Regulation of inflammatory genes in rheumatoid arthritis

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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.