CONTRIBUTIONS OF EA(Z) AND EB(Z) MHC GENES TO LUPUS SUSCEPTIBILITY INNEW-ZEALAND MICE

Unlike parental New Zealand Black (NZB) or New Zealand White (NZW) mic e, (NZB x NZW)F-1 mice exhibit a lupus-like disease characterized by I gG antoantibody production and severe immune complex-mediated nephriti s, In studies of the genetic susceptibility to disease in this F-1 mod el, the NZW MHC (H2(z)) has been strongly linked with the development of disease, and it was hypothesized that class II MHC genes, particula rly E-z genes, may underlie this genetic contribution, In the present study, we bred transgenic B6 mice expressing I-E-z or congenic B6 mice carrying H2(z) with NZB mice and used a backcross analysis to test th e hypothesis that Ea(z) and/or Eb(z) genes account for the effect of H 2(z) on disease, The genetic analysis of different backcross combinati ons showed that unlike mice carrying H2(z), mice inheriting E-z transg enes do not demonstrate increased IgG autoantibody production or incre ased incidence of nephritis. Surprisingly, in the same transgenic back cross mice, inheritance of the endogenous H2(b) from the B6 strain was strongly linked with the production of IgG autoantibodies, but not wi th disease, Additional experiments suggested that the level of IgG3 au toantibody production, which is controlled by H2, may be important in the pathogenesis of renal disease, Contributions to autoantibody produ ction were also detected from an NZB locus on distal chromosome 1 (pre viously named Nba2), Together, these studies provide new insight into the role of MHC in lupus-like autoimmunity.