Xenobiotic-Induced Type 1 Interferon-Independent Autoimmunity

描述（申请人提供）：浆细胞样树突状细胞（pDC）产生I型干扰素（IFN）和IFN-α诱导基因表达增加被认为是系统性红斑狼疮（SLE）发病机制的核心。I型IFN基因特征与SLE和几种其它系统性和器官特异性自身免疫性疾病中更严重的疾病相关。这表明，有显着的疾病亚组，其中不太严重的疾病可能是由于I型干扰素的独立机制。缺乏实验数据的机制，I型干扰素独立的自身免疫性是一个显着的障碍，我们了解的整体自身免疫性疾病的过程和治疗。我们对汞暴露引起的全身性自身免疫的研究揭示了该模型中的轻度疾病独立于I型IFN。人体接触汞也会导致轻微的全身性自身免疫反应。在其他外源性物质和药物中也观察到了较少的暴发性全身性疾病。因此，汞诱导的自身免疫可能提供了一个合适的动物模型，以研究I型IFN非依赖性自身免疫，其机制可能适用于多种环境因素。基于我们的初步研究，我们假设在I型IFN非依赖性自身免疫中，先天免疫应答由内体TLR介导，通过NF-κB活化导致促炎细胞因子产生和NF-κB依赖性与IFN-γ协同作用，导致IFN-γ诱导基因的表达增强。我们提出了四个具体目标来解决这一假设：-目标1）树突状细胞（DC）是I型IFN非依赖性自身免疫所必需的吗？目的2）内体Toll样受体（TLR）信号通路介导I型IFN非依赖性自身免疫吗？目的3）I型IFN非依赖性自身免疫中促炎细胞因子的表达是否受NF-κB的调节？目的4）促炎性IL-1α是否是I型IFN非依赖性自身免疫的IFN-γ依赖性所必需的？这些问题的答案将提供深入了解致病途径的多样性，导致系统性自身免疫性和扩大的概念基础上，自身免疫性疾病的研究。

DESCRIPTION (provided by applicant): Type I interferon (IFN) production by plasmacytoid dendritic cells (pDC) and increased expression of IFN-α inducible genes are argued to be central to the pathogenesis of systemic lupus erythematosus (SLE). The type I IFN gene signature is associated with more severe disease in SLE and several other systemic and organ- specific autoimmune diseases. This suggests that there are significant disease subgroups in which less severe disease may be due to type I IFN independent mechanisms. The scarcity of experimental data on the mechanisms of type I IFN independent autoimmunity is a significant barrier to our understanding of the totality of the autoimmune disease process and its treatment. Our studies of the systemic autoimmunity resulting from exposure to mercury reveal the mild disease in this model to be independent of type I IFN. Mercury exposure in humans also results in a mild expression of systemic autoimmunity. Less fulminant systemic disease has also been observed with other xenobiotics and drugs. Thus mercury-induced autoimmunity may offer a suitable animal model to study type I IFN independent autoimmunity, the mechanisms of which may be applicable to multiple environmental agents. Based on our preliminary studies we hypothesize that in type I IFN independent autoimmunity innate immune responses are mediated by endosomal TLRs via NF-κB activation leading to proinflammatory cytokine production and NF-κB dependent synergy with IFN-γ resulting in enhanced expression of IFN-γ induced genes. We propose to address this hypothesis in four specific aims:- Aim 1) Are dendritic cells (DCs) essential for type I IFN independent autoimmunity?, Aim 2) Do endosomal Toll-like Receptor (TLR) signaling pathways mediate type I IFN-independent autoimmunity?, Aim 3) Is proinflammatory cytokine expression in type I IFN independent autoimmunity regulated by NF-κB?, and Aim 4) Is proinflammatory IL-1α required for IFN-γ dependence of type I IFN independent autoimmunity? Answers to these questions will provide insight into the multiplicity of pathogenic pathways leading to systemic autoimmunity and broaden the conceptual foundation upon which autoimmune disease research is based.