Backcross analysis of genes linked to autoantibody production in New Zealand White mice.

Abstract

F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice are genetically predisposed to develop a lupus-like autoimmune disease characterized by IgG autoantibody production and an immune complex glomerulonephritis. Genes from both parental strains contribute to autoimmunity in the F1 animal. NZW mice produce mostly non-pathogenic autoantibodies to ssDNA and histones as their major autoimmune trait. We studied the genetics of this trait in order to gain insight into the NZW contribution to F1 disease. Genome-wide mapping of (NZW x BALB/c)F1 x NZW backcross mice showed that four NZW non-MHC loci on chromosomes 1, 11, 16, and 19 were linked with IgG autoantibody production. Another NZW locus on chromosome 14 appeared to be selectively linked with IgG anti-histone Abs. In this backcross, contributions from the nonautoimmune BALB/c strain were also apparent. Heterozygosity for the BALB/c MHC (H2d) was linked with IgG autoantibody production. This influence of H2d is therefore similar to that seen in (NZW x NZB)F1 mice, in which heterozygosity for H2d enhances autoantibody production and disease. Surprisingly, two non-MHC BALB/c loci were linked with IgM autoantibody levels, whereas no NZW loci had such an effect. Neither of these two loci have been previously linked with autoimmunity in lupus-prone mice. These data show that autoantibody production in NZW mice is a polygenic trait that is influenced by contributions from MHC and non-MHC genes. The results also support the hypothesis that NZW genes act to class-switch the autoantibody response, an effect that appears to contribute to disease in (NZB x NZW)F1 mice.