Influence of Innate Immunity on Xenobiotic-Induced Systemic Autoimmunity

描述(由申请人提供)：有大量证据表明，环境诱因与遗传和随机因素相结合，在系统性自身免疫性疾病中发挥着重要作用。先天性免疫在特发性和环境诱导的全身性自身免疫中都起着不可或缺的作用，内体Toll样受体和/或Ok93B1的要求在特发性、孕激素和汞诱导的自身免疫中提供了一个统一的机制。然而，在调节疾病发展的其他必需的先天分子和细胞成分上存在明显的差异。这些差异对我们理解自身免疫性疾病的整个过程及其可能的治疗是一个巨大的障碍。二氧化硅和汞都与人类和动物的自身免疫性疾病的表达有关。虽然关于二氧化硅诱导自身免疫的机制的信息很少，但矽肺与临床结缔组织疾病如系统性红斑狼疮的发病风险之间的联系表明，矽肺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、炎症体和caspase-1也是矽肺所必需的，我们的初步研究表明，caspase-1是诱导自身抗体所必需的，这支持了它们在二氧化硅诱导的自身免疫中的重要性。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，我们假设先天免疫系统的不同组成部分调节特定异物诱导的全身自身免疫的严重程度。我们建议从四个具体的目标来解决这一假说：-目的1)清道夫受体(SRs)对于异种生物诱导的系统自身免疫是必不可少的吗？目的2)TLR介导的I型干扰素是否调节异种生物诱导的系统自身免疫？目的3)异种生物诱导的自身免疫是由炎症体依赖还是独立机制引起的？目的4)干扰素-1是否需要促炎性IL-1？异种生物诱导的自身免疫的依赖性？更好地了解导致特发性和环境诱导的自身免疫的先天机制，应该会对激发和推动全身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.