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.
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.
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