Genetic Modifiers Of Autoimmune Disease In FcgammaRIIB Mutant Mice

Fc γ RIIB是一种有效的狼疮易感性基因，能够与多种其他基因座相互作用以改变自身免疫性疾病的诱导和进展。 缺乏这种分子的小鼠在C57 BL/6背景下会产生自发性抗核抗体和致命性肾小球肾炎。在BALB/c背景上的相同突变是不显著的，表明在BALB/c背景上存在抑制基因座，其限制了自身免疫的发展。为了研究这些背景遗传修饰剂在B6.FcRIIB-/-疾病模型中的影响，在B6.FcRIIB -/-和BALB.FcRIIB -/-小鼠之间进行杂交，并评价所得F1和F2代的自身免疫表型。连锁分析表明，12号和17号染色体可能含有ANA和肾小球肾炎的正连锁区域。我们将注意力集中在12号染色体区域，因为在该区间尚未发现明显的候选基因，因此增加了该位点的精细定位将导致识别改变自身免疫性疾病易感性的新基因的可能性。 一个新的同类系菌株的产生使我们能够确定来自BALB/c基因组的12号染色体的该区域的存在足以使B6.R2-/-小鼠对狼疮疾病具有抗性。 在FcRIIB-/-小鼠模型中对狼疮的其他遗传修饰因子的表征使我们能够确定Yaa小鼠中Y染色体携带的TLR 7基因的重复足以加重自身免疫性疾病。使用TLR 7的转基因过表达的进一步研究表明，TLR 7对于调节自身免疫和防止树突状细胞扩增是必需的。 这些小鼠 因此提供了一个很好的例子，说明控制先天受体的表达是多么重要。 并提供了一个理论框架，其中抗病毒先天反应，当不适当的调节，可导致自身反应性和致命的炎症性疾病。 我们目前正在研究其他抗病毒途径在引发系统性自身免疫性疾病中的作用。

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.