Genetic and Environmental Modifiers Of Autoimmune Disease

在我们过去的研究中，我们发现了几个狼疮易感基因，这些基因要么单独存在，要么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。我们已经扩展了这些研究，包括其他抗病毒途径，如rna传感器MDA5在系统性自身免疫性疾病的启动。

In our past studies we 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 agravate 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. We have expanded these studies to include other anti-viral pathways such as the RNA-sensor MDA5 in the initiation of systemic autoimmune disease. Our characterization of the lupus-prone FcgammaRIIB-deficient mouse strain has also allowed us to study correlation between autoimmune susceptibility and resistance to pathogen infection. On one hand, we have observed that certain viral infections can delay the onset of autoimmune disease: mice infected with VSV are less likely to generate spontaneous autoreactive responses. On the other hand, we have determined that a lupus-prone background confers selective advantage for resistance to lethal cerebral malaria. We expect that these studies will help dissect the requirements for autoimmune pathology and will address the effect of pathogen infections in overall incidence of autoimmune disease. Newly discovered genes will possibly uncover potential routes for modifying ongoing disease in lupus or other autoimmune diseases and will serve as predictors of disease susceptibility, progression and severity.