Influence of Innate Immunity on Xenobiotic-Induced Systemic Autoimmunity

描述（由申请人提供）：有大量证据表明，环境触发因素与遗传和随机因素结合在系统性自身免疫性疾病中起重要作用。先天免疫在特发性和环境诱导的全身自身免疫中都起着不可或缺的作用，对内体toll样受体和/或UNC93B1的需求为特发性、嘌呤和汞诱导的自身免疫提供了统一的机制。然而，介导疾病发展的其他必需的先天分子和细胞成分存在明显差异。这些差异对我们理解自身免疫性疾病的整体过程及其可能的治疗来说是一个重大障碍。二氧化硅和汞都与人类和动物自身免疫性疾病的表达有关。尽管关于二氧化硅诱导自身免疫机制的信息缺乏，但矽肺病与临床结缔组织疾病（如SLE）风险之间的联系表明，矽肺病的免疫检查点可能有助于二氧化硅诱导的自身免疫。小鼠矽肺不仅受1型干扰素的影响，还受IL-17的影响。NLRP3炎性小体和caspase-1也是矽肺病所必需的，我们的初步研究表明caspase-1是自身抗体诱导所必需的，这也支持了它们对二氧化硅诱导自身免疫的重要性。相反，我们的研究表明汞诱导的自身免疫不需要1型干扰素、NLRP3或caspase-1。基于这些观察结果，我们假设先天免疫系统的不同组成部分调节由特定外源性药物诱导的系统性自身免疫的严重程度。我们提出在四个具体目标中解决这一假设：目标1)清除受体（SRs）对外源性诱导的全身自身免疫是必需的吗？目的2:TLR介导的I型干扰素是否调节外源诱导的全身自身免疫？目的3)外源诱导的自身免疫是由炎性体依赖还是独立机制引起的？IFN-是否需要促炎IL-1 ？对外源性自身免疫的依赖性？对特发性和环境诱导的自身免疫的先天机制有了更深入的了解，将对引发和驱动系统性自身免疫的过程产生新的见解。

DESCRIPTION (provided by applicant): There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in systemic autoimmune disease. Innate immunity plays an indispensable role in both idiopathic and environmentally induced systemic autoimmunity, with the requirement for endosomal toll-like receptors and/or UNC93B1 providing a unifying mechanism in idiopathic, pristane- and mercury-induced autoimmunity. However there are clear differences in other required innate molecular and cellular components that mediate disease development. These differences represent a significant barrier to our understanding of the totality of the autoimmune disease process and its possible treatment. Both silica and mercury have been implicated in the expression of autoimmune disease in humans and animals. Although there is a paucity of information on mechanisms in silica-induced autoimmunity, the linkage between silicosis and the risk of developing clinical connective tissue diseases such as SLE, suggest that immunological checkpoints in silicosis may contribute to silica-induced autoimmunity. Murine silicosis is influenced not only by type 1 interferon but also by IL-17. The NLRP3 inflammasome and caspase-1 are also required for silicosis and their importance to silica-induced autoimmunity is supported by our preliminary studies showing that caspase-1 is required for autoantibody induction. In contrast our studies suggest that mercury-induced autoimmunity does not require type 1 interferon, NLRP3 or caspase-1. Based on these observations we hypothesize that distinct components of the innate immune system regulate the severity of systemic autoimmunity induced by specific xenobiotics. We propose to address this hypothesis in four specific aims:- Aim 1) Are Scavenger Receptors (SRs) Essential for Xenobiotic-Induced Systemic Autoimmunity? Aim 2) Does TLR mediated Type I interferon Regulate Xenobiotic-Induced Systemic Autoimmunity? Aim 3) Does xenobiotic-induced autoimmunity arise by inflammasome dependent or independent mechanisms? and Aim 4) Is proinflammatory IL-1 required for IFN-? dependence of xenobiotic-induced autoimmunity? Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new insights into the processes that instigate and drive systemic autoimmunity.