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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：
8468097
负责人：
Elisabeth Edda Fiebiger
金额：
$ 40.08万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468097
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 receptor receptor binding receptor expression research study stability testing trafficking treatment strategy uptake

项目摘要

Project Summary 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.

项目总结