Interferon in Systemic Lupus Erythematosus

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，发病率很高，原因是针对含有核酸的免疫复合体以及炎症细胞及其产物的自身抗体介导的终末器官损害。虽然与SLE免疫调节和效应机制相关的重要观察已经提出了一些治疗方法来抑制自身抗体的产生和消除组织损伤，但在SLE的传入阶段进行干预是非常可取的，因为此时自身免疫正在发展。不幸的是，关于这些早期事件的信息较少。最近的数据记录了狼疮患者外周血单个核细胞中由干扰素(IFN)调控的基因编码的mRNAs的显著过度表达。鉴于IFN对免疫功能的多方面影响，其中许多可导致自身免疫和炎症的产生，因此确定在SLE中导致I型干扰素(IFN-a)靶基因激活的上游触发因素和细胞内途径将是非常重要的。在这方面，我们的数据表明，在SLE患者中，RNA在激活干扰素途径中具有潜在的作用。这项拟议的研究将集中于分析导致干扰素-a及其下游靶基因表达增加的触发因素和途径。这项研究将解决这一假说，即通过RNA依赖的Toll样受体(TLR)途径激活基因表达是SLE中干扰素途径激活和免疫系统激活改变的重要机制。这些研究的具体目的是：1)确定在SLE中介导干扰素表达的TLR途径；2)研究SLE中TLR通路激活的刺激因素；3)确定SLE中TLR通路激活的下游靶点；4)研究SLE淋巴细胞对干扰素的反应。对这一重要途径的阐明将导致对系统性自身免疫性疾病中疾病介质的更有针对性的调节。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity due to end organ damage mediated by autoantibodies that target nucleic acid-containing immune complexes, along with inflammatory cells and their products. While important observations related to immune regulation and effector mechanisms in SLE have suggested some therapeutic approaches to inhibit autoantibody production and abrogate tissue damage, it would be highly desirable to intervene at the afferent stage of SLE, when autoimmunity is developing. Unfortunately, less information is available regarding these early events. Recent data have documented prominent overexpression of mRNAs encoded by genes regulated by interferons (IFNs) in peripheral blood mononuclear cells from lupus patients. In view of the pleiotropic effects of IFNs on diverse aspects of immune function, many of which could contribute to generation of autoimmunity and inflammation, it would be of high importance to determine the upstream triggers and intracellular pathways that account for activation of the type I IFN (IFN-a) target genes in SLE. In that regard, our data indicate a potential role for RNA in the activation of the IFN pathway in SLE patients. The proposed research will focus on an analysis of the triggers and pathways that account for the increased expression of IFN-a and its downstream target genes. The research will address the hypothesis that activation of gene expression through an RNA-dependent Toll-like receptor (TLR) pathway is an important mechanism of IFN pathway activation, and altered immune system activation, in SLE. The specific aims are: 1) To identify the TLR pathways that mediate IFN expression in SLE; 2) To study the stimuli for TLR pathway activation in SLE; 3) To characterize the downstream targets of TLR pathway activation in SLE; and 4) To study the response of SLE lymphocytes to IFN. Elucidation of this important pathway should lead to more targeted modulation of disease mediators in systemic autoimmune diseases.