Influence of Innate Immunity on Xenobiotic-Induced Systemic Autoimmunity

先天免疫对异生素诱导的系统性自身免疫的影响

• 批准号: 8720002
• 负责人: Kenneth Michael Pollard
• 金额: $ 42.21万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720002
• 关键词: Address; Affect; Alveolar Macrophages; Animals; Autoantibodies; Autoimmune Diseases; Autoimmunity; Binding; Caspase-1; Cell Death; Cells; Chemicals; Chronic; Clinical; Connective Tissue Diseases; Data; Dendritic Cells; Dependence; Development; Disease; Environmental Risk Factor; Exposure to; Family member; Foundations; Genes; Genetic; Heterogeneity; Human; IRF1 gene; Immune response; Immune system; Inflammation; Inflammatory; Interferon Type I; Interferons; Interleukin-1; Interleukin-17; Interleukin-18; Macrophage Activation; Mediating; Mercury; Molecular; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Play; Population; Pristane; Process; Publishing; Receptor Signaling; Risk; Role; Severities; Silicon Dioxide; Silicosis; Susceptibility Gene; Symptoms; Systemic Lupus Erythematosus; Testing; Toll-like receptors; United States; Xenobiotics; base; cytokine; environmental agent; insight; macrophage scavenger receptors; promoter; public health relevance; receptor; receptor function; research study; response; scavenger receptor; systemic autoimmune disease; uptake

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.

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相结合，在系统性自身免疫性疾病中发挥重要作用。先天免疫在特发性和环境诱导的全身性自身免疫中起着不可或缺的作用，对内体toll样受体和/或UNC 93 B1的需求在特发性、降植烷和汞诱导的自身免疫中提供了统一的机制。然而，在介导疾病发展的其他所需的先天分子和细胞组分中存在明显差异。这些差异代表了我们理解自身免疫性疾病过程及其可能治疗的整体的重大障碍。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。尽管关于矽尘诱导的自身免疫机制的信息很少，但矽尘病与发展成临床结缔组织疾病（如SLE）的风险之间的联系表明，矽尘病中的免疫检查点可能有助于矽尘诱导的自身免疫。小鼠矽肺不仅受到1型干扰素的影响，而且还受到IL-17的影响。NLRP 3炎性小体和半胱天冬酶-1也是硅肺所必需的，我们的初步研究表明半胱天冬酶-1是诱导自身抗体所必需的，这支持了它们对硅肺诱导的自身免疫的重要性。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，NLRP 3或半胱天冬酶-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异性外源性物质诱导的全身性自身免疫的严重程度。我们提出了四个具体的目标来解决这个假设：-目标1）清道夫受体（SR）是必不可少的外源性诱导的系统性自身免疫？目的2）TLR介导的I型干扰素能否调节外源性生物素诱导的全身性自身免疫？目的3）外源性生物素诱导的自身免疫是通过炎性小体依赖性机制还是非依赖性机制产生的？目的4）IFN-γ是否需要促炎性IL-1？异生物素诱导的自身免疫依赖性？更好地理解先天机制负责特发性和环境诱导的自身免疫性，应产生新的见解的过程中，煽动和驱动系统性自身免疫性。