Genetic analysis of the imperfect association of H-2 haplotype with lupus-like autoimmune disease.

Unlike parental New Zealand Black (NZB) or New Zealand White (NZW) mice, (NZB x NZW)F1 mice exhibit a lupus-like disease characterized by high serum levels of IgG anti-nuclear antibodies and a fatal immune complex glomerulonephritis. Previous results from studying [(NZB x NZW)F1 x NZB] backcross mice indicated that the NZW major histocompatibility complex (MHC) or gene(s) closely linked to this locus provides the major dominant NZW genetic contribution to the F1 disease. A surprising feature of the results was the 12% frequency of discordance between the autoimmune phenotype and the presence of the NZW H-2z haplotype. In the current study, we attempted to precisely define the position of the NZW gene(s) required for lupus-like renal disease by mapping genes in individual backcross mice that are both centromeric and telomeric to the MHC and then correlating genotypes for each locus with disease. The data indicate that an adjacent NZW locus does not provide a more accurate correlation with the autoimmune phenotype compared with MHC genes themselves. Thus, the imperfect association of MHC haplotype with disease in this murine model is not explained by genetic recombination with linked genes. These data may provide insight into the mechanisms by which MHC antigens increase the probability of developing autoimmune disease and may help explain the difficulty of defining MHC relationships in human systemic lupus erythematosus.