The role of HLA-DR-A and -B antigen in myasthenia gravis or other autommune disease pathogenesis is not well understood. It is possible to study the role of murine I-A, H-2K and H-2D molecules (the murine analogue of HLA molecules) in the pathogenesis of murine experimental autoimmune myasthenia gravis (EAMG). Previous studies have established the role of immune response genes in the I-A subregion on EAMG susceptibility. We propose to study the role of these molecules by determining the degree of EAMG susceptibility of the B6 I-A and H-2K locus mutant strain and by in vivo administration of anti I-A, H-2K and H-2D monoclonal antibodies (m-ab) before and after established autoimmunity to AChR. Further the generation of acetylcholine receptor specific suppressor cells in m-ab treated animals will be evaluated. We will study the cellular (T cells and/or macrophage) defect leading to low responsiveness to AChR in the I-A mutant strain bm12. Moreover, we will evaluate the role of I-A gene dose effect, 4jt gene (which controls the expression of murine T cell I-J expression), and gene complementation on EAMG pathogenesis. EAMG will be induced in B6 and B6 mutant strains by immunization with AChR in CFA. The following six critical parameters will be used in order to determine the degree of EAMG pathogenesis: (1) clinical muscle weakness, (2) electromyography, (3) AChR-specific lymphocyte proliferation, (4) autoantibody response to AChR, (5) amount of muscle AChR complexed with antibody and (6) carcass muscle AChR loss. The proposed investigations may lead to studies on the generation of AChR specific suppressor factors by AChR specific suppressor T cells and their therapeutic role in murine EAMG, and to studies on the possible immunotherapeutic role of HLA-DR antibody in human MG. Further, the proposed study might serve as a prototype for other organ specific animal and human models of autoimmune diseases where there is an H-2 or HLA linkage.
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