Toll-Like Receptors in Systemic Autoimmune Disease

描述（由申请人提供）：越来越明显的是，通过先天免疫系统的组分检测自身抗原可有助于多种慢性炎性疾病的发病机制。比如Toll样受体9和7（TLR 9，TLR 7）可以触发对自身核酸的反应。这一建议是基于最近的研究，已经确定TLR 9，TLR 7，和相关的下游转录因子，IRF 5，作为系统性红斑狼疮（SLE）的发展的关键因素。然而，这些分子在疾病发作和进展中所起的确切作用仍然不清楚，并且与TLR 7相比，对TLR 9引起的不同功能知之甚少。TLR 9和TLR 7都有助于自身抗体的产生和树突状细胞的活化，但TLR 9缺乏会加重自身免疫易感小鼠的疾病，而TLR 7缺乏会减轻疾病。值得注意的是，IRF（一种位于TLR 7和TLR 9下游的转录因子）的表达减少是治疗疾病的最有效手段。本申请的总体目标是更好地理解表达TLR 9和TLR 7的细胞类型如何促进SLE发病机制。具体的问题将被解决包括：（1）为什么TLR 7和TLR 9缺陷给自身免疫易感小鼠不一致的结果？(2)TLR 7和TLR 9之间的分子相互作用会导致活性减弱吗？(3)1型干扰素如何调节TLR引起的反应？(4)触发TLR 7和TLR 9的内源性配体是什么？以及（5）IRF 5何时、何地以及如何触发如此关键地调节SLE疾病发病机制的生物活性。这些问题最好由具有不同背景和专业知识的项目参与者小组回答- Marshak-Rothstein（免疫调节和B细胞活化）; Latz（TLR信号的运输和结构/功能分析）; Viglianti（染色质/RNA结构，逆转录病毒学）; Rifkin（树突状细胞生物学和肾脏疾病）和Shiomchik（SLE动物模型）。结合严格的TLR介导的激活和细胞定位的体外分析与细胞类型特异性TLR和缺陷或过度表达的影响在自身免疫性疾病的动物模型中的精确的体内分析应该提供重要的见解，这将促进非侵入性治疗SLE的发展。

DESCRIPTION (provided by applicant): It is becoming increasingly apparent that detection of auto antigens by components of the innate immune system can contribute to the pathogenesis of a variety of chronic inflammatory diseases. For example. Tolllike receptors 9 and 7 (TLR9, TLR7) can trigger responses to self nucleic acids. This proposal is based on recent studies that have identified TLR9, TLR7, and an associated downstream transcription factor, IRF5, as critical factors in the development of systemic lupus erythematosus (SLE). However the exact role played by these molecules is disease onset and progression is still unclear, and very little is known about the distinct functions elicited by TLR9 compared to TLR7. Both TLR9 and TLR7 contribute to autoantibody production and dendritic cell activation, but TLR9-deficiency exacerbates disease In autoimmune-prone mice while TLR7-deficiency reduces disease. Remarkably, reduced expression of IRF, a transcription factor downstream of both TLR7 and TLR9, is the most effective means of curing disease. The overall goal of the current application is to gain a better understanding of exactly how TLR9 and TLR7-expressing cell types contribute to SLE pathogenesis. Specific questions that will be addressed include: (1) why do TLR7 and TLR9 deficiency give discordant outcomes in autoimmune prone mice?; (2) can molecular interactions between TLR7 and TLR9 lead to attenuation of activity?; (3) how do type 1 interferons regulate TLR-elicited responses?; (4) what are the endogenous ligands that trigger TLR7 and TLR9?; and (5) when, where and how does IRF5 trigger the bioactivities that so critically regulate SLE disease pathogenesis. These questions can be best answered by a panel of program participants with diverse background and expertise - Marshak-Rothstein (immunoregulation and B cell activation); Latz (trafficking and structure/function analysis of TLR signaling); Viglianti (chromatin/RNA structure, retrovirology); Rifkin (dendritic cell biology and renal disease) and Shiomchik (animal models of SLE). The combined rigorous in vitro analysis of TLR-mediated activation and cell localization with the precise in vivo analysis of the impact of cell type specific TLR and deficiency or overexpression in animal models of autoimmune disease should provide important insights that will facilitate the development of non-invasive therapies for SLE.