Interferon in Systemic Lupus Erythematosus

系统性红斑狼疮中的干扰素

• 批准号: 7569207
• 负责人: Mary K Crow
• 金额: $ 3.69万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569207
• 关键词: Accounting; Address; Antigen-Antibody Complex; Apoptosis; Autoantibodies; Autoimmune Diseases; Autoimmunity; Cell Line; Cells; Chloroquine; Clinical; Crows; DNA; Data; Disease; Double-Stranded RNA; Epithelial Cells; Event; Family; Gene Activation; Gene Expression; Gene Targeting; Generations; Genes; Genetic Polymorphism; Human; Immune; Immune system; Infection; Inflammation; Inflammatory; Interferon Activation; Interferon Type I; Interferon Type II; Interferons; Laboratories; Lead; Ligation; Lupus; Lupus Erythematosus; Lymphocyte; Lymphocyte Function; Lymphopenia; Measures; Mediating; Mediator of activation protein; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Nucleic Acids; Organ; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Polymerase Chain Reaction; Population; Predisposition; Production; Protein Isoforms; Protein Overexpression; RNA; RNA Processing; RNA-Binding Proteins; Reaction; Regulation; Relative (related person); Research; Research Personnel; Role; Serological; Serum; Signal Pathway; Signal Transduction; Site; Staging; Stimulus; Study Subject; Support System; Systemic Lupus Erythematosus; T-Lymphocyte; TLR3 gene; TLR7 gene; Therapeutic; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Variant; Virus Diseases; cytokine; directed attention; immune function; insight; interest; member; neutralizing antibody; novel therapeutics; programs; receptor; response; transcription factor

PROVIDED. 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.

提供了 系统性红斑狼疮（SLE）是一种自身免疫性疾病， 由靶向含核酸免疫复合物的自身抗体介导的损伤，沿着 炎症细胞及其产物。虽然重要的观察结果涉及免疫调节和 SLE的效应机制提示了一些抑制自身抗体的治疗方法 产生和消除组织损伤，这将是非常可取的干预传入阶段的 SLE，当自身免疫发生时。不幸的是，关于这些早期的信息较少。 事件最近的数据已经证明了显著的过表达的mRNA编码的基因调控， 干扰素（IFN）的外周血单个核细胞从狼疮患者。鉴于多效性效应 IFN对免疫功能的各个方面的影响，其中许多可能有助于产生 自身免疫和炎症，这将是非常重要的，以确定上游触发， 说明SLE中I型IFN（IFN-a）靶基因活化的细胞内途径。在这方面， 我们的数据表明RNA在SLE患者IFN途径的激活中具有潜在的作用。拟议 研究将侧重于分析导致基因表达增加的触发因素和途径， IFN-α及其下游靶基因。这项研究将解决基因激活的假设， 通过RNA依赖性Toll样受体（TLR）途径表达是IFN-γ的重要机制。 通路激活和改变的免疫系统激活。具体目标是：1）识别 TLR通路介导SLE IFN的表达; 2）研究SLE中TLR通路激活的刺激因素， SLE; 3）表征SLE中TLR通路激活的下游靶点;和4）研究TLR通路激活的下游靶点。 SLE淋巴细胞对IFN的应答。阐明这一重要途径将导致更有针对性的 系统性自身免疫疾病中疾病介质的调节。