Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice

F-1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice are a model of human systemic lupus erythematosus. These mice develop a severe immune complex-mediated nephritis, in which antinuclear autoantibodies are believed to play the major role. We used a genetic analysis of(NZB x NZW)F-1 x NZW backcross mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin, which overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein, gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a distal chromosome 4 locus, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production.