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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075037-04
Application #
8274711
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Wheatley, Lisa M
Project Start
2009-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$426,344
Indirect Cost
$181,319
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Mudde, Anne C A; Lexmond, Willem S; Blumberg, Richard S et al. (2016) Eosinophilic esophagitis: published evidences for disease subtypes, indications for patient subpopulations, and how to translate patient observations to murine experimental models. World Allergy Organ J 9:23
Lexmond, Willem S; Goettel, Jeremy A; Lyons, Jonathan J et al. (2016) FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy. J Clin Invest 126:4030-4044
Goettel, Jeremy A; Biswas, Subhabrata; Lexmond, Willem S et al. (2015) Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood 125:3886-95
Lexmond, W S; Hu, L; Pardo, M et al. (2015) Accuracy of digital mRNA profiling of oesophageal biopsies as a novel diagnostic approach to eosinophilic oesophagitis. Clin Exp Allergy 45:1317-27
Lexmond, Willem S; Rufo, Paul A; Fiebiger, Edda et al. (2015) Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. PLoS Negl Trop Dis 9:e0004098
Shade, Kai-Ting C; Platzer, Barbara; Washburn, Nathaniel et al. (2015) A single glycan on IgE is indispensable for initiation of anaphylaxis. J Exp Med 212:457-67
Platzer, Barbara; Elpek, Kutlu G; Cremasco, Viviana et al. (2015) IgE/FcεRI-Mediated Antigen Cross-Presentation by Dendritic Cells Enhances Anti-Tumor Immune Responses. Cell Rep :
Platzer, B; Baker, K; Vera, M P et al. (2015) Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites. Mucosal Immunol 8:516-32
Platzer, Barbara; Stout, Madeleine; Fiebiger, Edda (2015) Functions of dendritic-cell-bound IgE in allergy. Mol Immunol 68:116-9
Wurbel, Marc-André; Le Bras, Severine; Ibourk, Mouna et al. (2014) CCL25/CCR9 interactions are not essential for colitis development but are required for innate immune cell protection from chronic experimental murine colitis. Inflamm Bowel Dis 20:1165-76

Showing the most recent 10 out of 32 publications