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New developments in FcεRI regulation, function and inhibition

New developments in FcεRI regulation, function and inhibition FcεRI is a multimeric immune Fc receptor that binds IgE with high affinity. It has a tetrameric structure on the surface of mast cells and basophils, consisting of one IgE-binding α-chain, one β-chain and two γ-chains for signal transduction. Human antigen-presenting cells and eosinophils express trimeric FcεRI, which lacks the β-chain. Cell-surface expression of FcεRI requires co-expression of γ-chains with the α-chain in humans, and both β- and γ-chains with the α-chain in rodents. Cell-surface expression of FcεRI is positively regulated by its ligand IgE. In humans, cell-surface expression is also regulated positively by the full-length β-chain and negatively by an alternatively spliced truncated β-chain variant. FcεRI is a key structure in IgE-mediated acute- and late-phase allergic reactions. Antigen-independent effects of IgE binding to FcεRI are responsible for increased mast-cell survival and might have a role in contact hypersensitivity and colitis. FcεRI on antigen-presenting cells has a role in efficient IgE-mediated antigen presentation, as well as in the release of pro-inflammatory mediators and in T-helper-cell polarization. FcεRI signal transduction leads to mast-cell and basophil effector responses such as degranulation, and lipid-mediator and cytokine synthesis. It is a complex process that can be separated into a primary pathway mediated by the protein tyrosine kinase LYN, the adaptor linker for activation of T cells (LAT) and Ca2+ mobilization, and a complementary pathway mediated by the protein tyrosine kinase FYN, the adaptor growth-factor-receptor-bound protein 2 (GRB2)-associated binding protein 2 (GAB2) and phosphoinositide 3-kinase (PI3K). The FcεRI Ca2+ activation signal is mediated by inositol-1,4,5-trisphosphate (InsP3), which results in the release of Ca2+ from intracellular stores, followed by the activation of store-operated calcium channels leading to extracellular Ca2+ influx. Sphingosine kinase 2 and its product sphingosine 1-phosphate are also involved in the regulation of extracellular Ca2+ influx. FcεRI signalling and effector functions are under the tight control of inhibitory receptors, which are characterized by immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and by other cell-surface structures such as tetraspanins. The inhibitory receptor FcγRIIB, upon allergen-specific IgG binding and co-ligation with FcεRI, mediates a negative-feedback loop that inhibits FcεRI signalling at the level of the PI3K product phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Enhancement of FcγRIIB-mediated inhibition is of considerable interest for the development of novel therapeutic approaches. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Immunology Springer Journals

New developments in FcεRI regulation, function and inhibition

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References (178)

Publisher
Springer Journals
Copyright
Copyright © 2007 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Immunology
ISSN
1474-1733
eISSN
1474-1741
DOI
10.1038/nri2072
Publisher site
See Article on Publisher Site

Abstract

FcεRI is a multimeric immune Fc receptor that binds IgE with high affinity. It has a tetrameric structure on the surface of mast cells and basophils, consisting of one IgE-binding α-chain, one β-chain and two γ-chains for signal transduction. Human antigen-presenting cells and eosinophils express trimeric FcεRI, which lacks the β-chain. Cell-surface expression of FcεRI requires co-expression of γ-chains with the α-chain in humans, and both β- and γ-chains with the α-chain in rodents. Cell-surface expression of FcεRI is positively regulated by its ligand IgE. In humans, cell-surface expression is also regulated positively by the full-length β-chain and negatively by an alternatively spliced truncated β-chain variant. FcεRI is a key structure in IgE-mediated acute- and late-phase allergic reactions. Antigen-independent effects of IgE binding to FcεRI are responsible for increased mast-cell survival and might have a role in contact hypersensitivity and colitis. FcεRI on antigen-presenting cells has a role in efficient IgE-mediated antigen presentation, as well as in the release of pro-inflammatory mediators and in T-helper-cell polarization. FcεRI signal transduction leads to mast-cell and basophil effector responses such as degranulation, and lipid-mediator and cytokine synthesis. It is a complex process that can be separated into a primary pathway mediated by the protein tyrosine kinase LYN, the adaptor linker for activation of T cells (LAT) and Ca2+ mobilization, and a complementary pathway mediated by the protein tyrosine kinase FYN, the adaptor growth-factor-receptor-bound protein 2 (GRB2)-associated binding protein 2 (GAB2) and phosphoinositide 3-kinase (PI3K). The FcεRI Ca2+ activation signal is mediated by inositol-1,4,5-trisphosphate (InsP3), which results in the release of Ca2+ from intracellular stores, followed by the activation of store-operated calcium channels leading to extracellular Ca2+ influx. Sphingosine kinase 2 and its product sphingosine 1-phosphate are also involved in the regulation of extracellular Ca2+ influx. FcεRI signalling and effector functions are under the tight control of inhibitory receptors, which are characterized by immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and by other cell-surface structures such as tetraspanins. The inhibitory receptor FcγRIIB, upon allergen-specific IgG binding and co-ligation with FcεRI, mediates a negative-feedback loop that inhibits FcεRI signalling at the level of the PI3K product phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Enhancement of FcγRIIB-mediated inhibition is of considerable interest for the development of novel therapeutic approaches.

Journal

Nature Reviews Immunology – Springer Journals

Published: May 1, 2007

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