Antibodies from myasthenic patients that compete with cholinergic agents for binding to nicotinic receptors.
We have purified immunoglobulins from sera of myasthenic patients and have identified antibodies directed against the cholinergic ligand-binding site of the nicotinic acetylcholine receptor. In the serum of one patient analyzed in detail these antibodies belonged to the IgG3 class, and their effects were as follows: (i) In chicken embryo myogenic cultures, antibody binding was both competitive with 125I-labeled alpha-bungarotoxin and irreversible on a time scale of hours. (ii) 125I-Labeled alpha-bungarotoxin was not displaced by antibody from preformed complexes and, conversely, antibody was not displaced by toxin. (iii) Antibody binding was competitive with some, but not all, nicotinic agents. Thus, acetylcholine, carbamoylcholine, and dimethyltubocurarine competed effectively whereas decamethonium and hexamethonium did not, suggesting that the two classes of nicotinic ligands probably interact at different, nonoverlapping receptor subsites. (iv) There was no competitive binding between these antibodies and the muscarinic antagonist atropine. (v) Both this class of myasthenic immunoglobulins and rabbit antibodies raised against Torpedo acetylcholine receptors increased the rate of receptor degradation. However, synthesis and degradation remained coupled and there was a compensating increase in receptor synthesis. We propose that immunoglobulins 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.
D000818:Animals; D001323:Autoantibodies; D001667:Binding, Competitive; D002038:Bungarotoxins / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D006801:Humans; D008024:Ligands; D009157:Myasthenia Gravis / Q000276:immunology*; D010277:Parasympathomimetics / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000276:immunology*; D011978:Receptors, Nicotinic / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D002038:Bungarotoxins; D008024:Ligands; D010277:Parasympathomimetics; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic