IEL and NKG2 Receptors in Celiac Disease

IEL 和 NKG2 受体在乳糜泻中的作用

• 批准号: 7485761
• 负责人: BANA JABRI
• 金额: $ 29.34万
• 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/7485761
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affinity; Antigens; Binding; Biochemical; Biological Assay; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Celiac Disease; Cells; Chronic; Class; Cytolysis; Data; Databases; Diet; Disease; Epithelial; Epithelial Cells; Epithelium; Family; Flow Cytometry; Frequencies; Genetic; Gliadin; Gluten; HLA G antigen; Heat shock proteins; Histocompatibility Antigens Class I; Human; Immunity; Immunohistochemistry; Incidence; Individual; Inflammation; Inflammatory Bowel Diseases; Intestines; Lamina Propria; Lead; Ligands; Link; Lymphocyte; Lymphocyte Activation; Lymphocyte Subset; Lymphoma; Mediating; Modeling; Molecular; Nature; Organ Culture Techniques; Patients; Pattern; Peptide Leader Sequences; Peptides; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphorylation; Population; Principal Investigator; Production; Property; Protein Isoforms; Proteins; Receptor Activation; Receptor Signaling; Regulation; Resolution; Scanning; Series; Signal Pathway; Signal Transduction; Specificity; Staging; Stress; Surface; System; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Ursidae Family; Wheat; alpha-beta T-Cell Receptor; base; cell transformation; cytokine; in vivo; intestinal epithelium; intraepithelial; novel; novel therapeutics; programs; receptor; 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，由饮食麸质引起的遗传易感性个体。虽然HLA-DQ2或DQ8限制的麦醇溶蛋白特异性CD4 T细胞是肠道层次的疾病的重要组成部分，但收敛观察表明，肠道内衬的上皮的压力会导致MHC类1的诱导MHC类（如内部和激活的）Inspithelial lymphiptiles lymphictel lymphiptiles（Intriptial cylytip cy）。活化的LEL不仅有助于上皮的破坏，而且会转化为淋巴瘤WHH的频率增加。该建议将在细胞和分子水平探索患病的腹腔上皮和叶子之间的相互作用。具体而言，研究将集中于HLA-E和MIC的上皮诱导以及它们与LELS表达的同源NKG2受体的相互作用。具体目标1将使用频谱分型和测序对IEL T细胞受体库的克隆组成进行高分辨率分析，并在疾病的不同阶段和正常对照阶段进行。具体目标2将确定识别HLA-E和MIC在乳糜泻上的NKG2受体的表达和功能的调节。具体的目标3将进一步剖析腹腔LELS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的表达，以及它们在体内和器官培养中的麦醇溶蛋白和应激的诱导。 总的来说，这些研究将通过与先天性和适应性免疫联系的新型配体/受体系统中的患病肠上皮中的人类效应CTL进行细致调节。