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

Abstract

Previous studies have suggested that MHC and non-MHC genes contribute to the development of autoimmune disease in F1 hybrids of New Zealand black (NZB) and white (NZW) mice. We conducted a genome-wide screen of 148 female (NZB x NZW)F1 x NZB backcross mice to map dominant NZW genetic loci linked with lupus disease traits. In this backcross analysis, inheritance of the NZW MHC (H2(d/z) vs. H2(d/d)) was strongly linked with the development of lupus nephritis (P approximately 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 gp70-anti-gp70 immune complexes. Non-MHC contributions from NZW seemed weak in comparison to MHC, although NZW loci on chromosomes 7 and 16 were noted to be suggestively linked with autoantibody production. Strikingly, H2(d/z) (compared with H2(d/d)) enhanced antinuclear antibodies in a coordinate fashion but did not affect anti-gp70 production in the current backcross. However, the opposite influence was noted for H2(d/z) (compared with H2(z/z)) when (NZB x NZW)F1 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 role for H2(z) compared with other dominant NZW loci in (NZB x NZW)F1 mice and provides an explanation as to why H2(d/z) heterozygosity is required for full expression of disease in this model.

Figure 1

Association of nephritis with genotypes at MHC and particular non-MHC loci in 148 (NZB × NZW)F₁ × NZB backcross mice. The results are shown as percentage of mice with severe nephritis, which correlated closely with early mortality (11), in relation to the genotypes shown.

Figure 2

The pattern of linkage with nephritis (determined by χ² analysis) as well as with IgG anti-dsDNA production and gp70 IC production (determined by mapmaker/qtl) in (NZB × NZW)F₁ × NZB backcross mice is shown for loci on chromosome 7. There are two peaks of linkage: one at D7Nds5 (close to the position of Sle3; ref. 14) and a second at D7Mit148 (close to the position of Nba3; ref. 12). Data are derived from 148 mice followed for development of nephritis, of which 131 were studied for both anti-dsDNA and gp70 IC.

Figure 3

Selective effects of H2^z in F₁ × NZB backcross mice vs. H2^d in F₁ × NZW backcross mice. The data are presented as linkage values (MLS) for H2^d/z vs. H2^d/d in F₁ × NZB backcross mice and for H2^d/z vs. H2^z/z in F₁ × NZW backcross mice. MLS > 1.4, P < 0.01; MLS > 2.35, P < 1 × 10⁻³; MLS > 3.3, P <1 × 10⁻⁴; MLS > 4.23, P < 1 × 10⁻⁵. Data are derived from 148 F₁ × NZB mice followed for nephritis, 131 F₁ × NZB mice studied serologically, 108 F₁ × NZW mice followed for nephritis, and 92 F₁ × NZW mice studied serologically.