TYPE I INTERFERONS IN LUPUS

描述（由申请人提供）：大量旨在确定与狼疮发病有关的基因的研究集中在细胞因子上，其中，编码多效型I型和II型干扰素（ifn）的基因已被证明是关键的致病效应物。在本提案中，我们概述了小鼠狼疮模型的实验，以进一步剖析I型ifn （ifn - α / β）发挥其不利作用的机制，并设计出抑制其活性的方法。需要解决的假设是：a) IFNAR1缺失在具有多种遗传异常和疾病严重程度的自发模型中减少狼疮的发展，并且该受体的生物阻滞剂在发育后和临床相关阶段应用时有效；b) ifn - β的产生是ifn - α介导的作用所必需的，ifn - α / β和ifn - γ协同作用导致疾病的全面表达，在缺乏ifn - α / β或ifn - γ信号传导的情况下，高水平的新发现的ifn -lambda可促进疾病的发生；c)过度激活和产生浆细胞样树突状细胞（pDCs），主要的ifn - α / β的产生，是疾病发病机制的核心异常，d)在疾病早期，ifn - α / β的产生和随后的自身免疫反应是由内源性凋亡物质在tlr不依赖的途径中启动的，而在疾病晚期，这些物质与自身抗体结合，在tlr依赖的途径中繁殖和扩增ifn - α / β的产生。这些研究将促进我们对ifn促进全身自身免疫机制的认识，并可能有助于狼疮和其他自身免疫性疾病的新疗法的发展。

DESCRIPTION (provided by applicant): A large body of research aimed at defining genes contributing to lupus pathogenesis has focused on cytokines and, among them, those encoding the pleiotropic type I and type II interferons (IFNs) have been shown to be key pathogenic effectors. In this proposal, we outline experiments in mouse lupus models to further dissect the mechanisms by which type I IFNs (IFN-alpha/beta) exert their adverse effects, and to devise means to curtail their activity. The hypotheses to be addressed are: a) IFNAR1 deletion reduces lupus development in spontaneous models with diverse genetic abnormalities and disease severity, and a biological blocker of this receptor is effective when applied post-developmentally and at clinically- relevant stages; b) IFN-beta production is required for the IFN-alpha-mediated effects, IFN-alpha/beta and IFN-gamma act coordinately to cause full disease expression, and high levels of the newly identified IFN-lambdas can promote disease in the absence of IFN-alpha/beta or IFN-gamma signaling; c) excessive activation and generation of plasmacytoid dendritic cells (pDCs), the major IFN-alpha/beta producers, are central abnormalities in disease pathogenesis, and d) at the early disease phase, IFN-alpha/beta production and the ensuing autoimmune responses are initiated by endogenous apoptotic materials acting in a TLR-independent pathway, while at the later disease phases, these materials, complexed with autoantibodies, propagate and amplify IFN-alpha/beta production in a TLR-dependent pathway. These studies will advance our knowledge of the mechanisms by which IFNs promote systemic autoimmunity and may contribute to the development of novel therapies for lupus and other autoimmune diseases.