Studies of 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：
7867985
负责人：
Elisabeth Edda Fiebiger
金额：
$ 42.49万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7867985
关键词：
Address Affect Affinity Allergens Allergic Allergic Disease Allergic Reaction Animal Model Animals Antigen Presentation Antigen-Presenting Cells Antigens Basophils Binding Binding Sites Biology Cell Line Cell membrane Cell model Cell surface Cells Charge Chronic Complex Core Protein Cross Presentation Dendritic Cells Dendritic cell activation Development Disease Effector Cell Endoplasmic Reticulum Epitopes Equilibrium Event Fc Receptor Fc epsilon RI Food Food Hypersensitivity Gastrointestinal tract structure Genetic Polymorphism Goals Human Hypersensitivity ITGAX gene IgE Immediate hypersensitivity Immune Immune response Immune system Immunologics Individual Inflammatory Response Inflammatory disease of the intestine Interleukin 2 Receptor Gamma Intestines MHC Class I Genes MHC Class II Genes Mediating Modeling Mucosal Immune Responses Mucositis Mucous Membrane Mus Nature Pathology Pathway interactions Patients Pattern Play Process Protein Isoforms Receptor Activation Regulation Research Role Sampling Signal Transduction Structure Surface Surface Antigens System T-Cell Activation Tail Testing Tissues Transgenic Animals Transgenic Mice Transmembrane Domain allergic response base cell type clinically relevant crosslink density dimer disorder control eosinophil gastrointestinal immune activation in vivo in vivo Model macrophage mast cell neutrophil oral tolerance pathogen programs promoter public health relevance receptor receptor binding receptor expression research study stability testing trafficking treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): 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 Fc- epsilon-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 Fc- epsilon-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. PUBLIC HEALTH RELEVANCE: The GI mucosa must balance the ability to respond to pathogens while remaining unresponsive to food and environmental antigens and the commensal microflora. Rising numbers of individuals suffer from food allergies and chronic intestinal inflammation. How IgE and Fc-epsilon-RI-IgE affect these diseases is unknown. A better understanding of the mechanisms that control Fc-epsilon-RI-IgE-mediated activation of the immune system will point towards new treatment strategies for allergy and antigen-induced mucosal inflammation in the GI tract.

描述（由申请人提供）：该研究计划的目的是检验以下假设，即FC-EPSILON-RI-IGE介导的摄取剂胃肠道的树突状细胞（DC），从而影响肠道炎症反应和肠道炎症反应和I型超敏反应。 FC-EPSILON-RI是高亲和力IgE FC受体，是一种多聚体免疫识别受体，可通过其α链中的单价表位结合IgE。 IgE-FC-EPSILON-RI复合物的抗原诱导的交联导致细胞通过受体的信号亚基（FC-EPSILON-RI-BETA和公共伽马链的二聚体）激活。 FC-Epsilon-Ri的独特特征是其细胞类型和特定物种的表达模式。在小鼠中，受体仅以肥大细胞和嗜碱性粒细胞上的异驱精（Alpha，beta和两个伽马链）表示。在人类中，FC-EPSILON-RI作为肥大细胞和嗜碱性粒细胞上的异武器组装，但也是缺乏β亚基的异构体。独特的是，Fc- epsilon-Ri的人类异三聚体形式在抗原呈递细胞上表达，包括肠中的DC。受体的表面表达与过敏性疾病相关，并且在过敏反应过程中控制IgE介导的细胞激活。与其他多聚体免疫识别受体不同，表面表达受到内质网中亚基的共译水平的调节。但是调节机制仍然未知。 AIM 1将阐明单个FC-EPSILON-RI亚基的结构特征，该亚基决定受体组装，从而表面表达Fc- Epsilon-Ri复合物。 AIM 2将确定人三聚体FC- EPSILON-RI是否在DC或巨噬细胞上起作用，通过IgE介导的摄取途径呈现抗原。这组实验将使用表达的FC- Epsilon-ri-ri-himine细胞，使我们能够研究受体介导的抗原表现的功能后果，以在MHC II类和MHC I类途径中进行T细胞激活。 AIM 3将使用有条件地表达DC上FC-EPSILON-RI的人α链的转基因动物在体内研究IgE介导的肠道免疫反应。公共卫生相关性：Gi Mucosa必须平衡对病原体反应的能力，同时对食物和环境抗原和共生微生物无反应。数量增加的人患有食物过敏和慢性肠炎。 IgE和FC-Epsilon-Ri-IgE如何影响这些疾病。更好地理解控制FC-EPSILON-RI-IGE介导的免疫系统激活的机制将指向GI区域中对过敏和抗原引起的粘膜炎症的新治疗策略。