Studies using morphologic, biochemical, electrophysiologic, and immunologic approaches to MG and EAMG have demonstrated several immunopathologic mechanisms for defective synaptic transmission at the neuromuscular junction. These postsynaptic mechanisms, which are mediated by antibodies directed against AChRs include: complement-mediated lysis of the postsynaptic membrane, an increase in the AChR degradation rate by cross-linking of the receptors, blockade of the cholinergic binding sites of AChRs, alterations of the ionic channel functions, and cell-mediated immune attacks on the endplate. Complement-mediated membrane lysis has been demonstrated in MG and EAMG muscles, and in muscle cultures treated with MG antibodies. Most investigators now agree that this mechanism plays a major role in the pathogenesis of defective neuromuscular transmission in MG. While antibodies from MG and EAMG accelerate the rate of both junctional and extrajunctional receptor degradation, AChR loss by this mechanism may be compensated for by an increase of AChR incorporation in some cases. Blockade of the receptor and changes in ion channel properties are produced by some subpopulations of antibodies bound to certain specific determinants of AChR. These antibodies, however, constitute a small proportion of pathogenic antiboides found in MG and EAMG, and their importance appears limited. Macrophages appears to play a critical role in the destruction of the skeletal muscle endplates in acute and passive EAMG, but the effector role of cell-mediated immune responses is not documented in human MG. The mechanisms playing major roles in the development of MG may vary from one patient to another, depending on the subclasses of the antibodies present as well as the antigenic specificity of the antibodies. The recent elucidation of the molecular structure of the AChR and the application of monoclonal antibodies to these studies have advanced our understanding of the antigen-antibody interaction in MG and EAMG. Future advances may disclose the pathogenically important subpopulations of AChR antibodies, and give rise to the development of more specific treatments for MG.
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