Interferon in Systemic Lupus Erythematosus

系统性红斑狼疮中的干扰素

• 批准号: 7033222
• 负责人: Mary K Crow
• 金额: $ 42.5万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033222
• 关键词: DNA; RNA; autoantibody; autoimmunity; cell line; clinical research; cytokine; family; gene expression; gene targeting; genes; immune complex; immune system; infection; inflammation; interferons; intracellular; lymphocyte; neutralizing antibody; nucleic acids; receptor; role; serum; systemic lupus erythematosus; tissues; toll like receptor

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.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种发病率高的自身免疫性疾病，由靶向含核酸免疫复合物、炎症细胞及其产物的自身抗体介导的终末器官损伤引起。虽然与SLE免疫调节和效应机制相关的重要观察结果表明，一些治疗方法可以抑制自身抗体的产生和消除组织损伤，但在SLE传入期进行干预是非常可取的，因为此时自身免疫正在形成。不幸的是，关于这些早期事件的信息很少。最近的数据表明，在狼疮患者的外周血单核细胞中，干扰素（IFNs）调控基因编码的mrna显著过表达。鉴于IFN对免疫功能各方面的多效性作用，其中许多可能导致自身免疫和炎症的产生，因此确定SLE中I型IFN （IFN-a）靶基因激活的上游触发因素和细胞内通路将具有重要意义。在这方面，我们的数据表明RNA在SLE患者IFN通路激活中的潜在作用。拟议的研究将侧重于分析IFN-a及其下游靶基因表达增加的触发因素和途径。本研究将探讨通过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。具体目的是：1)确定在SLE中介导IFN表达的TLR通路；2)研究SLE TLR通路激活的刺激因素；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。