Walsh & Hoyt: Etiology and Pathogenesis

The earliest clues that the ACh receptor was the molecular target in MG came from experimental autoimmune MG; immunization with purified ACh receptor faithfully reproduced in rabbits and rodents the immunologic and electrophysiologic features of the human disease. At about the same time, Fambrough et al. demonstrated that myasthenic patients had less than one-third of the ACh receptors present in normal control subjects. This reduction in the number of available ACh receptors is usually caused by the actions of antibodies to those receptors. Such antibodies are found in the serum of 8090% of patients with MG. In addition to increased degradation and decrease in ACh receptor number, receptor blockade may be caused by steric hindrance of the ligand ACh by binding of the antibody to a portion of the receptor molecule near the active site. Across patients, the serum anti-ACh receptor antibody concentration does not correlate well with disease severity. There is recent evidence that genetic polymorphisms in the genes for the alpha and beta subunits of the ACh receptor may predispose certain individuals to develop MG. Despite the frequency of mutations in the sigma subunit in congenital ACh receptor deficiency (discussed later), there is no apparent linkage between such mutations and the development of autoimmune MG. There is also no evidence for linkage of beta or gamma subunit polymorphisms with MG.