Monoclonal autoantibodies to acetylcholine receptors: evidence for a dominant idiotype and requirement of complement for pathogenicity.
An antigenic determinant of mammalian muscle acetylcholine receptors (AChR) remote from the ACh-binding site and exposed extracellularly at the neuromuscular junction has been defined by monoclonal autoantibodies (McAb's). The determinant is a dominant antigen in the rat's autoimmune response to AChR. It was defined by four IgG McAb's (from two individual donor rats) which shared a common idiotype (Id) complementary to the AChR determinant. These four McAb's bound to AChR in vivo and induced experimental autoimmune myasthenia gravis (EAMG). They also bound to nonjunctional AChR on living myotubes in culture at 37 degrees and caused loss of alpha-bungarotoxin (alpha-BT) binding sites. The McAb's did not inhibit binding of alpha-BT to solubilized AChR or to nonjunctional AChR in membranes of muscle cells held at 4 degrees C. Impairment of neuromuscular transmission by the McAb's required activation of complement via the classical pathway. In the absence of C3 leads to C9, or in isolated deficiency of C4, binding of McAb's to at least 62% of AChR for 72 hours in vivo did not alter miniature endplate potentials (MEPPs) or EPPs or reduce the muscle's content of AChR. The common Id was detectable in sera of rats immunized with AChR of either Torpedo, eel or syngeneic muscle. Anti-Id antibodies raised against 3 of the McAb's inhibited in vitro binding of each of the 4 McAb's to AChR; absorption of one anti-Id by a second McAb removed inhibitory activity for all McAb's. However, when rats with high titers of anti-Id were challenged by immunization with torpedo AChR, the severity of EAMG was undiminished despite a continuing excess of anti-Id antibodies. Success of the anti-Id approach to therapy of myasthenia gravis may require definition of several antigenic determinants of human muscle AChR with which patients' auto-antibodies interact in vivo.
D000200:Action Potentials; D000818:Animals; D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000032:analysis*; D003167:Complement Activation; D003181:Complement C4 / Q000172:deficiency; D004594:Electrophysiology; D000939:Epitopes; D006168:Guinea Pigs; D007130:Immunoglobulin Idiotypes / Q000032:analysis*; D009132:Muscles / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology*; D014101:Torpedo
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D003181:Complement C4; D000939:Epitopes; D007130:Immunoglobulin Idiotypes; D011950:Receptors, Cholinergic