Xenobiotic-Induced Type 1 Interferon-Independent Autoimmunity

浆细胞样树突状细胞（pDC）产生I型干扰素（IFN）和IFN-γ表达增加 诱导基因被认为是系统性红斑狼疮（SLE）发病机制的核心。的类型 IFN基因特征与SLE和其他几种系统性和器官性疾病中更严重的疾病相关。 特异性自身免疫性疾病这表明，有一些重要的疾病亚组， 疾病可能是由于I型IFN非依赖性机制。缺乏实验数据， I型干扰素非依赖性自身免疫的机制是我们理解整体免疫的一个重要障碍， 自身免疫性疾病的过程及其治疗。我们研究了全身性自身免疫， 暴露于汞揭示了该模型中的轻度疾病不依赖于I型IFN。汞暴露 也导致系统性自身免疫的轻度表达。爆发性全身性疾病较少 也被观察到与其他外源性物质和药物。因此，汞诱导的自身免疫可能提供了一个合适的 研究I型IFN非依赖性自身免疫的动物模型，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型干扰素独立 自身免疫性先天免疫应答由内体TLR通过NF-B活化介导， 促炎细胞因子的产生和NF-B依赖性与IFN-γ的协同作用，导致增强 IFN-γ诱导基因的表达。我们建议在四个具体目标中解决这一假设： 树突状细胞（DC）对I型IFN非依赖性自身免疫至关重要？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？，目的3）是促炎性的 NF-B？调节的I型IFN非依赖性自身免疫中的细胞因子表达，（4）目标是 I型IFN依赖性自身免疫是否需要促炎性IL-1？的答案 这些问题将有助于深入了解导致全身性疾病的多种致病途径。 自身免疫性和扩大概念基础上，自身免疫性疾病的研究是基于。

Type I interferon (IFN) production by plasmacytoid dendritic cells (pDC) and increased expression of IFN-¿ 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-¿B activation leading to proinflammatory cytokine production and NF-¿B dependent synergy with IFN-¿ resulting in enhanced expression of IFN-¿ 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-¿B?, and Aim 4) Is proinflammatory IL-1¿ required for IFN-¿ 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.