TYPE I INTERFERONS IN LUPUS

狼疮中的 I 型干扰素

• 批准号: 7876912
• 负责人: Argyrios N Theofilopoulos
• 金额: $ 38.53万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876912
• 关键词: Address; Adverse effects; Affect; Apoptotic; Area; Attention; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Biological; Cells; Complementary DNA; Complex; Dendritic Cells; Development; Disease; Exhibits; Family; Gene Deletion; Generations; Genes; Genetic; Human; IFNAR1 gene; Immune response; In Vitro; Inbred NZB Mice; Interferon Type I; Interferon Type II; Interferon-alpha; Interferon-beta; Interferons; Knowledge; Laboratories; Lupus; Mediating; Modeling; Molecular Abnormality; Mus; Pathogenesis; Pathway interactions; Phase; Phenotype; Plasmids; Production; Property; Relative (related person); Research; Role; Severity of illness; Signal Transduction; Staging; Stimulus; clinically relevant; cytokine; in vivo; lupus prone mice; novel; polypeptide; receptor; research study; response; type I interferon receptor; vector

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.

描述（由申请人提供）：旨在确定狼疮发病机制基因的大量研究都集中在细胞因子上，其中编码多效性 I 型和 II 型干扰素 (IFN) 的细胞因子已被证明是关键的致病效应子。在本提案中，我们概述了小鼠狼疮模型中的实验，以进一步剖析 I 型干扰素 (IFN-α/β) 发挥不良作用的机制，并设计出抑制其活性的方法。要解决的假设是： a) IFNAR1 缺失会减少具有多种遗传异常和疾病严重程度的自发模型中的狼疮发育，并且该受体的生物阻断剂在发育后和临床相关阶段应用时是有效的； b) IFN-α 介导的效应需要 IFN-β 的产生，IFN-α/β 和 IFN-γ 协调作用以引起全面的疾病表达，并且高水平的新鉴定的 IFN-lambda 可以在缺乏的情况下促进疾病IFN-α/β或IFN-γ信号传导； c) 浆细胞样树突状细胞 (pDC)（主要 IFN-α/β 产生者）的过度激活和产生是疾病发病机制的核心异常，以及 d) 在疾病早期阶段，IFN-α/β 产生和随后的自身免疫反应由内源性凋亡物质以 TLR 独立途径起作用，而在疾病后期，这些物质与自身抗体复合，传播并放大 IFN-α/β 的产生在 TLR 依赖性途径中。这些研究将增进我们对干扰素促进全身自身免疫机制的了解，并可能有助于开发狼疮和其他自身免疫性疾病的新疗法。