FcgammaRIIB is a potent lupus susceptibility gene capable of interacting with a variety of other loci to modify both the induction and progression of autoimmune disease. Mice deficient in this molecule develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis when on the C57BL/6 background. The same mutation on the BALB/c background is unremarkable, indicating the existence of suppressor loci on the BALB/c background which restrict the development of autoimmunity. To study the impact of these background genetic modifiers in the B6.FcRIIB-/- disease model, a cross between B6.FcRIIB -/- and BALB.FcRIIB -/- mice was performed and the resulting F1 and F2 generations evaluated for autoimmune phenotypes. Linkage analysis indicated that chromosomes 12, and 17 were likely to contain regions with positive linkage for ANA and glomerulonephritis. We have focused our attention to the Chromosome 12 region because far no obvious candidate genes have been found in that interval, thus increasing the likelihood that fine mapping of this locus will lead to the identification of novel genes that modify susceptibility of autoimmune disease. The generation of a new congenic strain has allowed us to determine that the presence of this region of chromosome 12 from the BALB/c genome is sufficient to render B6.R2-/- mice resistant to lupus disease. Characterization of other genetic modifiers of lupus in the FcRIIB-/- mouse model allowed us to determine that a duplication in the TLR7gene carried by the Y-chromosome in Yaa mice is sufficient to agravate autoimmune disease. Further studies using transgenic overexpression of TLR7 have shown that TLR7 is essential to regulate autoimmunity and prevent dendritic cell expansion. These mice thus provide a prime example of how important it is to control the expression of innate receptors. And provides a theoretical framework in which anti-viral innate responses, when not properly regulated, can result in autoreactivity and lethal inflammatory disease. We are currently studying the role of other anti-viral pathways in the initiation of systemic autoimmune disease.
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