IEL and NKG2 Receptors in Celiac Disease

IEL 和 NKG2 受体在乳糜泻中的作用

• 批准号: 7120637
• 负责人: BANA JABRI
• 金额: $ 30.51万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-09 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120637
• 关键词: T cell receptor; biological signal transduction; biopsy; celiac disease; cell transformation; clinical research; cytolysis; flow cytometry; gastrointestinal epithelium; human subject; immunocytochemistry; lymphocyte; natural killer cells; organ culture; patient oriented research; plant proteins; receptor expression

DESCRIPTION (provided by applicant): Celiac disease is a common inflammatory intestinal disease induced by dietary gluten in genetically predisposed individuals. While the presence of HLA-DQ2 or DQ8-restricted gliadin-specific CD4 T cells is an essential component of the disease in the gut lamina propria, convergent observations indicate that stress of the epithelium lining the gut leads to the induction of MHC class-1 like ligands which in turn expand and activate intraepithelial lymphocytes (IEL) with cytolytic activity. Activated lELs not only contribute to the destruction of the epithelium, but they undergo transformation into lymphomas whh increased frequency. This proposal will explore at the cellular and molecular level the interactions between the diseased celiac epithelium and lELs. Specifically, studies will focus on the epithelial induction of HLA-E and MIC and their interaction with their cognate NKG2 receptors expressed by lELs. Specific aim 1 will use spectratyping and sequencing to perform high resolution analysis of the clonal composition of the IEL T cell receptor repertoire at different stages of the disease and in normal controls. Specific aim 2 will determine the regulation of expression and function of the NKG2 receptors that recognize HLA-E and MIC on celiac lELs. Specific aim 3 will further dissect the molecular and biochemical basis of NKG2 receptor signaling in celiac lELs. Specific aim 4 will study the expression of HLA-E and MIC by celiac intestinal epithelial cells and their induction by gliadin and stress in vivo and in organ culture. Collectively, these studies will dissect the fine regulation of human effector CTLs in a diseased intestinal epithelium by a novel ligand/receptor system linking innate and adaptive immunity.

描述（由申请人提供）：乳糜泻是一种常见的炎症性肠道疾病，由遗传易感个体中的膳食麸质诱发。虽然 HLA-DQ2 或 DQ8 限制性麦醇溶蛋白特异性 CD4 T 细胞的存在是肠道固有层疾病的重要组成部分，但综合观察结果表明，肠道内壁上皮的压力会导致 MHC 1 类的诱导类似配体，反过来又扩增并激活具有溶细胞活性的上皮内淋巴细胞（IEL）。激活的 lEL 不仅会破坏上皮细胞，而且会以增加的频率转化为淋巴瘤。该提案将在细胞和分子水平上探讨患病乳糜泻上皮和 lEL 之间的相互作用。具体来说，研究将集中于 HLA-E 和 MIC 的上皮诱导以及它们与 lEL 表达的同源 NKG2 受体的相互作用。具体目标 1 将使用谱型分析和测序对疾病不同阶段和正常对照中 IEL T 细胞受体库的克隆组成进行高分辨率分析。具体目标 2 将确定识别 HLA-E 和 MIC 对乳糜泻 IEL 的 NKG2 受体的表达和功能的调节。具体目标 3 将进一步剖析乳糜泻 IEL 中 NKG2 受体信号传导的分子和生化基础。具体目标 4 将研究腹腔肠上皮细胞的 HLA-E 和 MIC 表达以及体内和器官培养中麦醇溶蛋白和应激对它们的诱导。 总的来说，这些研究将通过连接先天免疫和适应性免疫的新型配体/受体系统来剖析患病肠上皮细胞中人类效应 CTL 的精细调节。