TYPE I INTERFERONS IN LUPUS

描述(申请人提供)：大量旨在确定狼疮发病机制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)的那些已被证明是关键的致病效应因子。在这项建议中，我们概述了在小鼠狼疮模型中的实验，以进一步剖析I型干扰素(干扰素-α/β)产生不利影响的机制，并设计出抑制其活性的方法。要解决的假设是：a)在具有不同遗传异常和疾病严重程度的自发模型中，IFNAR1缺失减少了狼疮的发生，当在发育后期和临床相关阶段应用该受体的生物阻滞剂时是有效的；b)干扰素-β的产生是干扰素-α介导的效应所必需的，干扰素-α/β和干扰素-γ协同作用导致疾病的全面表达，新发现的高水平的干扰素-lambdas在缺乏干扰素-α/β或干扰素-γ信号的情况下可以促进疾病的发生；C)血浆细胞样树突状细胞(PDCs)的过度激活和产生是疾病发病机制的中心异常。d)在疾病早期，干扰素-α/β的产生和随后的自身免疫反应是由内源性的凋亡物质以TLR非依赖的途径启动的，而在疾病后期，这些物质与自身抗体复合，以TLR依赖的途径增殖和放大干扰素-α/β的产生。这些研究将促进我们对干扰素促进系统自身免疫的机制的了解，并可能有助于狼疮和其他自身免疫性疾病的新疗法的开发。

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.