General Description
The high affinity Immunoglobulin E receptor (FcεRI) is a tetrameric membrane protein complex (Fig. 1) expressed on mast cells and basophils (1), which belongs to the family of immunoreceptors involved in antigen recognition (2). It is composed of one α subunit containing one transmembrane domain, one β subunit spanning the membrane four times and two disulfide-linked (Cys5) γ subunits containing one transmembrane domain, respectively. The α subunit contains in its extra-cytoplasmic part two Ig-like domains (D1 and D2). D2 contains two sites binding one of the two IgE heavy chains (3). The β and γ subunits are involved in signal transduction. They contain within their intracytoplasmic domains a signaling motif known as ITAM (Immunoreceptor tyrosine based activation motif).
The three subunits were initially cloned from the rat RBL-2H3 mast cell line (4-6). The presence of all three subunit αβγ2 was found to be required for cell surface expression and IgE binding in rodent receptors (6). Human receptors can be expressed in the absence of the β chain and exists as a trimeric αγ2 and as a tetrameric αβγ2 complex (7). This may involve a retention signal within the extracellular domain as rodent alpha extracellular domains are retained in the ER in contrast to human soluble α chains (8). As a consequence, the human receptor is expressed, besides in mast cells/basophils, in monocytes/macrophages, eosinophils, dendritic cells and platelets as a trimeric receptor (9). Recent data show that under certain conditions (viral, plasmodium infection) rodent receptors can also be expressed in other cells (Dendritic cells, neutrophils) in the absence of β (10, 11).
IgE binding
The IgE monomer binds the FcεRI α chain in a 1:1 stoichiometry with high affinity (Fig.2). The forward reaction has a single-valued rate constant (k) of about 105 M-1s-1. The dissociation rate is slow (k-1<10-5 s-1) accounting for the high affinity for the interaction. As a consequence the ligand cannot easily be displaced. The receptor binds only the epsilon isotype, but the species specificity is not perfect. Rodent IgE (rat, mouse) can bind both rodent and human receptors, while human IgE does not bind to rodent receptors (7). Monomeric IgE binding also strongly enhances the expression of FcεRI, by a mechanism which involves stabilization of receptors at the cell surface by preventing receptor degradation during recycling, by recruiting of a preformed pool of receptors and by stimulating continued basal level of protein synthesis (13).
Transmembrane signaling
Antigen-specific IgE molecules bound to FcεRI induces transmembrane signaling when aggregated of receptor-bound IgE with a specific antigen. Initial experiments showed that dimeric aggregation is sufficient to induce a signal. However, the signal is much stronger upon aggregation by multivalent antigens. Signaling can be interrupted with small haptens, which disengage clustered receptors and immediately halt an ongoing FcεRI signaling process (1). The receptor itself has no known enzymatic activity. Receptor aggregation induces phosphorylation of ITAM tyrosine residues by non receptor tyrosine kinases thereby allowing coupling to downstream non receptor tyrosine kinases such as the src family kinases lyn, fyn and p72Syk for signal amplification (14). Although it was thought for long that cell activation occurs only after receptor aggregation it was found that certain (but not all) monomeric IgEs at high concentrations were also capable of inducing certain types of responses such as survival and mast cell differentiation (15, 16), which may involve an aggregation mechanism that takes place in the absence of antigen (17).
Physiology and Pathophysiology
FcεRI enables mast cells and basophils to participate in adaptive immune function by relaying the antigen binding specificity of the IgE ligand to cell signaling. Predominant effector functions include 1) release of inflammatory mediators (histamine, tryptase, chymase, carboxypeptidase A, proteoglycans etc) prestored in cytoplasmic granules by degranulation 2) the release of newly syntesized arachidonoic acid metabolites (prostaglandins, leukotrienes) and 3) the secretion of numerous cytokines and chemokines (1, 18). FcεRI expressed in humans on antigen presenting cells has also been reported to mediate the presentation of antigen (19). In physiology, FcεRI-induced effector functions are thought to majorly involve host defense mechanisms against parasites such as for example during helminth infections, where IgE antibodies are particularly elevated, or in responses against ticks (20). It is without doubt that the major pathologic role of FcεRI is to mediate type I allergic reactions causing the symptoms of anaphylaxis, hay fever, asthma, urticaria etc (21). Interestingly, the latter has been shown to involve at least in part autoantibodies directed to FcεRI (22). IgE autoantibodies have been shown to activate basophils, which contributes to the establishment of an amplification loop promoting the development severe autoimmune systemic lupus erythematosus (23).
Pharmacology
Although many small molecular weight inhibitors can inhibit FcεRI-activated responses, at present no small pharmacologic compound exists that specifically block the activation of this receptor. So far, only the biotherapeutic approach has been crowned with success. A joint development program by Tanox, Novartis and Genentech has yielded a humanized monoclonal antibody Omalizumab (Xolair) that binds IgE at a site that overlaps with receptor binding and specifically blocks the interaction with the FcεRI. Omalizumab does not recognize receptor-bound IgE. Consequently it does not aggregate receptors and initiate the release of inflammatory mediators. This antibody, besides blocking IgE-binding, also downregulates FcεRI expression, in agreement with the described function of IgE to enhance receptor expression. Omalizumab is used majorly used for the treatment of severe asthma with a proven implication of IgE Omalizumab is generally well tolerated, although in some patients anaphylactic reactions have occurred, requiring administration by a doctor.
Structure Box
| Symbola | FCER1A |
| Symbol | MS4A2 |
| Symbol | FCER1G |
| PDB | www.rcsb.org/pdb/home/home.do 1F6A |
| Uniprod | www.uniprot.org P12319 (hu FCER1A) |
| Uniprod | www.uniprot.org Q01362 (hu MS4A2) |
| Uniprod | www.uniprot.org P30273 (hu FCER1G) |
| Pfam | pfam.sanger.ac.uk/family/PF02189 ITAM |
| Genecards | www.genecards.org FCERIA |
| Genecards | www.genecards.org MS4A2 |
| Genecards | www.genecards.org FCERIG |
| OMIM | www.nslij-genetics.org FCER1 |
| a: www.genenames.org |
Animal Models
| 1. | Kinet, J. P. 1999. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol 17:931-972. |
| 2. | Keegan, A. D., and W. E. Paul. 1992. Multichain immune recognition receptors: similarities in structure and signaling pathways. Immunol Today 13:63-68. |
| 3. | Garman, S. C., B. A. Wurzburg, S. S. Tarchevskaya, J. P. Kinet, and T. S. Jardetzky. 2000. Structure of the Fc fragment of human IgE bound to its high-affinity receptor Fc epsilonRI alpha. Nature 406:259-266. |
| 4. | Kinet, J. P., H. Metzger, J. Hakimi, and J. Kochan. 1987. A cDNA presumptively coding for the alpha subunit of the receptor with high affinity for immunoglobulin E [published erratum appears in Biochemistry 1988 Nov 15;27(23):8694]. Biochemistry 26:4605-4610. |
| 5. | Kinet, J. P., U. Blank, C. Ra, K. White, H. Metzger, and J. Kochan. 1988. Isolation and characterization of cDNAs coding for the beta subunit of the high-affinity receptor for immunoglobulin E. Proc Natl Acad Sci U S A 85:6483-6487. |
| 6. | Blank, U., C. Ra, L. Miller, K. White, H. Metzger, and J. P. Kinet. 1989. Complete structure and expression in transfected cells of high affinity IgE receptor. Nature 337:187-189. |
| 7. | Miller, L., U. Blank, H. Metzger, and J. P. Kinet. 1989. Expression of high-affinity binding of human immunoglobulin E by transfected cells. Science 244:334-337. |
| 8. | Blank, U., C. S. Ra, and J. P. Kinet. 1991. Characterization of truncated alpha chain products from human, rat, and mouse high affinity receptor for immunoglobulin E. J Biol Chem 266:2639-2646. |
| 9. | Wang, B., A. Rieger, O. Kilgus, K. Ochiai, D. Maurer, D. Fodinger, J. P. Kinet, and G. Stingl. 1992. Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med 175:1353-1365. |
| 10. | Porcherie, A., C. Mathieu, R. Peronet, E. Schneider, J. Claver, P. H. Commere, H. Kiefer-Biasizzo, H. Karasuyama, G. Milon, M. Dy, J. P. Kinet, J. Louis, U. Blank, and S. Mecheri. 2011. Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria. J Exp Med 208:2225-2236. |
| 11. | Grayson, M. H., D. Cheung, M. M. Rohlfing, R. Kitchens, D. E. Spiegel, J. Tucker, J. T. Battaile, Y. Alevy, L. Yan, E. Agapov, E. Y. Kim, and M. J. Holtzman. 2007. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med 204:2759-2769. |
| 12. | Kulczycki, A., Jr., and H. Metzger. 1974. The interaction of IgE with rat basophilic leukemia cells. II. Quantitative aspects of the binding reaction. J Exp Med 140:1676-1695. |
| 13. | Borkowski, T. A., M. H. Jouvin, S. Y. Lin, and J. P. Kinet. 2001. Minimal requirements for IgE-mediated regulation of surface Fc epsilon RI. J Immunol 167:1290-1296. |
| 14. | Benhamou, M., J. S. Gutkind, K. C. Robbins, and R. P. Siraganian. 1990. Tyrosine phosphorylation coupled to IgE receptor-mediated signal transduction and histamine release. Proc Natl Acad Sci U S A 87:5327-5330. |
| 15. | Asai, K., J. Kitaura, Y. Kawakami, N. Yamagata, M. Tsai, D. P. Carbone, F. T. Liu, S. J. Galli, and T. Kawakami. 2001. Regulation of mast cell survival by IgE. Immunity 14:791-800. |
| 16. | Kalesnikoff, J., M. Huber, V. Lam, J. E. Damen, J. Zhang, R. P. Siraganian, and G. Krystal. 2001. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14:801-811. |
| 17. | Kitaura, J., J. Song, M. Tsai, K. Asai, M. Maeda-Yamamoto, A. Mocsai, Y. Kawakami, F. T. Liu, C. A. Lowell, B. G. Barisas, S. J. Galli, and T. Kawakami. 2003. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the Fc{varepsilon}RI. Proc Natl Acad Sci U S A. |
| 18. | Blank, U., and J. Rivera. 2004. The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol 25:266-273. |
| 19. | Maurer, D., C. Ebner, B. Reininger, E. Fiebiger, D. Kraft, J. P. Kinet, and G. Stingl. 1995. The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation. J Immunol 154:6285-6290. |
| 20. | Beghdadi, W., L. C. Madjene, M. Benhamou, N. Charles, G. Gautier, P. Launay, and U. Blank. 2011. Mast cells as cellular sensors in inflammation and immunity. Front Immunol 2:37. |
| 21. | Galli, S. J., M. Tsai, and A. M. Piliponsky. 2008. The development of allergic inflammation. Nature 454:445-454. |
| 22. | Fiebiger, E., D. Maurer, H. Holub, B. Reininger, G. Hartmann, M. Woisetschlager, J. P. Kinet, and G. Stingl. 1995. Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? J Clin Invest 96:2606-2612. |
| 23. | Charles, N., D. Hardwick, E. Daugas, G. G. Illei, and J. Rivera. 2010. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat Med 16:701-707. |
| 24. | Winchester, D. E., A. Jacob, and T. Murphy. 2006. Omalizumab for asthma. N Engl J Med 355:1281-1282. |
| 25. | Holgate, S. T., R. Djukanovic, T. Casale, and J. Bousquet. 2005. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy 35:408-416. |
References:
| 1. | Kinet, J. P. 1999. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol 17:931-972. |
| 2. | Keegan, A. D., and W. E. Paul. 1992. Multichain immune recognition receptors: similarities in structure and signaling pathways. Immunol Today 13:63-68. |
| 3. | Garman, S. C., B. A. Wurzburg, S. S. Tarchevskaya, J. P. Kinet, and T. S. Jardetzky. 2000. Structure of the Fc fragment of human IgE bound to its high-affinity receptor Fc epsilonRI alpha. Nature 406:259-266. |
| 4. | Kinet, J. P., H. Metzger, J. Hakimi, and J. Kochan. 1987. A cDNA presumptively coding for the alpha subunit of the receptor with high affinity for immunoglobulin E [published erratum appears in Biochemistry 1988 Nov 15;27(23):8694]. Biochemistry 26:4605-4610. |
| 5. | Kinet, J. P., U. Blank, C. Ra, K. White, H. Metzger, and J. Kochan. 1988. Isolation and characterization of cDNAs coding for the beta subunit of the high-affinity receptor for immunoglobulin E. Proc Natl Acad Sci U S A 85:6483-6487. |
| 6. | Blank, U., C. Ra, L. Miller, K. White, H. Metzger, and J. P. Kinet. 1989. Complete structure and expression in transfected cells of high affinity IgE receptor. Nature 337:187-189. |
| 7. | Miller, L., U. Blank, H. Metzger, and J. P. Kinet. 1989. Expression of high-affinity binding of human immunoglobulin E by transfected cells. Science 244:334-337. |
| 8. | Blank, U., C. S. Ra, and J. P. Kinet. 1991. Characterization of truncated alpha chain products from human, rat, and mouse high affinity receptor for immunoglobulin E. J Biol Chem 266:2639-2646. |
| 9. | Wang, B., A. Rieger, O. Kilgus, K. Ochiai, D. Maurer, D. Fodinger, J. P. Kinet, and G. Stingl. 1992. Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med 175:1353-1365. |
| 10. | Porcherie, A., C. Mathieu, R. Peronet, E. Schneider, J. Claver, P. H. Commere, H. Kiefer-Biasizzo, H. Karasuyama, G. Milon, M. Dy, J. P. Kinet, J. Louis, U. Blank, and S. Mecheri. 2011. Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria. J Exp Med 208:2225-2236. |
| 11. | Grayson, M. H., D. Cheung, M. M. Rohlfing, R. Kitchens, D. E. Spiegel, J. Tucker, J. T. Battaile, Y. Alevy, L. Yan, E. Agapov, E. Y. Kim, and M. J. Holtzman. 2007. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med 204:2759-2769. |
| 12. | Kulczycki, A., Jr., and H. Metzger. 1974. The interaction of IgE with rat basophilic leukemia cells. II. Quantitative aspects of the binding reaction. J Exp Med 140:1676-1695. |
| 13. | Borkowski, T. A., M. H. Jouvin, S. Y. Lin, and J. P. Kinet. 2001. Minimal requirements for IgE-mediated regulation of surface Fc epsilon RI. J Immunol 167:1290-1296. |
| 14. | Benhamou, M., J. S. Gutkind, K. C. Robbins, and R. P. Siraganian. 1990. Tyrosine phosphorylation coupled to IgE receptor-mediated signal transduction and histamine release. Proc Natl Acad Sci U S A 87:5327-5330. |
| 15. | Asai, K., J. Kitaura, Y. Kawakami, N. Yamagata, M. Tsai, D. P. Carbone, F. T. Liu, S. J. Galli, and T. Kawakami. 2001. Regulation of mast cell survival by IgE. Immunity 14:791-800. |
| 16. | Kalesnikoff, J., M. Huber, V. Lam, J. E. Damen, J. Zhang, R. P. Siraganian, and G. Krystal. 2001. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14:801-811. |
| 17. | Kitaura, J., J. Song, M. Tsai, K. Asai, M. Maeda-Yamamoto, A. Mocsai, Y. Kawakami, F. T. Liu, C. A. Lowell, B. G. Barisas, S. J. Galli, and T. Kawakami. 2003. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the Fc{varepsilon}RI. Proc Natl Acad Sci U S A. |
| 18. | Blank, U., and J. Rivera. 2004. The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol 25:266-273. |
| 19. | Maurer, D., C. Ebner, B. Reininger, E. Fiebiger, D. Kraft, J. P. Kinet, and G. Stingl. 1995. The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation. J Immunol 154:6285-6290. |
| 20. | Beghdadi, W., L. C. Madjene, M. Benhamou, N. Charles, G. Gautier, P. Launay, and U. Blank. 2011. Mast cells as cellular sensors in inflammation and immunity. Front Immunol 2:37. |
| 21. | Galli, S. J., M. Tsai, and A. M. Piliponsky. 2008. The development of allergic inflammation. Nature 454:445-454. |
| 22. | Fiebiger, E., D. Maurer, H. Holub, B. Reininger, G. Hartmann, M. Woisetschlager, J. P. Kinet, and G. Stingl. 1995. Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? J Clin Invest 96:2606-2612. |
| 23. | Charles, N., D. Hardwick, E. Daugas, G. G. Illei, and J. Rivera. 2010. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat Med 16:701-707. |
| 24. | Winchester, D. E., A. Jacob, and T. Murphy. 2006. Omalizumab for asthma. N Engl J Med 355:1281-1282. |
| 25. | Holgate, S. T., R. Djukanovic, T. Casale, and J. Bousquet. 2005. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy 35:408-416. |