Regulation of inflammatory genes in rheumatoid arthritis

描述(由申请人提供)： 类风湿关节炎(RA)是一种影响大量人群的炎症性自身免疫性疾病。CD4+辅助T(Th)细胞在类风湿关节炎中起主要作用，它通过调节关节组织中自身抗体的产生和炎症反应而发挥作用。在自身免疫反应中，自身反应性Th细胞分化为THL细胞，产生IFNGamma和TNFpha，并调节细胞免疫。然而，缺乏IFNGamma或其受体的动物对CIA的易感性更高，这表明其他Th1细胞因子在自身免疫功能中可能更重要。TH的激活和功能受共刺激分子的调节。ICOS是一种由活化的T细胞表达的新型共刺激受体。ICOS配体B7H在B细胞上结构性表达，并在非淋巴组织和细胞中作为炎症反应的结果被诱导。虽然ICOS被我们和其他人证明对Th2的分化很重要，但我们最近发现DBA/1背景的ICOS-/-小鼠对CIA完全抵抗。这种耐药性与IL-17的选择性缺陷有关，IL-17是一种广泛与RA有关的细胞因子。我们进一步发现，IL-17在体外分化的THL细胞中以ICOS依赖的方式选择性表达。然而，IL-17调节Th分化的分子机制以及它在RA中如何发挥作用的分子机制还不清楚。因此，我们建议利用基因表达谱工具来研究这些机制。首先，我们将研究IL-17+小鼠THL细胞中的基因表达。我们将评估IL-17是否由启动关节炎的Thl细胞的一个不同亚群表达。其次，我们将比较ICOS+/+和ICOS-/-Thl细胞的基因表达谱，以确定调控IL-17表达的因素。第三，我们将研究IL-17在关节组织炎症反应中的作用。我们将在体外和体内检测IL-17暴露后滑膜成纤维细胞和巨噬细胞基因表达的变化。此外，我们将把我们在动物研究中产生的结果扩展到人类患者样本。这项研究将极大地促进我们对IL-17在RA中的具体调控和功能的认识，并可能为该疾病创造新的诊断标志物和治疗靶点。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that affects a large human population. CD4+ helper T (Th) cells play a major role in RA, by mediating autoantibody production and inflammatory reactions in the joint tissue. In the autoimmune reaction, auto-reactive Th cells differentiate into Thl cells that make IFNgamma and TNFalpha and regulate cellular immunity. However, animals deficient in IFNgamma or its receptors exhibited greater susceptibility to CIA, suggesting that other Thl cytokine may be more important in autoimmune function. Th activation and function are regulated by co-stimulatory molecules. ICOS is a novel co-stimulatory receptor expressed by activated T cells. ICOS ligand, B7H is constitutively expressed on B-cells and induced in non-lymphoid tissues and cells as a result of inflammatory reactions. Although ICOS has been shown by us and others to be important for Th2 differentiation, we recently found ICOS-/- mice onDBA/1 background to be completely resistant to CIA. This resistance is associated with a selective deficiency of IL-17, a cytokine widely implicated in RA. We further found IL-17 is selectively expressed by Thl cells differentiated in vitro in an ICOS-dependent manner. However, the molecular mechanisms by which IL-17 is regulated in Th differentiation and how it exerts its function in RA have been poorly defined. Therefore, we propose to utilize the gene-expression profiling tools to study these mechanisms. First, we will characterize the gene expression in IL-17+ mouse Thl cells. We will assess if IL-17 is expressed by a distinct subset of Thl cells that initiate the arthritis. Secondly, we will compare gene expression profiles of ICOS+/+ and ICOS-/- Thl cells to identify factors regulating IL-17 expression. Thirdly, we will examine the role of IL-17 on inflammatory responses of the joint tissue. We will examine gene expression changes in the synovial fibroblasts and macrophages after exposure to IL-17 in vitro and in vivo. Furthermore, we will extend the results we yield in our animal studies to the human patient samples. This study will greatly advance our knowledge on the specific regulation and function of IL-17 in RA, and will likely generate novel diagnostic markers and therapeutic targets for this disease.