TYPE I INTERFERONS IN LUPUS

描述（由申请人提供）：大量旨在确定有助于狼疮发病机制的基因的研究集中在细胞因子上，其中，编码多效性I型和II型干扰素（IFN）的细胞因子已被证明是关键的致病效应物。在这个提议中，我们概述了在小鼠狼疮模型中的实验，以进一步剖析I型IFN（IFN-α/β）发挥其不利影响的机制，并设计出减少其活性的方法。a）IFNAR 1缺失减少了具有不同遗传异常和疾病严重程度的自发模型中的狼疮发展，并且当在发育后和临床相关阶段应用时，该受体的生物阻断剂是有效的; B）IFN-β的产生是IFN-α介导的作用所必需的，IFN-α/β和IFN-γ协同作用以引起完全的疾病表达，并且高水平的新鉴定的IFN-γ可以在缺乏IFN-α/β或IFN-γ信号传导的情况下促进疾病; c）浆细胞样树突状细胞（pDC）（主要的IFN-α/β产生者）的过度活化和产生是疾病发病机制中的中心异常，和d）在疾病早期，IFN-α/β的产生和随后的自身免疫应答是由内源性凋亡物质在TLR非依赖性途径中起作用而引发的，而在疾病后期，这些物质与自身抗体复合，在TLR依赖性途径中传播和扩增IFN-α/β的产生。这些研究将推进我们对IFN促进系统性自身免疫的机制的认识，并可能有助于开发狼疮和其他自身免疫性疾病的新疗法。

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.