IL-23/Th17 pathways and Inflammatory Bowel Disease

描述（由申请人提供）：IL-23/Th17通路在炎症性肠病（IBD）中介导肠道炎症的关键作用已通过IBD患者的表达研究、IBD实验小鼠模型和遗传关联研究得到证实。IL23R的许多独立多态性已被确定，可赋予溃疡性结肠炎和克罗恩病的风险和保护，以及其他炎症性疾病，如强直性脊柱炎和牛皮癣。这些遗传关联中最重要的是R381Q单核苷酸多态性（SNP），它导致IL23R细胞质尾部近端氨基酸发生变化。这种多态性导致患IBD的风险降低2-3倍，因此在健康个体中富集。我们实验室的研究已经确定了R381Q IL23R SNP在人类CD4+和CD8+ T细胞中的功能后果；R381Q IL23R个体在体外减少循环中产生IL-17和IL-22的CD4+和CD8+ T细胞，减少STAT3对IL-23刺激的激活。我们假设这是由于通过R381Q IL23R信号传导减少导致Th17和Tc17细胞分化和扩增的减少。本研究将利用转染了IL23R多态性的细胞和来自具有IL23R多态性个体的离体细胞的联合方法来定义T细胞扩增和分化的变化，鉴定改变的T细胞信号通路，并确定抗原递呈细胞：T细胞相互作用的复合效应，最终导致循环Th17和Tc17细胞的减少。在人原代细胞中研究这些应答对于理解IL-23/Th17通路在人免疫应答中的复杂性至关重要。

DESCRIPTION (provided by applicant): The critical role of the IL-23/Th17 pathway in mediating the intestinal inflammation observed in inflammatory bowel disease (IBD) has been demonstrated through expression studies in patients with IBD, experimental mouse models of IBD and genetic association studies. A number of independent polymorphisms in IL23R have been identified to confer both risk and protection from developing ulcerative colitis and Crohn's disease, as well as other inflammatory disorders such as ankylosing spondylitis and psoriasis. The most significant of these genetic associations is the R381Q single nucleotide polymorphism (SNP) which results in an amino acid change in the proximal IL23R cytoplasmic tail. This polymorphism leads to a 2-3-fold decreased risk of developing IBD, such that it is enriched in healthy individuals. Studies in our laboratory have identified functional consequences of the R381Q IL23R SNP in both human CD4+ and CD8+ T cells; R381Q IL23R individuals have decreased circulating IL-17- and IL-22- producing CD4+ and CD8+ T cells ex vivo and decreased STAT3 activation to IL-23 stimulation. We hypothesize that this is due to a combination of decreased Th17 and Tc17 cell differentiation and expansion secondary to decreased signaling through R381Q IL23R. This proposal will utilize combined approaches with cells transfected with IL23R polymorphisms and ex vivo cells from individuals with IL23R polymorphisms to define changes in T cell expansion and differentiation, identify altered T cell signaling pathways and determine the compound effects of antigen presenting cell:T cell interactions that ultimately contribute to the decrease in circulating Th17 and Tc17 cells. Addressing these responses in primary human cells is critical to understanding the complexity of the IL-23/Th17 pathway in human immune responses.