PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

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The overall goal of this study is to characterize the sequence of events through which anti-acetylcholine receptor (anti-AChR) antibodies induce the abnormalities in the antibody-mediated autoimmune disease, myasthenia gravis (MG). It involves an analysis of the three forms of experimental autoimmune myasthenia gravis (EAMG), described in our laboratory, that are induced by injection of monoclonal antibody (mAb) to AChR. The acute form follows a single injection of mAb and is associated with cellular inflammation and necrosis of the muscle endplate membrane. The chronic phase, which occurs after repeated injections, is characterized by simplified endplate membranes with decreased AChR content in the absence of inflammation, as is typical for MG. However, these animals failed to demonstrate significant weakness or electrophysiologic evidence of blocked neuromuscular transmission. The hyperacute form, which is induced only by anti-AChR mAbs that block AChR function, may be viewed as the mirror image of the chronic form i.e. marked blockade of neuromuscular transmission with morphologically normal endplates. The specific aims of this proposal consist of an analysis of the mechanisms involved in the production of both the hyperacute and the chronic forms of EAMG in rats. A more complete model of MG will then be produced using various types of mAbs acting via different mechanisms, and perhaps at different times in the course of the illness. Finally the hypotheses derived from these animal studies will be tested by analyzing the characteristics of the antibodies from patients with MG in relation to the disease characteristics. The study will make use of a wide range of immunologic, biochemical, electrophysiologic and morphologic techniques. The knowledge gained from the study of this "model" autoimmune disease should provide clues to the development of specific immunotherapy of MG as well as providing information that is likely to be applicable to other less well understood autoimmune diseases.