HOW SUBTLE DIFFERENCES IN MHC CLASS-II AFFECT THE SEVERITY OF EXPERIMENTAL MYASTHENIA-GRAVIS

Myasthenia gravis is an autoimmune disorder characterized by muscle we akness, due to an antibody-mediated deficit of acetylcholine receptors (AChRs) at neuromuscular junctions. We analyzed the factors that dete rmine the severity of experimental myasthenia gravis (EAMG) induced by immunization with Torpedo AChR, in two congenic strains of mice-He mi ce, which are highly susceptible to EAMG; and bm12 mice, which are rel atively resistant, and differ only in a change of three amino acids in MHC Class II. We prepared large numbers of AChR-specific T cell hybri domas from each strain and characterized their epitope specificities a nd T cell receptor (TCR) gene usage: Half the B6 hybridomas responded to a single AChR peptide (alpha 146-162), and their TCR genes encoded restricted V alpha and V beta chains and CDR3 motifs. bm12 hybridomas had different epitope specificities and different, less restricted TCR genes. APCs were able to present AChR or AChR-derived peptides virtua lly exclusively to hybridomas of their own strain. Levels of antibodie s to Torpedo and autoantibodies to mouse AChR were higher in B6 mice, and were biased toward the IgG2b isotype. We conclude that the ''bette r fit'' of MHC II, peptide, and TCR in the B6 mice enhanced cognate in teractions of APCs with T cells, and T cells with B cells, resulting i n a more abundant and pathogenic AChR antibody response, and thus more severe EAMG. (C) 1998 Academic Press.