Xenobiotic-Induced Type 1 Interferon-Independent Autoimmunity

描述(由申请人提供)：由浆细胞样树突状细胞产生的I型干扰素和干扰素-α诱导基因的表达增加被认为是系统性红斑狼疮发病机制的核心。I型干扰素基因信号与系统性红斑狼疮和其他几种系统性和器官特异性自身免疫性疾病中更严重的疾病有关。这表明，有一些重要的疾病亚组，其中不太严重的疾病可能是由于I型干扰素的非依赖机制。缺乏关于I型干扰素非依赖性自身免疫机制的实验数据是我们理解自身免疫性疾病整个过程及其治疗的重要障碍。我们对汞暴露引起的系统自身免疫的研究表明，在这个模型中，轻微的疾病独立于I型干扰素。人体接触汞也会导致系统自身免疫的温和表达。其他外来物和药物也观察到了不太剧烈的系统性疾病。因此，汞诱导的自身免疫可能为研究I型干扰素非依赖性自身免疫提供一种合适的动物模型，其机制可能适用于多种环境因素。根据我们的初步研究，我们推测，在I型干扰素非依赖性自身免疫中，天然免疫反应是由内体TLRs介导的，通过激活NF-κB导致促炎细胞因子的产生，并依赖于NF-κB与干扰素-γ的协同作用，导致干扰素-γ诱导的基因表达增强。目的1)树突状细胞(DC)是否是I型干扰素非依赖性自身免疫所必需的？目的2)胞体Toll样受体(TLR)信号通路是否介导I型干扰素非依赖性自身免疫？目的3)在I型干扰素非依赖性自身免疫中促炎细胞因子的表达是否受核因子κB的调节？目的4)促炎细胞因子α对I型干扰素非依赖性自身免疫的干扰素-γ依赖性是否必需？对这些问题的回答将有助于深入了解导致系统性自身免疫的多种致病途径，并拓宽自身免疫性疾病研究的概念基础。

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.