Definition of myasthenogenic sites of the human acetylcholine receptor using synthetic peptides.
Experimental autoimmune myasthenia gravis (EAMG) and antibodies that modulate AChRs from cultured human muscle are induced by a disulfide-looped peptide comprising the human acetylcholine receptor (AChR) alpha-subunit residues 125-147 (H alpha 125-147). To delineate the essential antigenic requirements for induction of EAMG by this peptide, a series of peptides was synthesized: (a) a nonlooped analog (Cys 128 replaced by Ser) stimulated modulating autoantibodies, induced EAMG, and bound antibodies induced by native AChR; (b) H alpha 131-147, a heptadecylpeptide shorter by 6 N-terminal residues, induced modulating antibodies, EAMG, and T cells that responded to H alpha 125-147, but not to H alpha 137-147; (c) H alpha 137-147, an undecapeptide shorter than H alpha 125-147 by 12 N-terminal residues, did not stimulate T cells or induce antibody production, but it bound antibodies generated by the longer peptides. Thus, when coupled to an epitope that could stimulate helper T cells, the region 137-147 was able to stimulate B cells. This study has defined a myasthenogenic region of the human AChR's alpha-subunit, 17 amino acids long, that contains several distinct epitopes, including at least one N-terminal site inducing T-cell responses (region 131-136) and two possibly overlapping sites that induce antibodies (regions 131-136 and 137-147). Further definition of antigenic sites inducing helper and suppressor T-cell responses and stimulating production of autoantibodies to AChR is essential to the goal of antigen-specific immunotherapy for myasthenia gravis.
D000200:Action Potentials; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D009045:Motor Endplate / Q000503:physiopathology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D011978:Receptors, Nicotinic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D010446:Peptide Fragments; D011978:Receptors, Nicotinic