The lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC-and non-MHC-encoded genes. Studies in this model have indicated that the H2 d/z MHC type, compared with H2 d/d or H2 z/z, is critical for disease development. C57BL/6 (B6) mice (H2 b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6. Nba2 to NZW results in H2 b/z F 1 offspring that develop severe lupus nephritis. Despite the importance of H2 z in past studies, we found no enhancement of autoantibody production or nephritis in H2 b/z vs H2 b/b B6. Nba2 mice, and inheritance of H2 z/z markedly suppressed autoantibody production.(B6. Nba2× NZW) F 1 mice, compared with MHC-matched B6. Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F 1 mice, kidneys of some B6. Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6. Nba2 and F 1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F 1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.