Region of peptide 125-147 of acetylcholine receptor alpha subunit is exposed at neuromuscular junction and induces experimental autoimmune myasthenia gravis, T-cell immunity, and modulating autoantibodies.
A major antigenic region of native nicotinic acetylcholine receptors (AcChoR) has been identified by using a synthetic disulfide-looped peptide corresponding to alpha-subunit residues 125-147 of Torpedo electric organ AcChoR: Lys-Ser-Tyr-Cys-Glu-Ile-Ile-Val-Thr-His-Phe- Pro-Phe-Asp-Gln-Gln-Asn-Cys-Thr-Met-Lys-Leu-Gly. The peptide bound 26-56% of polyclonal antibodies induced in rat, rabbit, and dog by immunization with native AcChoR. Rats inoculated with 50 micrograms of unconjugated peptide developed helper T-cell responses, delayed hypersensitivity, and antibodies to native AcChoR. Anti-peptide antibodies were more reactive with native than denatured AcChoR and bound to the alpha subunit. Some reacted exclusively with mammalian muscle AcChoR, some induced modulation of AcChoR on cultured myotubes, but none inhibited binding of alpha-bungarotoxin to solubilized or membrane-associated AcChoR. Repeated immunization induced experimental autoimmune myasthenia gravis: clinical signs in one rat and electrophysiologic and/or biochemical signs in 10 of 11 rats. Thus, at least part of the corresponding region of the mammalian AcChoR alpha subunit is extracellular at the neuromuscular junction and a potential target for pathogenic autoantibodies in patients with acquired myasthenia gravis.
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology*; D001665:Binding Sites; D002038:Bungarotoxins / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology; D009045:Motor Endplate / Q000276:immunology; D009121:Muscle Denervation; D009157:Myasthenia Gravis / Q000276:immunology*; D009469:Neuromuscular Junction / Q000276:immunology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000276:immunology; D051381:Rats; D011978:Receptors, Nicotinic / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014101:Torpedo
D001323:Autoantibodies; D002038:Bungarotoxins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011978:Receptors, Nicotinic