Backcross Analysis of Genes Linked to Autoantibody Production in New Zealand White Mice

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 (H2^d) was linked with IgG autoantibody production. This influence of H2^d is therefore similar to that seen in (NZW X NZB)F₁ mice, in which heterozygosity for H2^d 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.