The Contribution of H-2^bm12 and Non H-2 Background Genes on Murine Lupus in NZB.H-2^bm12/b Mice

We have previously demonstrated the influence of the I-A^bm12 gene mutation on the appearance of IgG anti-dsDNA antibodies when placed on an NZB genetic background. To further enhance our understanding of the interaction of the bm12 mutation on disease expression, lethally irradiated NZB.H-2^bm12/b F1 mice were reconstituted with T-cell-depleted bone marrow cells from 3- to 6-week-old donors of four different congenic strains, NZB.H-2^bm12, NZB.H-2^b, B6.C-H-2^bm12 and C57BL/6 (H-2^b) mice. All animals when then serially followed for the appearance of IgM and IgG anti-ss and dsDNA antibodies. Significant alterations of T-cell subsets, high levels of IgG anti-dsDNA antibodies and proteinuria were found only in recipient NZB.H-2^bm12/b F1 mice that were reconstituted with T-cell-depleted NZB.H-2^bm12 bone marrow cells. Such activity was not found in F1 mice engrafted and fully reconstituted with NZB.H-2^b, B6.C-H-2^bm12 or C57BL/6 (H-2^b) T-cell depleted bone marrow cells. Additionally, to evaluate the importance of the NZB background (non-H-2) genes, we transferred T-cell-depleted bone marrow cells from NZB.H-2^bm12 mice into H-2 compatible B6.C-H-2^bm12 mice and vice versa. Without NZB background genes, an increase in CD4^- CD8^- T-cells, IgG anti-dsDNA, splenomegaly, and proteinuria were not observed. These data suggest that the H-2^bm12 gene and the NZB background genes in bone marrow-derived cells are both necessary for the altered expression of T-cell subsets and anti-DNA production. These results also suggest that micro-environmental influences on the hematopoietic cells, including the thymic micro-environment, are necessary for the clinical appearance of murine lupus.