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，它们要么单独作用，要么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。我们先前确定，Ig G受体FcGammaRIIB缺陷的小鼠会发生自发的抗核抗体和致死性肾小球肾炎。在FcGammaRIIB缺陷的小鼠模型中，对狼疮的其他遗传修饰因素的表征使我们能够确定，仅仅复制TLR7基因就足以引起自身免疫性疾病。我们利用TLR7的转基因过表达表明，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。这些研究提供了一个理论框架，如果没有适当的调控，抗病毒的先天反应可能会导致自身反应性和致命性炎症性疾病。我们扩大了这些研究，以包括其他抗病毒途径，如RNA传感器MDA5在启动系统性自身免疫性疾病中的作用。 我们对易患狼疮的FcGammaRIIB缺陷小鼠品系的表征也使我们能够研究自身免疫易感性和对病原体感染的抵抗力之间的相关性。一方面，我们观察到某些病毒感染可以推迟自身免疫性疾病的发生：感染VSV的小鼠不太可能产生自发的自身反应。另一方面，我们已经确定，易患狼疮的背景为抵抗致死性脑型疟疾提供了选择性优势。 我们期望这些研究将有助于剖析自身免疫病理学的要求，并解决病原体感染对自身免疫性疾病总发病率的影响。新发现的基因可能会发现修改狼疮或其他自身免疫性疾病正在进行的疾病的潜在途径，并将作为疾病易感性、进展和严重程度的预测因子。

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 prevent dendritic cell expansion. 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.