Control of separate pathogenic autoantibody responses marks MHC gene contributions to murine lupus

Previous studies have suggested that MHC and non-MHC genes contribute to th e development of autoimmune disease in F-1 hybrids of New Zealand black (NZ B) and white (NZW) mice. We conducted a genome-wide screen of 148 female (N ZB x NZW)F-1 x NZB backcross mice to map dominant NZW genetic loci linked w ith lupus disease traits. In this backcross analysis, inheritance of the NZ W MHC (H2(d/z) vs. H2(d/d)) was strongly linked with the development of lup us nephritis (P approximate to 1 x 10(-16)), increasing the risk of disease by over 30-fold. H2(d/z) was also linked with elevated serum levels of IgG autoantibodies to single-stranded DNA, double-stranded DNA, histones, and chromatin but not with anti-gp70 autoantibodies, measured as circulating gp 70-anti-gp70 immune complexes. Non-MHC contributions from NZW seemed weak i n comparison to MHC, although NZW loci on chromosomes 7 and 16 were noted t o be suggestively linked with autoantibody production. Strikingly, H2(d/z) (compared with H2d/d) enhanced antinuclear antibodies in a coordinate fashi on but did not affect anti-gp70 production in the current backcross, Howeve r, the opposite influence was noted for H2(d/z) (compared with H2(z/z)) whe n (NZB x NZW) F-1 x NZW backcross mice were analyzed. These results suggest that H2(z) and H2(d) haplotypes differentially regulate two different sets of nephritogenic autoantibody responses. This study confirms a critical ro le for H2(z) compared with other dominant NZW loci in (NZB x NZW) F-1 mice and provides an explanation as to why H2(d/z) heterozygosity is required fo r full expression of disease in this model,