Unlike parental New Zealand Black (NZB) or New Zealand White (NZW) mice, (NZB x NZW)F1 mice exhibit a lupus-like disease characterized by IgG autoantibody production and severe immune complex-mediated nephritis. In studies of the genetic susceptibility to disease in this F1 model, the NZW MHC (H2z) has been strongly linked with the development of disease, and it was hypothesized that class II MHC genes, particularly Ez genes, may underlie this genetic contribution. In the present study, we bred transgenic B6 mice expressing I-Ez or congenic B6 mice carrying H2z with NZB mice and used a backcross analysis to test the hypothesis that Ea(z) and/or Eb(z) genes account for the effect of H2z on disease. The genetic analysis of different backcross combinations showed that unlike mice carrying H2z, mice inheriting Ez transgenes do not demonstrate increased IgG autoantibody production or increased incidence of nephritis. Surprisingly, in the same transgenic backcross mice, inheritance of the endogenous H2b from the B6 strain was strongly linked with the production of IgG autoantibodies, but not with disease. Additional experiments suggested that the level of IgG3 autoantibody production, which is controlled by H2, may be important in the pathogenesis of renal disease. Contributions to autoantibody production were also detected from an NZB locus on distal chromosome 1 (previously named Nba2). Together, these studies provide new insight into the role of MHC in lupus-like autoimmunity.