PATHOGENIC MECHANISMS IN MYASTHENIA

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Myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG) are T-cell-dependent antibody (Ab)-mediated autoimmune disease directed at the acetylcholine receptor (AChR) in the endplate membrane of the neuromuscular junction (NMJ). Three pathogenic mechanisms by which the Abs induce the characteristic abnormalities at the NMJ have been proposed from studies of EAMG and MG: complement-mediated endplate membrane destruction increased AChR turnover by Ab crosslinking of adjacent AChRs, and functional blockage of intact AChRs. Our previous studies and those from other laboratories have suggested the hypothesis that the major mechanism is complement-mediated endplate membrane destruction. To test this hypothesis-syngeneic recombinant/chimeric (rec/chi) Abs will be produced from our library of rat anti-AChR monoclonal Abs, which have been engineered to have reduced or absent complement activating activity, but to retain the functions associated with the other two possible pathogenic mechanisms. These rec/chi Abs will be analyzed in vitro for their antigen binding and their effector functions and in vivo for their ability to induce the passively-transferred form of EAMG in syngeneic rats. Rec/chi Abs that are incapable of inducing EAMG will be tested, singly or in combination, for their ability to bock both passively- and actively-induced EAMG. Abs of this type will potentially represent a new antigen-specific treatment of MG. Therefore, similar human autologous rec/chi Abs will developed from anti-AChR B cells obtained from patients with MG, and their effector functions analyzed in vitro.