Genetic and Environmental Modifiers Of Autoimmune Disease

我们过去的工作已经发现了几个狼疮易感基因，这些基因本身或通过与各种其他遗传因素相互作用，改变自身免疫性疾病的诱导和进展。我们之前确定IgG受体FcgammaRIIB缺乏的小鼠会产生自发的抗核抗体和致命的肾小球肾炎。在fcgammariib缺陷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，仅仅是Tlr7基因的重复就足以加重自身免疫性疾病。通过对TLR7的转基因过表达，我们发现TLR7对调节自身免疫和树突状细胞稳态至关重要。这些小鼠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。这些研究提供了一个理论框架，其中抗病毒先天反应，如果不适当调节，可导致自身反应性和致命的炎症性疾病。

Our past work has uncovered several lupus susceptibility genes that, either by themselves or by interacting with a variety of other genetic factors, modify both the induction and progression of autoimmune disease. We previously determined that mice deficient in the IgG receptor FcgammaRIIB develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis. Characterization of other genetic modifiers of lupus in the FcgammaRIIB-deficient mouse model allowed us to determine that a mere duplication of the Tlr7 gene is sufficient to aggravate autoimmune disease. We showed, using transgenic overexpression of TLR7, that TLR7 is essential to regulate autoimmunity and dendritic cell homeostasis. These mice provide a prime example of how important it is to control the expression of innate receptors. These studies provide a theoretical framework in which anti-viral innate responses, when not properly regulated, can result in autoreactivity and lethal inflammatory disease. During the past year we have analyzed the specific role of a variety of anti-viral pathways and their possible production of interferon in the development of autoimmune disease. We have also investigated the effect of malaria infection in the progression of lupus disease. In particular we have: 1) made considerable progress in understanding the functional state and clonal selection of CD8 cells in lupus 2) investigated the role of type I interferon and the anti-viral sensor MAVS in B cell responses 3) studied a possible suppresor role of CD8 cells primed by a virus in systemic autoimmunity, 4) determined that a single infection with a malaria parasite provides a long lasting protective effect in lupus that is targeting end organ disease and does not alter tolerance mechanisms. Studying the role of innate responses against pathogens in autoimmune-prone settings may shed light on gender bias, influence of infections, and the stochastic pathogenesis that is often seen in the development of autoimmunity. Studying the protective effect of various infections provides new views of possible effect of infection with pathogens over the course of disease in human patients. Our work with malaria infections has provided a new model to investigate potential end organ therapeutic targets in SLE. We have investigated the protective effect of a single infection with a malaria parasite on lethal autoimmune glomerulonephritis. SLE is characterized by high levels of serum autoantibodies and systemic immune activation. A common cause of lethality is the immune mediated destruction of kidney glomeruli. We have determined that a single malaria infection early in life can protect from kidney involvement while increasing overall levels of autoantibodies and systemic inflammation. Our results indicate a possible route for lupus protection that specifically targets renal function, which remains a cause of the substantial morbidity and mortality in SLE patients.