubMed  CAS  Google Scholar 

  • Lindstrom J., Schoepfer R., and Whiting P. (1987) Molecular studies of the neuronal nicotinic acetyl-choline receptor family.Molecular Neurobiology 1, 281–337.

    Article  PubMed  CAS  Google Scholar 

  • Lindstrom J., Schoepfer R., Whiting P., Anand R., Conroy W. G., Saedi M. S., and Das M. (1991) Monoclonal antibody probes for nicotinic receptors of muscles and nerves.Biochem. Soc. Trans. 19, 115–120.

    PubMed  CAS  Google Scholar 

  • Lindstrom J. M., Seybold M. E., Lennon V. A., Whitting S., and Duane D. (1976b) Antibody to acetylcholine receptor in myasthenia gravis: Prevalence, clinical correlates and diagnostic value.Neurology. 26, 1054–1059.

    PubMed  CAS  Google Scholar 

  • Lindstrom J., Shelton D., and Fugii Y. (1988) Myasthenia gravis.Adv. Immunol. 42, 233–284.

    Article  PubMed  CAS  Google Scholar 

  • Lindstrom J., Tzartos S. J., and Gullick W. (1981) Structure and function of the acetylcholine receptor molecule studied using monoclonal antibodies.Ann. NY Acad. Sci. 377, 1–19.

    Article  PubMed  CAS  Google Scholar 

  • Luetje C. W., Patrick J., and Seguela P. (1990) Nicotine receptors in the mammalian brain.FASEB J. 4, 2753–2760.

    PubMed  CAS  Google Scholar 

  • Lukas R. J. and Bencherif M. (1991) Heterogeneity and regulation of nicotinic acetylcholine receptors.Intl. Rev. Neurobiol., in press.

  • Luther M. A., Schoepfer R., Whiting P., Casey B., Blatt Y., Montal M. S., Montal M., and Lindstrom J. (1989) A muscle acetylcholine receptor is expressed in the human cerebellar medulloblastoma cell line TE671.J. Neurosci. 9, 1082–1096.

    PubMed  CAS  Google Scholar 

  • McAllister R. M., Isaacs H., Rongey R., Peer M., Au W., Soukup S. W., and Gardner M. B. (1977) Establishment of a human meduloblastoma cell line.Int. J. Cancer 20, 206–212.

    Article  PubMed  CAS  Google Scholar 

  • McCarthy M. P., Earnest J. P., Young E. F., Choe S., and Stroud R. M. (1986) The molecular neurobiology of the acetylcholine receptor.Ann. Rev. Neurosci. 9, 383–413.

    Article  PubMed  CAS  Google Scholar 

  • Maelicke A. (1988) Structure and function of the nicotinic acetylcholine receptor.Handb. Exp. Pharmacol. 86, 267–313.

    Google Scholar 

  • Maelicke A., Plumer-Wilk R., Fels G., Spencer S. R., Engelhard M., Veltel D., and Conti-Tronconi B. M. (1989) Epitope mapping employing antibodies raised against short synthetic peptides: A study of the nicotinic acetylcholine receptor.Biochemistry 28, 1396–1405.

    Article  PubMed  CAS  Google Scholar 

  • Marx A., O'Connor R., Geuder K. I., Hoppe F., Schalke B., Tzartos S., Kalies I., Kirchner T., and Muller-Hermelink H. K. (1990) Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis-associated thymomas.Lab. Invest. 62, 279–286.

    PubMed  CAS  Google Scholar 

  • Merlie J. P. and Smith M. M. (1986) Synthesis and assembly of acetylcholine receptor, a multisubunit membrane glycoprotein.J. Membr. Biol. 91, 1–10.

    Article  PubMed  CAS  Google Scholar 

  • Mihovilovic M. and Richman D. P. (1984) Modification of α-bungarotoxin and cholinergic ligand-binding properties ofTorpedo acetylcholine receptor by an anti-acetylcholine receptor monoclonal antibody.J. Biol. Chem. 259, 15,051–15,059.

    CAS  Google Scholar 

  • Mihovilovic M. and Richman D. P. (1986) Monoclonal antibodies as probes of the α-bungarotoxin and cholinergic binding regions of the acetylcholine receptor.J. Biol. Chem. 262, 4987–4986.

    Google Scholar 

  • Mishina M., Kurosaki T., Tobimatsu T., Morimoto Y., Noda M., Yamamoto T., Terao M., Lindstrom J. M., Takahashi T., Kuno M., and Numa S. (1984) Expression of functional acetylcholine receptor from cloned cDNAs.Nature 307, 604–608.

    Article  PubMed  CAS  Google Scholar 

  • Mitra A. K., McCarthy M. P., and Stroud R. M. (1984) 3-Dimensional structure of the nicotinic acetylcholine receptor and location of the major associated 43-kd cytoskeletal protein, determined at 22-Å by low dose electron microscopy and X-ray diffraction to 12.5-Å.J. Cell Biol. 109, 755–774.

    Article  Google Scholar 

  • Mochly-Rosen C. and Fuchs S. (1981) Monoclonal anti-acetylcholine receptor antibodies directed against the cholinergic binding site.Biochemistry 20, 5920–5924.

    Article  PubMed  CAS  Google Scholar 

  • Morel E., Eymard B., Vernet-der Garabedian B., Pannier C., Dulac O., and Bach J. F. (1988a) Neonatal myasthenia gravis. A new clinical and immunologic appraisal on 30 cases.Neurology 38, 138–142.

    PubMed  CAS  Google Scholar 

  • Morel E., Vernet-der Garabedian B., Eymard B., Raimond F., Bustarret F.-A., and Bach J.-F. (1988b) Binding and blocking antibodies to the human acetylcholine receptor: are they selected in various myasthenia gravis forms?Immunol. Res. 7, 212–217.

    Article  PubMed  CAS  Google Scholar 

  • Mulac-Jericevic B., Kurisaki J.-I., and Atassi M. Z. (1987) Profile of the continuous antigenic regions on the extracellular part of the α chain of an acetylcholine receptor.Proc. Natl. Acad. Sci. USA 84, 3633–3637.

    Article  PubMed  CAS  Google Scholar 

  • Nef P., Oneyser C., Alloid C., Couturier S., and Ballivet M. (1988) Genes expressed in the brain define three distinct neuronal nicotinic acetylcholine receptor.EMBO J. 7, 595–601.

    PubMed  CAS  Google Scholar 

  • Neumann D., Barchan D., Fridkin M., and Fuchs S. (1986) Analysis of ligand binding to the synthetic dodecapeptide 185–196 of the acetylcholine receptor α subunit.Proc. Natl. Acad. Sci. USA 83, 9250–9253.

    Article  PubMed  CAS  Google Scholar 

  • Newsom-Davis J., Harcourt G., and Beeson D. (1989) Myasthenia Gravis. Nicotinic acetylcholine receptors as targets for autoimmune attack.Biochem. Soc. Trans. 17, 635–637.

    PubMed  CAS  Google Scholar 

  • Numa S. (1987) Structure and function of ionic channels.Chem. Scripta 27B, 5–19.

    CAS  Google Scholar 

  • Oberthur W., Muhn P., Baumann H., Lottspeich F., Wittmann-Leibold B., and Hucho F. (1986) The reaction site of a non-competitive antagonist in the delta-subunit of the nicotinic acetylcholine receptor.EMBO J. 5, 1815–1819.

    PubMed  CAS  Google Scholar 

  • Oosterhuis H. J. G. H., ed. (1984) Myasthenia Gravis.Clinical Neurology and Neurosurgery Monographs, vol. 5. Churchill Livingstone, Edinburgh, 1–269.

    Google Scholar 

  • Papadouli I., Potamianos S., Hadjidakis I., Bairaktari E., Tsikaris V., Sakarellos C., Cung M. T., Marraud M., and Tzartos S. J. (1990) Antigenic role of single residues within the main immunogenic region of the nicotinic acetylcholine receptor.Biochem. J. 269, 239–245.

    PubMed  CAS  Google Scholar 

  • Papadouli I., Sakarellos C., and Tzartos S. J. (1991) Further characterization of the main immunogenic region of the acetylchoiine receptor and study of synthetic analogs with improved antigenicity. Submitted.

  • Patrick J. and Lindstrom J. L. (1973) Autoimmune response to acetylcholine receptors.Science 180, 871, 872.

    Article  PubMed  CAS  Google Scholar 

  • Paulson H. L. and Claudio T. (1990) Temperature-sensitive expression of all-Torpedo andTorpedo-rat hybrid AChR in mammalian muscle cells.J. Cell Biol. 110, 1705–1717.

    Article  PubMed  CAS  Google Scholar 

  • Protti M. P., Manfredi A. A., Straub C., Howard J. F., and Conti-Tronconi B. M. (1990) Immunodominant regions for T-helper-cell sensitization on the human nicotinic receptor alpha-subunit in myasthenia gravis.Proc. Natl. Acad. Sci. USA 87, 7792–7796.

    Article  PubMed  CAS  Google Scholar 

  • Ralston S., Sarin V., Thanh H. L., Rivier J., Fox J. L., and Lindstrom J. (1987) Synthetic peptides used to locate the α-bungarotoxin binding site and immunogenic regions on α-subunits of the nicotinic acetylcholine receptor.Biochemistry 26, 3261–3266.

    Article  PubMed  CAS  Google Scholar 

  • Ratnam M., Le Nguyen D., Rivier J., Sargent P., and Lindstrom J. (1986b) Transmembrane topography of the nicotinic acetylcholine receptor: immunochemical tests contradict theoretical predictions based on hydrophobicity profile.Biochemistry 25, 2633–2643.

    Article  PubMed  CAS  Google Scholar 

  • Ratnam M., Sargent P., Sarin V., Fox J. L., Le Nguyen D., Rivier J., Criado M., and Lindstrom J. (1986a) Location of antigenic determinants on primary sequences of the subunits of the nicotinic acetylcholine receptor by peptide mapping.Biochemistry 25, 2621–2632.

    Article  PubMed  CAS  Google Scholar 

  • Riechmann L., Clark M., Waldmann H., and Winter G. (1988) Reshaping human antibodies for therapy.Nature 332, 323–327.

    Article  PubMed  CAS  Google Scholar 

  • Russell A. S. and Lindstrom J. M. (1978) Penicillamine-induced myasthenia gravis associated with antibodies to acetylcholine receptor.Neurology. 28, 847–849.

    PubMed  CAS  Google Scholar 

  • Saedi M. S., Anand R., Conroy W. G., and Lindstrom J. (1990) Determination of amino acids critical to the main immunogenic region of intact acetylcholine receptors by in vitro mutagenesis.FEBS Lett. 267, 55–59.

    Article  PubMed  CAS  Google Scholar 

  • Saedi M. S., Conroy W. G., and Lindstrom J. (1991) Assembly ofTorpedo acetylcholine receptors inXenopus oocytes.J. Cell Biol. 112, 1007–1015.

    Article  PubMed  CAS  Google Scholar 

  • Sargent P., Hedges B., Tsavaler L., Clemmons L., Tzartos S. J., and Lindstrom J. (1984) The structure and transmembrane nature of the acetylcholine receptor in amphibian skeletal muscle as revealed by cross-reacting monoclonal antibodies.J. Cell Biol. 98, 609–618.

    Article  PubMed  CAS  Google Scholar 

  • Sargent P. B., Pike S. H., Nadel D. B., and Lindstrom J. M. (1989) Nicotinic acetylcholine receptor-like molecules in the retina, retinotectal pathway, and optic tectum of the frog.J. Neurosci. 9, 565–573.

    PubMed  CAS  Google Scholar 

  • Scadding G. K., Vincent A., Newsom-Davis J., and Henry K. (1981) Acetylcholine receptor antibody synthesis by thymic lymphocytes: Correlation with thymic histology.Neurology 31, 935–943.

    PubMed  CAS  Google Scholar 

  • Schluep M., Willcox N., Vincent A., Dhoot G. K., and Newsom-Davis J. (1987) Acetylcholine receptors in human thymic myoid cells in situ: An immuno-histological study.Ann. Neurol. 22, 212–222.

    Article  PubMed  CAS  Google Scholar 

  • Schuetze S. M., Vicini S., and Hall Z. W. (1985) Myasthenic serum selectively blocks acetylcholine receptors with long channel open times at developing rat endplates.Proc. Natl. Acad. Sci. USA 82, 2533–2537.

    Article  PubMed  CAS  Google Scholar 

  • Shelton G. D., Cardinet G. H. III, and Lindstrom J. M. (1988) Canine and human myasthenia gravis autoantibodies recognize similar regions on the acetylcholine receptor.Neurology 38, 1417–1423.

    PubMed  CAS  Google Scholar 

  • Sophianos D. and Tzartos S. J. (1989) Fab fragments of monoclonal antibodies protect the human acetylcholine receptor against degradation caused by myasthenic sera.J. Autoimmun. 2, 777–789.

    Article  PubMed  CAS  Google Scholar 

  • Souroujon M. C., Neumann D., Pizzighella S., Safran A., and Fuchs S. (1986) Localization of a highly immunogenic region on the acetylcholine receptor α subunit.Biochem. Biophys. Res. Commun. 135, 82–89.

    Article  PubMed  CAS  Google Scholar 

  • Strange P. G. (1988) The structure and mechanism of neurotransmitter receptors.Biochem. J. 249, 309–318.

    PubMed  CAS  Google Scholar 

  • Stratton M. R., Darling J., Pilkington G. J., Lantos P. L., Reeves B. R., and Cooper C. S. (1989) Characterization of the human cell line TE671.Carcinogenesis 10, 899–905.

    PubMed  CAS  Google Scholar 

  • Stroud R. M., McCarthy M. P., and Shuster M. (1990) Nicotinic acetylcholine receptor superfamily of ligand-gated ion channels.Biochemistry 29, 11,009–11,023.

    Article  CAS  Google Scholar 

  • Swanson L., Lindstrom J., Tzartos S. J., Schmued L., O'Leary D. D., and Cowan W. M. (1983) Immunohistochemical localization of monoclonal antibodies to the nicotinic acetylcholine receptor in the midbrain of the chick.Proc. Natl. Acad. Sci. USA 80, 4532–4536.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J. (1990) Studying the acetylcholine receptor with monoclonal antibodies,Current Aspects of the Neurosciences, vol. 3, N. Osborne, ed., Macmillan, London, UK, pp. 195–226.

    Google Scholar 

  • Tzartos S. J. and Changeux J.-P. (1984) Lipid-dependent recovery of α-bungarotoxin and monoclonal antibody binding to the purified α-subunit fromTorpedo marmorata acetylcholine receptor.J. Biol. Chem. 259, 11,512–11,519.

    CAS  Google Scholar 

  • Tzartos S. J., Efthimiadis A., Morel E., Eymard B., and Bach J. F. (1990a) Neonatal myasthenia gravis: antigenic specificities of antibodies in sera from mothers and their infants.Clin. Exp. Immunol. 80, 376–380.

    PubMed  CAS  Google Scholar 

  • Tzartos S. J., Hochschwender S., Vasquez P., and Lindstrom J. (1987) Passive transfer of experimental autoimmune myasthenia gravis by monoclonal antibodies to the main immunogenic region of the acetylcholine receptor.J. Neuroimmunol. 15, 185–194.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J., Kokla A., Walgrave S., and Conti-Tronconi B. (1988b) Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67–76 of the α-subunit.Proc. Natl. Acad. Sci. USA 85, 2899–2903.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J., Langeberg L., Hochschwender S., and Lindstrom J. (1983) Demonstration of a main immunogenic region on acetylcholine receptors from human muscle using monoclonal antibodies to human receptor.FEBS. Lett. 158, 116–118.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J., Langeberg L., Hochschwender S., Swanson L., and Lindstrom J. (1986a) Characteristics of monoclonal antibodies to denaturedTorpedo and to native calf acetylcholine receptors: species, subunit and region specificity.J. Neuroimmunol. 10, 235–253.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J., Sophianos D., Zimmermann K., and Starzinski-Powitz A. (1986b) Antigenic modulation of human muscle acetylcholine receptor by myasthenic sera. Serum titer determines receptor internalization.J. Immunol. 136, 3231–3237.

    PubMed  CAS  Google Scholar 

  • Tzartos S. J. and Lindstrom J. L. (1980) Monoclonal antibodies to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits.Proc. Natl. Acad. Sci. USA 77, 755–759.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J., Loutrari H. V., Tang F., Kokla A., Walgrave S. L., Milius R. P., and Conti-Tronconi B. M. (1990b) The main immunogenic region ofTorpedo electroplax and human muscle acetylcholine receptor. Localization and micro-heterogeneity revealed by the use of synthetic peptides.J. Neurochem. 54, 51–61.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J., Morel E., Efthimiadis A., Bustarret A. F., D'Anglejan J., Drosos A., and Moutsopoulos H. M. (1988a) Fine antigenic specificities of antibodies in sera from patients with D-penicillamine-induced myasthenia gravis.Clin. Exp. Immunol. 74, 80–86.

    PubMed  CAS  Google Scholar 

  • Tzartos S. J., Papadouli I., Potamianos S., Hadjidakis I., Bairaktari H., Tsikaris V., Sakarellos C., Cung M. T., and Marraud M. (1989) Fine stuctural characterization of the main immunogenic region of the nicotinic acetylcholine receptor,Molecular Biology of Neuroreceptors and Ion Channels, Maelicke A., ed.,NATO ASI Series H, vol. 32, Springer-Verlag, Berlin, pp. 361–371.

    Google Scholar 

  • Tzartos S. J., Rand D. E., Einarson B. E., and Lindstrom J. M. (1981) Mapping of surface structures ofElectrophorus acetylcholine receptor using monoclonal antibodies.J. Biol. Chem. 256, 8635–8645.

    PubMed  CAS  Google Scholar 

  • Tzartos S. J. and Remoundos M. S. (1990) Fine localization of the major α-bungarotoxin binding site to residues α189–195 of theTorpedo acetylcholine receptor. Residues 189, 190 and 195 are indispensable for binding.J. Biol. Chem. 265, 21,462–21,467.

    CAS  Google Scholar 

  • Tzartos S. J., Seybold M., and Lindstrom J. (1982) Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies.Proc. Natl. Acad. Sci. USA 79, 188–192.

    Article  PubMed  CAS  Google Scholar 

  • Tzartos S. J., Sophianos D., and Efthimiadis A. (1985) 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. 134, 2343–2349.

    PubMed  CAS  Google Scholar 

  • Tzartos S. J. and Starzinski-Powitz A. (1986) Decrease in acetylcholine receptor content of human myotube cultures mediated by monoclonal antibodies to α, β and γ subunits.FEBS Lett. 196, 91–95.

    Article  PubMed  CAS  Google Scholar 

  • Verschuuren J. J. G. M. (1989) Experimental autoimmune myasthenia gravis. Antibodies, idiotypes and anti-idiotypes. PhD thesis, University of Limburg at Maastricht, The Netherlands.

    Google Scholar 

  • Verschuuren J. J. G. M., Graus Y. M. F., Bos N. A., Tzartos S. J., Van Breda Vriesman P. J. C., and De Baets M. H. (1991) Paratope and framework related crossreactive idiotopes on anti-acetylcholine receptor antibodies.J. Immunol. 146, 941–948.

    PubMed  CAS  Google Scholar 

  • Villarroel A., Herlitze S., Koenen M., and Sakmann B. (1991) Location of a threonine residue in the alpha-subunit M2 transmembrane segment that determines the ion flow through the acetylcholine receptor channel.Proc. R. Soc. Lond. [Biol.] 243, 69–74.

    Article  CAS  Google Scholar 

  • Vincent A. and Newsom-Davis J. (1982) Acetylcholine receptor antibody characteristics in myasthenia gravis. I. Patients with generalized myasthenia or disease restricted to ocular muscles.Clin. Exp. Immunol. 49, 257–265.

    PubMed  CAS  Google Scholar 

  • Vincent A. and Newsom-Davis J. (1985) Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays.J. Neurol. Neurosurg. Psychiatr. 48, 1246–1252.

    Article  PubMed  CAS  Google Scholar 

  • Wada K., Ballivet M., Boulter J., Connolly J., Wada E., Deneris E. S., Swanson L. W., Heinemann S., and Patrick J. (1988) Functional expression of a new pharmacological subtype of brain nicotinic acetylcholine receptor.Science 240, 330–334.

    Article  PubMed  CAS  Google Scholar 

  • Wan K. and Lindstrom J. (1985) Effects of monoclonal antibodies on the function of purified acetylcholine receptor fromTorpedo californica reconstituted into liposomes.Biochemistry 24, 1212–1221.

    Article  PubMed  CAS  Google Scholar 

  • Watters D. and Maelicke A. (1983) Organization of ligand binding sites at the acetylcholine receptor: A study with monoclonal antibodies.Biochemistry 22, 1811–1819.

    Article  PubMed  CAS  Google Scholar 

  • Wekerle H., Ketelsen U.-P., Zurn A. D., and Fulpius B. W. (1978) Intrathymic pathogenesis of myasthenia gravis: transient expression of acetylcholine receptors on thymus-derived myogenic cells.Eur. J. Immunol. 8, 579–582.

    Article  PubMed  CAS  Google Scholar 

  • Whiting P. and Lindstrom J. (1986) Purification and characterization of a nicotinic acetylcholine receptor from chick brain.Biochemistry 25, 2082–2093.

    Article  PubMed  CAS  Google Scholar 

  • Whiting P. J. and Lindstrom J. M. (1988) Characterization of bovine and human neuronal nicotinic acetylcholine receptors using monoclonal antibodies.J. Neurosci. 8, 3395–3404.

    PubMed  CAS  Google Scholar 

  • Whiting P. J., Schoepfer R., Swanson L. W., Simmons D. M., and Lindstrom J. M. (1987) Functional acetylcholine receptor in PC12 cells reacts with a monoclonal antibody to brain nicotinic receptors.Nature 327, 515–518.

    Article  PubMed  CAS  Google Scholar 

  • Whiting P. J., Vincent A., and Newsom-Davis J. (1986) Myasthenia gravis: monoclonal anti-human acetylcholine receptor antibodies used to analyse antibody specificities and responses to treatment.Neurology 36, 612–617.

    PubMed  CAS  Google Scholar 

  • Willcox N. and Vincent A. (1988) Myasthenia gravis as an example of organ-specific autoimmune disease,B Lymphocytes in Human Disease, Bird A. G. and Calvert J., eds., Blackwells, Oxford, UK, pp. 469–506.

    Google Scholar 

  • Williams C. L. and Lennon V. A. (1986) Thymic B lymphocyte clones from patients with myasthenia gravis secrete monoclonal striational auto-antibodies reacting with myosin, α actinin, or actin.J. Exp. Med. 164, 1043–1059.

    Article  PubMed  CAS  Google Scholar 

  • Wilson P. T. and Lentz T. L. (1988) Binding of α-bungarotoxin to synthetic peptides corresponding to residues 173–204 of the α subunit ofTorpedo calf, and human acetylcholine receptor and restoration of high-affinity binding by sodium dodecyl sulfate.Biochemistry 27, 6667–6674.

    Article  PubMed  CAS  Google Scholar 

  • Wilson P. T., Lentz T. L., and Hawrot E. (1985) Mapping of the alpha-bungarotoxin binding site on the primary amino acid sequence of theTorpedo acetylcholine receptor.Ann. NY Acad. Sci. 463, 243–246.

    Article  Google Scholar 

  • Wood H., Beeson D., Vincent A., and Newsom-Davis J. (1989) Epitopes on human acetylcholine receptor α-subunit: Binding of monoclonal antibodies to recombinant and synthetic peptides.Biochem. Soc. Trans. 17, 220–221.

    CAS  Google Scholar 

  • Xu Q., DuPont B. L., Fairclough R. H., and Richman D. P. (1988) An anti-acetylcholine receptor monoclonal antibody that blocks agonist binding also modifies antibody binding to the main immunogenic region of the receptor.Neurology 38, Suppl. 1, 135.

    Google Scholar 

  • Zhang Y., Frutiger S., Hughes G. J., Savoy M. C., and Barkas T. (1990a) Identification of T-cell epitopes of autoantigens using recombinant proteins. Studies on experimental autoimmune myasthenia gravis.Immunology 71, 538–543.

    PubMed  CAS  Google Scholar 

  • Zhang Y., Schluep M., Frutiger S., Hughes G. J., Jeannet M., Steck A., and Barkas T. (1990b) Immunological heterogeneity of autoreactive lymphocytes-T against the nicotinic acetylcholine receptor in myasthenic patients.Eur. J. Immunol 20, 2577–2583.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry, Hellenic Pasteur Institute, 127, Vas. Sofias Ave., 11521, Athens, Greece

    S. J. Tzartos, H. Loutrari, A. Mamalaki & I. Papadouli

  2. Laboratoire de Chimie-Physique Macromoleculaire, CNRS-UA-494, ENSIC-INPL, BP 451, 54001, Nancy, France

    M. T. Cung, P. Demange & M. Marraud

  3. Department of Chemistry, University of Ioannina, Box 1186, 45110, Ioannina, Greece

    C. Sakarellos & V. Tsikaris

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  1. S. J. Tzartos
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  2. M. T. Cung
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Tzartos, S.J., Cung, M.T., Demange, P. et al. The main immunogenic region (MIR) of the nicotinic acetylcholine receptor and the anti-MIR antibodies. Mol Neurobiol 5, 1–29 (1991). https://doi.org/10.1007/BF02935610

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