The contribution of i-a^bm12 to the production of autoantibodies to dsDNA

The development of IgG autoantibodies to dsDNA in NZBxNZW Fl (NZB/W) and NZBxSWR Fl (SNF1) mice have been linked to specific alleles of MHC class II genes contributed by the NZW and SWR parents respectively. Recently, our laboratory has shown that the introduction of the bml2 mutation into NZB mice (NZB.H-2^bm12) results in mice which are phenotypically similar to NZB/W Fl mice and, in particular, develop IgG anti-dsDNA antibodies. A variety of immune abnormalities have been described in autoimmune NZB (H-2^d) mice. It is, however, unclear at present, whether all these abnormalities are due to the influence or effect of a single set of linked genes or due to multiple genes. It was reasoned that NZB.H-2^bml2 mice provide a unique opportunity to examine this issue. Specifically, we bred a series of five different Fl colonies of mice: (a) NZB.H-2^bml2/b Fl;b) NZB.H-2^bml2/d Fl;c) NZB-H-2^b/d Fl;d) NZB-H-2^bm12xB6.C-H-2^bm12 Fl (NZB/B6.H-2^bm12 Fl);and (e) NZBxB6.C-H-2^bm12 Fl (NZB/B6.H-2^d/bm12 Fl) mice. All groups of mice were serially followed for the appearance of IgM and IgG anti-ssDNA and anti-dsDNA antibodies, splenic CFU-B, spontaneous secretion of IgM, FMF analysis, proteinuria and survival. We report herein that H-2^bm12 genes have a dominant influence on the appearance of IgG anti-dsDNA antibodies. In contrast, antibodies to ssDNA, IgM secreting cells, CFU-B and Ly-1 B cells are linked to genes from the NZB background. Finally, we particularly note an absence of IgG antibodies to dsDNA in NZB-H-2^b/d Fl mice.