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，无论是通过自身还是通过与各种其他遗传因素相互作用，都可以改变自身免疫性疾病的诱导和进展。我们先前确定IgG受体Fc γ RIIB缺陷的小鼠产生自发的抗核抗体和致命的肾小球肾炎。在Fc γ RIIB缺陷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Tlr7基因的单纯重复足以加重自身免疫性疾病。 我们发现，使用转基因过表达的TLR7，TLR7是必不可少的调节自身免疫和树突状细胞的稳态。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，当没有适当的调节，可导致自身反应性和致命的炎症性疾病。 在过去的一年中，我们分析了各种抗病毒途径的具体作用及其可能产生的干扰素在自身免疫性疾病的发展。我们还研究了疟疾感染在狼疮疾病进展中的作用。 特别是，我们有：1）在理解狼疮中CD 8细胞的功能状态和克隆选择方面取得了相当大的进展2）研究了I型干扰素和抗病毒传感器MAVS在B细胞应答中的作用3）研究了由病毒引发的CD 8细胞在系统性自身免疫中的可能抑制作用，4）确定疟疾寄生虫的单次感染在狼疮中提供了针对终末器官疾病的持久保护作用，并且不会改变耐受机制。 研究先天性应答在自身免疫易感环境中对病原体的作用可能会揭示性别偏见，感染的影响以及在自身免疫发展中经常看到的随机发病机制。 研究各种感染的保护作用为病原体感染在人类患者疾病过程中可能产生的影响提供了新的观点。 我们在疟疾感染方面的工作为研究SLE潜在的终末器官治疗靶点提供了一个新的模型。 我们研究了单次感染疟原虫对致死性自身免疫性肾小球肾炎的保护作用。 SLE的特征是高水平的血清自身抗体和全身免疫激活。 致死的常见原因是免疫介导的肾小球破坏。我们已经确定，生命早期的单一疟疾感染可以防止肾脏受累，同时增加自身抗体和全身炎症的总体水平。我们的研究结果表明，一种可能的途径，狼疮保护，特别是针对肾功能，这仍然是一个原因，大量的发病率和死亡率在SLE患者。

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.