IL-23/Th17 pathways and Inflammatory Bowel Disease

描述（由申请人提供）：IL-23/Th 17通路在介导炎症性肠病（IBD）中观察到的肠道炎症中的关键作用已通过IBD患者、IBD实验小鼠模型的表达研究和遗传关联研究得到证实。已经鉴定了IL 23 R中的许多独立的多态性，以赋予发生溃疡性结肠炎和克罗恩病以及其他炎性疾病如强直性脊柱炎和银屑病的风险和保护。这些遗传关联中最显著的是R381 Q单核苷酸多态性（SNP），其导致近端IL 23 R胞质尾区的氨基酸变化。这种多态性导致发生IBD的风险降低2-3倍，使得它在健康个体中富集。我们实验室的研究已经鉴定了R381 Q IL 23 R SNP在人CD 4+和CD 8 + T细胞中的功能后果; R381 Q IL 23 R个体具有减少的循环IL-17-和IL-22-产生的CD 4+和CD 8 + T细胞离体和减少的STAT 3对IL-23刺激的活化。我们假设这是由于Th 17和Tc 17细胞分化和扩增降低的组合，继发于通过R381 Q IL 23 R的信号传导降低。该提案将利用IL 23 R多态性转染的细胞和来自IL 23 R多态性个体的离体细胞的组合方法来定义T细胞扩增和分化的变化，鉴定改变的T细胞信号传导途径，并确定抗原呈递细胞：T细胞相互作用的复合效应，其最终导致循环Th 17和Tc 17细胞的减少。在原代人类细胞中解决这些应答对于理解IL-23/Th 17途径在人类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.