Genetic Modifiers Of Autoimmune Disease In FcgammaRIIB Mutant Mice

FcGammaRIIB是一种有效的狼疮易感基因，能够与多种其他基因座相互作用，改变自身免疫性疾病的发生和发展。在C57BL/6背景下，缺乏该分子的小鼠会出现自发的抗核抗体和致死性肾炎。BALB/c背景上的相同突变不明显，提示BALB/c背景上存在制约自身免疫发生发展的抑制子基因。我们已经确定了12号染色体的一个区域，该区域足以使B6 FcGammaRIIB-/-小鼠对狼疮疾病产生抵抗力。我们已经确定了这种抑制效应的候选基因，目前正在研究它们作为可能的治疗方法的用途。 在FcGammaRIIB-/-小鼠模型中对狼疮的其他遗传修饰物的表征使我们能够确定YAA小鼠Y染色体携带的TLR7基因的重复足以引起自身免疫性疾病。利用TLR7转基因过表达的进一步研究表明，TLR7在调节自身免疫和防止树突状细胞扩张方面是必不可少的。这些小鼠提供了一个最好的例子，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，在该框架中，如果没有适当的调控，抗病毒先天反应可能会导致自身反应性和致命性炎症性疾病。我们目前正在研究其他抗病毒途径在启动全身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. We have identified a region of Chromosome 12 that is sufficient to render B6.FcgammaRIIB-/- mice resistant to lupus disease. We have identified candidate genes for this suppressor effect and are currently studying their use as possible therapies. Characterization of other genetic modifiers of lupus in the FcgammaRIIB-/- 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 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.