Antibodies from myasthenic patients that compete with cholinergic agents for binding to nicotinic receptors.

Abstract

Ig from sera of [myasthenia gravis] patients were purified; antibodies directed against the cholinergic ligand-binding site of the nicotinic acetylcholine receptor were identified. In the serum of 1 patient analyzed in detail these antibodies belonged to the IgG3 class. In chicken embryo myogenic cultures, antibody binding was competitive with 125I-labeled .alpha.-bungarotoxin and irreversible on a time scale of hours. 125I-labeled .alpha.-bungarotoxin was not displaced by antibody from preformed complexes and, conversely, antibody was not displaced by toxin; Antibody binding was competitive with some, but not all, nicotinic agents. Acetylcholine, carbamoylcholine and dimethyltubocurarine competed effectively; decamethonium and hexamethonium did not, suggesting the 2 classes of nicotinic ligands probably interact at different, nonoverlapping receptor subsites. There was no competitive binding between these antibodies and the muscarinic antagonist atropine. This class of myasthenic Ig and rabbit antibodies raised against Torpedo acetylcholine receptors increased the rate of receptor degradation. Synthesis and degradation remained coupled; there was a compensating increase in receptor synthesis. Ig directed against the ligand-binding site of acetylcholine receptors may account for the characteristic curare-like symptoms of early myasthenia and their response to cholinesterase inhibition, for the apparent decrease in receptors measurable by 125I-labeled .alpha.-bungarotoxin binding, and for initiating localized complement activation at the postsynaptic membrane.