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Studies on Fc-epsilon-RI as an antigen presentation structure at mucosal surfaces

Fc-ε-RI 作为粘膜表面抗原呈递结构的研究

基本信息

批准号：
7691540
负责人：
Elisabeth Edda Fiebiger
金额：
$ 42.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2009-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7691540
关键词：
Address Affect Affinity Allergic Animals Antigen Presentation Antigen-Presenting Cells Antigens Basophils Binding Biology Cell Line Cell membrane Cell model Cell surface Cells Charge Complex Core Protein Cross Presentation Dendritic Cells Disease Effector Cell Endoplasmic Reticulum Environment Epitopes Event Fc Receptor Fc epsilon RI Gastrointestinal tract structure Genetic Polymorphism Goals Human Hypersensitivity ITGAX gene IgE IgE Receptors Immediate hypersensitivity Immune Immune response Individual Inflammatory Response Interleukin 2 Receptor Gamma Intestinal Mucosa Intestines Knock-in Mouse MHC Class I Genes MHC Class II Genes Mediating Monitor Mucosal Immune Responses Mus Mutation Pathway interactions Patients Pattern Process Protein Isoforms Regulation Research Role Signal Transduction Structure Surface T-Cell Activation Tail Testing Tissues Transgenic Animals Transmembrane Domain Transport Process abstracting cell type clinically relevant crosslink density dimer disorder control eosinophil in vivo in vivo Model macrophage mast cell neutrophil programs promoter receptor receptor binding receptor expression research study response trafficking uptake

项目摘要

Abstract The goal of this research program is to test the hypothesis that dendritic cells (DCs) of the gastro intestinal tract process lumenal antigens by Fc-epsilon-RI-IgE mediated uptake, thereby affecting the intestinal inflammatory response and type I hypersensitivity. Fc-epsilon-RI, the high affinity IgE Fc-receptor, is a multimeric immune recognition receptor that binds IgE through a monovalent epitope in its alpha chain. Antigen-induced crosslinking of the IgE-Fc-epsilon-RI complex causes cell activation via the signaling subunits of the receptor (Fc-epsilon-RI-beta and a dimer of the common gamma chain). A unique feature of Fc-epsilon- RI is its cell type- and species-specific expression pattern. In mice, the receptor is expressed only as a heterotetramer (alpha, beta, and two gamma chains) on mast cells and basophils. In humans, Fc-epsilon-RI assembles as a heterotetramer on mast cells and basophils, but additionally also as a heterotrimer lacking the beta subunit. Uniquely, the human heterotrimeric form of Fc-epsilon-RI is expressed on antigen presenting cells, including DCs in the intestine. Surface expression of the receptor correlates with allergic diseases, and controls IgE-mediated cell activation during the allergic response. Unlike other multimeric immune recognition receptors, surface expression is regulated at the level of co-translational assembly of subunits in the endoplasmic reticulum; but the mechanism of regulation remains unknown. Aim 1 will elucidate structural features of individual Fc-epsilon-RI subunits that dictate receptor assembly and thus surface expression of Fcepsilon- RI complexes. Aim 2 will determine if the human trimeric Fc-epsilon-RI functions on DCs or macrophages to present antigen via IgE-mediated uptake pathways. This set of experiments will use Fcepsilon- RI-expressing murine cells that allow us to study functional consequences of receptor-mediated antigen presentation for T cell activation in the MHC class II and the MHC class I pathways. Aim 3 will investigate IgE-mediated intestinal immune responses in vivo using a transgenic animal conditionally expressing the human alpha-chain of Fc-epsilon-RI on DCs.

抽象的该研究计划的目标是检验胃肠道树突状细胞 (DC) 的假设肠道过程中腔内抗原通过Fc-epsilon-RI-IgE介导的摄取，从而影响肠道炎症反应和 I 型超敏反应。 Fc-epsilon-RI，高亲和力 IgE Fc 受体，是一种多聚体免疫识别受体，通过其 α 链中的单价表位结合 IgE。抗原诱导的 IgE-Fc-ε-RI 复合物交联通过信号亚基引起细胞激活受体（Fc-ε-RI-β 和共同伽玛链的二聚体）。 Fc-epsilon 的独特功能- RI 是其细胞类型和物种特异性的表达模式。在小鼠中，该受体仅表达为肥大细胞和嗜碱性粒细胞上的异四聚体（α、β 和两条 γ 链）。在人类中，Fc-ε-RI 作为异四聚体在肥大细胞和嗜碱性粒细胞上组装，但也作为缺乏 β亚基。独特的是，Fc-ε-RI 的人异源三聚体形式在抗原呈递上表达细胞，包括肠道中的 DC。受体的表面表达与过敏性疾病相关，并且控制过敏反应期间 IgE 介导的细胞激活。与其他多聚体免疫识别不同受体，表面表达在亚基的共翻译组装水平上受到调节内质网；但调节机制仍不清楚。目标 1 将阐明结构单个 Fc-ε-RI 亚基的特征决定受体组装，从而决定 Fc-ε-RI 的表面表达 RI 复合物。目标 2 将确定人三聚体 Fc-epsilon-RI 是否在 DC 或巨噬细胞通过 IgE 介导的摄取途径呈递抗原。这组实验将使用Fcepsilon- 表达 RI 的小鼠细胞使我们能够研究受体介导的功能后果 MHC II 类和 MHC I 类途径中 T 细胞激活的抗原呈递。目标3将有条件地使用转基因动物研究 IgE 介导的肠道免疫反应在 DC 上表达 Fc-ε-RI 的人类 α 链。