Interferon in Systemic Lupus Erythematosus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种自身免疫性疾病，由于靶向含核酸免疫复合物、沿着炎性细胞及其产物的自身抗体介导的终末器官损伤，具有显著的发病率。虽然与SLE中的免疫调节和效应器机制相关的重要观察已经提出了一些抑制自身抗体产生和消除组织损伤的治疗方法，但在SLE的传入阶段进行干预是非常可取的，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。最近的数据表明，狼疮患者外周血单个核细胞中干扰素（IFN）调控的基因编码的mRNA显著过表达。鉴于IFN对免疫功能的多方面的多效性作用，其中许多可能有助于自身免疫和炎症的产生，确定导致SLE中I型IFN（IFN-α）靶基因活化的上游触发因子和细胞内途径将是非常重要的。在这方面，我们的数据表明RNA在SLE患者IFN途径的激活中的潜在作用。拟议的研究将侧重于分析导致IFN-a及其下游靶基因表达增加的触发因素和途径。该研究将解决这一假设，即通过RNA依赖性Toll样受体（TLR）途径激活基因表达是SLE中IFN途径激活和免疫系统激活改变的重要机制。具体目标是：1）确定SLE中介导IFN表达的TLR通路; 2）研究SLE中TLR通路激活的刺激物; 3）表征SLE中TLR通路激活的下游靶点; 4）研究SLE淋巴细胞对IFN的反应。阐明这一重要途径将导致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.