Toll-Like Receptors in Systemic Autoimmune Disease

描述（由申请人提供）：越来越明显的是，先天免疫系统成分检测自身抗原可以促进多种慢性炎症性疾病的发病机制。为例。toll样受体9和7 （TLR9、TLR7）可触发对自身核酸的应答。这一建议是基于最近的研究已经确定TLR9、TLR7和相关的下游转录因子IRF5是系统性红斑狼疮（SLE）发展的关键因素。然而，这些分子在疾病发生和进展中所起的确切作用尚不清楚，TLR9与TLR7相比所引发的独特功能也知之甚少。TLR9和TLR7都有助于自身抗体的产生和树突状细胞的激活，但在自身免疫易感性小鼠中，TLR9缺乏会加重疾病，而TLR7缺乏会减轻疾病。值得注意的是，降低IRF （TLR7和TLR9的下游转录因子）的表达是治疗疾病的最有效手段。当前应用的总体目标是更好地了解表达TLR9和tlr7的细胞类型是如何促进SLE发病的。将解决的具体问题包括：(1)为什么TLR7和TLR9缺乏会在自身免疫性易感小鼠中产生不一致的结果？(2) TLR7和TLR9之间的分子相互作用是否会导致活性衰减？(3) 1型干扰素如何调控tlr诱导的应答？(4)触发TLR7和TLR9的内源性配体是什么？(5) IRF5在何时、何地以及如何触发对SLE疾病发病机制至关重要的生物活性。这些问题可以由具有不同背景和专业知识的项目参与者小组最好地回答-马沙克-罗斯坦（免疫调节和B细胞活化）；Latz （TLR信号的传输和结构/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，以及对自身免疫性疾病动物模型中细胞类型特异性TLR和缺乏或过表达的影响的精确体内分析，应该提供重要的见解，这将促进SLE非侵入性治疗的发展。

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.