Anti-Idiotypic Route to Anti-Acetylcholine Receptor Antibodies and Experimental Myasthenia Gravis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 79; no. 15; pp. 4810 - 4814
• Main Authors: Wassermann, N. H., Penn, A. S., Freimuth, P. I., Treptow, N., Wentzel, S., Cleveland, W. L., Erlanger, B. F.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01.08.1982; National Acad Sciences
• Subjects: acetylcholine; Agonists; Animals; Antibodies; Antibody Specificity; antigenic determinants; Autoantibodies - immunology; Binding sites; Electrophorus; Epitopes; Immunization; Immunoenzyme techniques; Immunoglobulin Idiotypes - immunology; Ligands; Molecules; Muscle weakness; Myasthenia gravis; Myasthenia Gravis - etiology; Myasthenia Gravis - immunology; Parasympathomimetics - immunology; Quaternary Ammonium Compounds - immunology; Rabbits; Receptors; Receptors, Cholinergic - immunology; Torpedo
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.79.15.4810

trans-3, 3′-Bis[α -(trimethylammonio)methyl]azobenzene bromide (BisQ) is a potent agonist of the acetylcholine receptor (AcChoR) of Electrophorus electricus. BisQ is highly constrained, suggesting that its structure is complementary to the combining site of the AcChoR when the latter is in its activated state. Antibodies produced in rabbits to a conjugate of bovine serum albumin and a derivative of BisQ mimicked the binding characteristics of the AcChoR with respect to the order of binding of a variety of agonists and to the preferred recognition of decamethonium ion (an agonist) over hexamethonium ion (an antagonist). Immunization of three rabbits with purified anti-BisQ yielded antisera having binding characteristics of anti-AcChoR in that, by complement fixation and enzyme immunoassay, cross-reactions with receptor preparations from rat, Torpedo, and eel could be demonstrated in sera of all three rabbits immunized. Two of the three rabbits showed signs of muscle weakness similar to that seen after immunization with the AcChoR. One of the rabbits was injected intramuscularly with neostigmine and showed temporary improvement. Another showed post-tetanic exhaustion of hindlimb muscles after stimulation of the sciatic nerve at 50 Hz. Antibodies reactive with the AcChoR, therefore, were elicited by immunization with an antibody to a potent ligand of the AcChoR without the necessity of isolating the receptor itself. A similar mechanism may play a part in the etiology of at least some autoimmune diseases in which antibodies to various other receptors are involved.