1 Nature Reviews Immunology 2007 Vol: 7(5):365-378. DOI: 10.1038/nri2072

New developments in FcεRI regulation, function and inhibition

The high-affinity Fc receptor for IgE (FcRI), a multimeric immune receptor, is a crucial structure for IgE-mediated allergic reactions. In recent years, advances have been made in several important areas of the study of FcRI. The first area relates to FcRI-mediated biological responses that are antigen independent. The second area encompasses the biological relevance of the distinct signalling pathways that are activated by FcRI; and the third area relates to the accumulated evidence for the tight control of FcRI signalling through a broad array of inhibitory mechanisms, which are being developed into promising therapeutic approaches.

Mentions
Figures
Figure 1: Composition of the FcRI complex (tetrameric and trimeric structures) and biological functions.a | The tetrameric form of the high-affinity Fc receptor for IgE (FcRI) consists of one IgE-binding -chain with two immunoglobulin-like domains (depicted by the loops in the extracellular part), one -chain and two -chains with intracellular immunoreceptor tyrosine-based activation motifs (ITAMs) for signal transduction. Tetrameric FcRI is expressed by mast cells and basophils. Upon crosslinking of FcRI by IgE and antigen, a signalling cascade leads within minutes to the release of preformed mediators, such as histamine, and lipid-mediator synthesis. These events produce an immediate-type allergic reaction characterized by vasodilation, increased vascular permeability, upregulation of vascular adhesion molecules and bronchoconstriction. Upon prolonged stimulation, a late-phase allergic reaction is induced, which in addition leads to cytokine and chemokine production, inducing the recruitment of inflammatory cells and T-cell activation. With continuous or repetitive stimulation in chronic inflammation, FcRI-bearing mast cells and basophils can contribute to the features of the specific inflammatory response (such as bronchial hyper-reactivity). Antigen-independent effects are mediated by IgE binding to FcRI, and may result in increased survival of the cell. b | Trimeric FcRI lacks the -chain and is expressed by antigen-presenting cells (APCs; and eosinophils). Crosslinking of FcRI by IgE and antigen leads to the endocytosis of FcRI and IgE-bound antigen, followed by their uptake in MHC-class-II-rich compartments, in which antigen processing and loading of antigenic peptides onto MHC class II molecules occurs, and ultimately to the presentation of the antigenic-peptide–MHC-class-II complexes to T cells. This is an efficient process for allergen presentation, although its causal role in atopic diseases remains to be determined. FcRI crosslinking also induces signalling, which leads to the production of pro-inflammatory cytokines and, depending on the APC subtype, the upregulation or downregulation of production of T helper 1 (TH1)-cell-polarizing factors. TCR, T-cell receptor. Figure 2: Regulation of human FcRI cell-surface expression by mast cells and basophils.In humans, interleukin-4 (IL-4) induces the production of immature core-glycosylated -chains of the high-affinity Fc receptor for IgE (FcRI) in the endoplasmic reticulum (ER). In the absence of other FcRI chains, the immature -chain remains in the ER. Unknown signals lead to the co-translational production of -chains and of the classical full-length -chain. The -chains mask an ER retention signal in the -chain, leading to the export of the tetrameric structure (2) or of the trimeric structure of the FcRI (2; not shown) from the ER. This is followed by full maturation of the FceRI by terminal glycosylation in the Golgi compartment, and finally its transport to the cell surface; this process is more efficient for the tetrameric complexes, which are also more stable on the cell surface than those complexes that lack the -chain. The FcRI ligand, IgE, stabilizes FcRI complexes on the cell surface and limits their internalization. In the presence of ongoing FcRI synthesis, this inhibition of FceRI internalization leads to the accumulation of more FcRI complexes on the cell surface. However, if the truncated -chain variant, T, is produced by alternative splicing, this prevents the FcRI complex from reaching the cell surface and leads to proteasomal degradation of immature FcRI complexes. Figure 3: Simplified model of FcRI signalling.a | In the primary pathway, LYN is activated and phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) in the - and -chains of the high-affinity Fc receptor for IgE (FcRI), which leads to SYK association with -chains and subsequent SYK activation. SYK phosphorylates LAT (linker for activation of T cells), which recruits GADS (growth-factor-receptor-bound protein 2 (GRB2)-related adaptor protein), SLP76 (SH2-domain-containing leukocyte protein of 76 kDa), VAV (not shown) and PLC (phospholipase C). PLC activation occurs through this complex and through PI3K (phosphoinositide 3-kinase)-mediated membrane recruitment of BTK (Bruton's tyrosine kinase) and phosphorylation of PLC by BTK. Activated PLC produces DAG (diacylglycerol), which activates classical PKCs (protein kinases C), and InsP3 (inositol-1,4,5-trisphosphate), which induces Ca2+ release from the ER (endoplasmic reticulum) through InsP3 receptors (InsP3Rs). Store depletion then leads to STIM1 (stromal interaction molecule 1)-guided opening of the store-operated channel (SOC), which produces an extracellular Ca2+ influx and ICRAC (calcium-release-activated current). Classical PKC activation and Ca2+ mobilization ultimately lead to degranulation. b | In the complementary pathway, FYN and SYK activation induce a signalling complex with VAV (not shown), GRB2, GAB2 (GRB2-associated binding protein 2) and PI3K, possibly organized by NTAL (non-T-cell activation linker). PI3K activation leads to the membrane recruitment of PDK1 (3-phosphoinositide-dependent protein kinase 1), which then activates PKC, ultimately leading to degranulation. Sphingosine kinases (SPHKs) can be activated by PLD (phospholipase D), LYN or FYN. SPHK activation leads to extracellular Ca2+ influx, probably by relieving the suppressive effect of sphingosine on the ICRAC. c | GRB2 and SOS (son-of-sevenless homologue) are associated with both the primary and complementary pathways and lead to RAS activation, which then leads to the activation of the ERK (extracellular-signal-related kinase) MAPK (mitogen-activated protein kinase) cascade and eicosanoid production via PLA2. d | Cytokine production is regulated by various transcription factors, the activation of which is dependent on Ca2+, PKC and AKT signals (via BCL-10/MALT1?). BCL-10, B-cell lymphoma-10; MALT10, mucosa-associated-lymphoid-tissue lymphoma-translocation protein 1; PtdIns(3,4,5)P3, phosphatidylinositol-3,4,5-trisphosphate; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; RABGEF1, RAB guanine-nucleotide-exchange factor 1; RASGRP1, RAS guanyl-nucleotide-releasing protein 1; S1P, sphingosine 1-phosphate. Figure 4: Principle of antigen-specific FcRI inhibition by a chimeric molecule consisting of an important cat allergen and IgG-Fc.Membrane-bound IgG can form immune complexes with allergens. IgG is tethered to the membrane by binding the low-affinity Fc receptor for IgG (FcRIIB). When an allergen simultaneously binds IgE and IgG, the activating high-affinity Fc receptor for IgE (FcRI) is brought together with the inhibitory FcRIIB, thereby silencing the FcRI-mediated activation pathway through the phosphatase SRC-homology-2-domain-containing inositol-5-phosphatase (SHIP1) and docking protein 1 (DOK1). Zhu and colleagues144 report a strategy that takes advantage of the natural capacity of FcRIIB to inhibit the allergenic activity of FcRI. They designed a chimeric molecule — a fusion of a cat allergen (Fel d1) and the Fc fragment of human IgG (IgG-Fc) — that abolished allergic reactions to Fel d1 in vitro and in a mouse model. Similar fusion molecules could be designed to counter other types of allergy. LYN, FYN and SYK are protein tyrosine kinases. ERK, extracellular-signal-regulated kinase; BTK, Bruton's tyrosine kinase; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; PLC, phospholipase C; RASGAP, RAS GTPase-activating protein. Modified with permission from Ref. 143 © (2005) Massachusetts Medical Society.
Altmetric
References
  1. Kinet, J. P. The high-affinity IgE receptor (FcRI): from physiology to pathology. Annu. Rev. Immunol. 17, 931-972 , (1999) .
    • . . . The -chain belongs to the immunoglobulin superfamily and comprises two extracellular immunoglobulin-related domains that bind a single IgE molecule, a transmembrane domain that contains a conserved aspartic-acid residue and a short cytoplasmic tail1 . . .
    • . . . The intracellular tail of the -chain has no apparent signalling function1. . . .
    • . . . The FcRI - and -chains have no role in ligand binding1 . . .
    • . . . Whereas the human -chain is an amplifier of FcRI signals and cell-surface expression, the -chains are the main and indispensable FcRI signalling units1 . . .
    • . . . For example, the high- and low-affinity Fc receptors for IgG (FcRI and FcRIII, respectively), and the Fc receptor for IgA (FcRI) associate with the -chain depending on the cellular context1. . . .
    • . . . Monocytes, Langerhans cells, eosinophils and dendritic cells (DCs) express trimeric 2 FcRI complexes1 (the differences between human and murine FcRI are summarized in Table 1) . . .
    • . . . Assembly, maturation and transport of the FcRI complex to the cell surface occur as follows1 . . .
    • . . . In humans, both 2 and 2 complexes are present on the cell surface of mast cells and basophils, and 2 complexes are present on APCs and eosinophils1 . . .
    • . . . This topic and the role of FcRI-bearing cells in host defence and asthma have been reviewed extensively elsewhere1, 38, 42 . . .
    • . . . In humans, trimeric FcRI 2 is expressed by professional APCs such as DCs (including epidermal Langerhans cells), monocytes and macrophages (for more detail see Refs 1,52) . . .
    • . . . After antigen crosslinking of FcRI-bound IgE, a complex intracellular signalling cascade is initiated, which ultimately leads to effector functions (see earlier reviews Refs 1,70–72) (Fig. 3) . . .
    • . . . The - and -chains of FcRI contain ITAMs, which after tyrosine phosphorylation bind the SH2 domains of protein tyrosine kinases (PTKs), mainly the SRC family kinases LYN and FYN, as well as SYK1, 70, 73 (Fig. 3) . . .
    • . . . LYN also transphosphorylates ITAMs in neighbouring FcRI receptor complexes1, 70, resulting in signal amplification . . .
  2. Letourneur, O., Sechi, S., Willette-Brown, J., Robertson, M. W. & Kinet, J. P. Glycosylation of human truncated FcRI chain is necessary for efficient folding in the endoplasmic reticulum. J. Biol. Chem. 270, 8249-8256 , (1995) .
    • . . . Glycosylation is required to mediate proper interaction between the -chain and the folding machinery in the endoplasmic reticulum (ER)2 . . .
    • . . . This association supports core glycosylation of FcRI, which is required for proper folding, signal-peptide cleavage, export from the ER12 and subsequent cell-surface expression2 . . .
  3. Wurzburg, B. A., Garman, S. C. & Jardetzky, T. S. Structure of the human IgE-Fc C 3-C4 reveals conformational flexibility in the antibody effector domains. Immunity 13, 375-385 , (2000) .
    • . . . The extracellular region of the -chain has been crystallized as an isolated protein and in a complex with the Fc fragment of an IgE3, 4, 5, 6, 7 . . .
  4. Wan, T. et al. The crystal structure of IgE Fc reveals an asymmetrically bent conformation. Nature Immunol. 3, 681-686 , (2002) .
    • . . . The extracellular region of the -chain has been crystallized as an isolated protein and in a complex with the Fc fragment of an IgE3, 4, 5, 6, 7 . . .
  5. Mackay, G. A. et al. Mutagenesis within human FcRI differentially affects human and murine IgE binding. J. Immunol. 168, 1787-1795 , (2002) .
    • . . . The extracellular region of the -chain has been crystallized as an isolated protein and in a complex with the Fc fragment of an IgE3, 4, 5, 6, 7 . . .
  6. Garman, S. C., Kinet, J. P. & Jardetzky, T. S. Crystal structure of the human high-affinity IgE receptor. Cell 95, 951-961 , (1998) .
    • . . . The extracellular region of the -chain has been crystallized as an isolated protein and in a complex with the Fc fragment of an IgE3, 4, 5, 6, 7 . . .
  7. Garman, S. C., Wurzburg, B. A., Tarchevskaya, S. S., Kinet, J. P. & Jardetzky, T. S. Structure of the Fc fragment of human IgE bound to its high-affinity receptor FcRI. Nature 406, 259-266.This study describes the interaction of IgE with FcRI and provides valuable information for the design of inhibitors of IgE binding to FcRI , (2000) .
    • . . . The extracellular region of the -chain has been crystallized as an isolated protein and in a complex with the Fc fragment of an IgE3, 4, 5, 6, 7 . . .
  8. Cambier, J. C. Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J. Immunol. 155, 3281-3285 , (1995) .
    • . . . This results in the association of the - and -chains with intracellular signalling molecules through their SRC homology 2 (SH2) domains8 . . .
  9. Hasegawa, S. et al. Functional expression of the high affinity receptor for IgE (FcRI) in human platelets and its' intracellular expression in human megakaryocytes. Blood 93, 2543-2551 , (1999) .
    • . . . The expression of FcRI, with unclear subunit composition, has been reported on human platelets and neutrophils9, 10, 11 . . .
  10. Gounni, A. S. et al. Human neutrophils express the high-affinity receptor for immunoglobulin E (FcRI): role in asthma. FASEB J. 15, 940-949 , (2001) .
    • . . . The expression of FcRI, with unclear subunit composition, has been reported on human platelets and neutrophils9, 10, 11 . . .
  11. Joseph, M. et al. Expression and functions of the high-affinity IgE receptor on human platelets and megakaryocyte precursors. Eur. J. Immunol. 27, 2212-2218 , (1997) .
    • . . . The expression of FcRI, with unclear subunit composition, has been reported on human platelets and neutrophils9, 10, 11 . . .
  12. Fiebiger, E., Tortorella, D., Jouvin, M. H., Kinet, J. P. & Ploegh, H. L. Cotranslational endoplasmic reticulum assembly of FcRI controls the formation of functional IgE-binding receptors. J. Exp. Med. 201, 267-277 , (2005) .
    • . . . Non-covalent association of the newly synthesized FcRI core protein with FcRI - and -chains occurs co-translationally in the ER12 . . .
    • . . . This is accompanied by the accumulation of T2 complexes in the ER, which contain non-glycosylated 'backbone' FcRI with an uncleaved signal peptide12 . . .
  13. Geiger, E. et al. IL-4 induces the intracellular expression of the chain of the high-affinity receptor for IgE in in vitro-generated dendritic cells. J. Allergy Clin. Immunol. 105, 150-156 , (2000) .
    • . . . In human mast cells and antigen-presenting cells (APCs), the T helper 2 (TH2)-cell-derived cytokine interleukin-4 (IL-4) can induce FcRI expression13, 14, 15, 16 . . .
  14. Novak, N. et al. Evidence for a differential expression of the FcRI chain in dendritic cells of atopic and nonatopic donors. J. Clin. Invest. 111, 1047-1056 , (2003) .
    • . . . In human mast cells and antigen-presenting cells (APCs), the T helper 2 (TH2)-cell-derived cytokine interleukin-4 (IL-4) can induce FcRI expression13, 14, 15, 16 . . .
    • . . . In the absence of -chains, the -chain is retained in its immature form in the ER14, 23, 24, 25 . . .
    • . . . Other studies confirmed similar effects of IgE on the levels of surface FcRI on basophils, mast cells, monocytes and DCs14, 34, 35, 36 . . .
    • . . . Monomeric IgE can also induce the upregulation of cell-surface expression of trimeric FcRI by DCs by a comparable mechanism14 . . .
  15. Toru, H. et al. Induction of the high-affinity IgE receptor (FcRI) on human mast cells by IL-4. Int. Immunol. 8, 1367-1373 , (1996) .
    • . . . In human mast cells and antigen-presenting cells (APCs), the T helper 2 (TH2)-cell-derived cytokine interleukin-4 (IL-4) can induce FcRI expression13, 14, 15, 16 . . .
  16. Xia, H. Z. et al. Effect of recombinant human IL-4 on tryptase, chymase, and Fc receptor type I expression in recombinant human stem cell factor-dependent fetal liver-derived human mast cells. J. Immunol. 159, 2911-2921 , (1997) .
    • . . . In human mast cells and antigen-presenting cells (APCs), the T helper 2 (TH2)-cell-derived cytokine interleukin-4 (IL-4) can induce FcRI expression13, 14, 15, 16 . . .
  17. Hasegawa, M. et al. Regulation of the human FcRI-chain distal promoter. J. Immunol. 170, 3732-3738 , (2003) .
    • . . . A new study of the distal human FCERIA promoter confirmed that IL-4 increases the intracellular expression of FcRI (Ref. 17) . . .
  18. Malveaux, F. J., Conroy, M. C., Adkinson, N. F., Jr. & Lichtenstein, L. M. IgE receptors on human basophils. Relationship to serum IgE concentration. J. Clin. Invest. 62, 176-181 , (1978) .
    • . . . The atopic status of humans correlates with the surface levels of FcRI on mast cells, basophils, monocytes and DCs18, 19, 20, 21, 22 . . .
    • . . . The first observation of the potential regulation of FcRI by its ligand IgE was made when Malveaux et al.18 found a correlation between serum IgE levels and the amount of IgE bound to basophils . . .
  19. Maurer, D. et al. Expression of functional high affinity immunoglobulin E receptors (FcRI) on monocytes of atopic individuals. J. Exp. Med. 179, 745-750 , (1994) .
    • . . . The atopic status of humans correlates with the surface levels of FcRI on mast cells, basophils, monocytes and DCs18, 19, 20, 21, 22 . . .
    • . . . Maurer et al.19, 53, 54 showed that monocytes and DCs from allergic patients present birch-pollen allergen to T cells more efficiently when specific IgE is added, which leads to the channelling of IgE–FcRI-bound antigen into intracellular MHC-class-II-rich compartments and the presentation of antigen-derived peptides . . .
    • . . . FcRI crosslinking on monocytes, Langerhans cells and DCs from atopic patients can induce protein-tyrosine kinase activation, calcium mobilization and the activation of pro-inflammatory transcription factors such as nuclear factor-B (NF-B)19, 55, 56, 57 . . .
  20. Sihra, B. S., Kon, O. M., Grant, J. A. & Kay, A. B. Expression of high-affinity IgE receptors (FcRI) on peripheral blood basophils, monocytes, and eosinophils in atopic and nonatopic subjects: relationship to total serum IgE concentrations. J. Allergy Clin. Immunol. 99, 699-706 , (1997) .
    • . . . The atopic status of humans correlates with the surface levels of FcRI on mast cells, basophils, monocytes and DCs18, 19, 20, 21, 22 . . .
  21. Semper, A. E. et al. Surface expression of FcRI on Langerhans' cells of clinically uninvolved skin is associated with disease activity in atopic dermatitis, allergic asthma, and rhinitis. J. Allergy Clin. Immunol. 112, 411-419 , (2003) .
    • . . . The atopic status of humans correlates with the surface levels of FcRI on mast cells, basophils, monocytes and DCs18, 19, 20, 21, 22 . . .
  22. Wollenberg, A., Kraft, S., Hanau, D. & Bieber, T. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J. Invest. Dermatol. 106, 446-453 , (1996) .
    • . . . The atopic status of humans correlates with the surface levels of FcRI on mast cells, basophils, monocytes and DCs18, 19, 20, 21, 22 . . .
  23. Ryan, J. J., Kinzer, C. A. & Paul, W. E. Mast cells lacking the high affinity immunoglobulin E receptor are deficient in FcRI messenger RNA. J. Exp. Med. 182, 567-574 , (1995) .
    • . . . In the absence of -chains, the -chain is retained in its immature form in the ER14, 23, 24, 25 . . .
  24. Kraft, S., Wessendorf, J. H., Hanau, D. & Bieber, T. Regulation of the high affinity receptor for IgE on human epidermal Langerhans cells. J. Immunol. 161, 1000-1006 , (1998) .
    • . . . In the absence of -chains, the -chain is retained in its immature form in the ER14, 23, 24, 25 . . .
  25. Albrecht, B., Woisetschlager, M. & Robertson, M. W. Export of the high affinity IgE receptor from the endoplasmic reticulum depends on a glycosylation-mediated quality control mechanism. J. Immunol. 165, 5686-5694 , (2000) .
    • . . . In the absence of -chains, the -chain is retained in its immature form in the ER14, 23, 24, 25 . . .
  26. Miller, L., Blank, U., Metzger, H. & Kinet, J. P. Expression of high-affinity binding of human immunoglobulin E by transfected cells. Science 244, 334-337 , (1989) .
    • . . . Early transfection studies have indicated that the -chain masks an ER-retention motif in the -chain, and this leads to export and maturation of the FcRI complex26. . . .
  27. Blank, U. et al. Complete structure and expression in transfected cells of high affinity IgE receptor. Nature 337, 187-189 , (1989) .
    • . . . Murine FcRI has an obligatory tetrameric 2 structure27 . . .
  28. Blank, U., Ra, C. S. & Kinet, J. P. Characterization of truncated chain products from human, rat, and mouse high affinity receptor for immunoglobulin E. J. Biol. Chem. 266, 2639-2646 , (1991) .
    • . . . The ER-retention signal might be located in the extracellular domain of the murine -chain28. . . .
  29. Donnadieu, E., Jouvin, M. H. & Kinet, J. P. A second amplifier function for the allergy-associated FcRI- subunit. Immunity 12, 515-523 , (2000) .
    • . . . Classical full-length FcRI acts as an amplifier of FcRI cell-surface expression on human cells by promoting maturation and trafficking of associated FcRI and possibly by stabilizing the cell-surface-expressed FcRI complex29 . . .
  30. Donnadieu, E. et al. Competing functions encoded in the allergy-associated FceRI gene. Immunity 18, 665-674 , (2003) .
    • . . . The splice variant produces a truncated protein termed T30 . . .
    • . . . In human basophils, T and the classical -chain are co-expressed in variable proportions30, which indicates that the T:-chain ratio could regulate FcRI cell-surface expression and thereby influence susceptibility to allergic disorders. . . .
  31. Quarto, R., Kinet, J. P. & Metzger, H. Coordinate synthesis and degradation of the -, - and -subunits of the receptor for immunoglobulin E. Mol. Immunol. 22, 1045-1051 , (1985) .
    • . . . Later, monomeric IgE was shown to increase FcRI expression on the cell surface31, 32 . . .
  32. Furuichi, K., Rivera, J. & Isersky, C. The receptor for immunoglobulin E on rat basophilic leukemia cells: effect of ligand binding on receptor expression. Proc. Natl Acad. Sci. USA 82, 1522-1525 , (1985) .
    • . . . Later, monomeric IgE was shown to increase FcRI expression on the cell surface31, 32 . . .
  33. Yamaguchi, M. et al. IgE enhances mouse mast cell FcRI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions. J. Exp. Med. 185, 663-672 , (1997) .
    • . . . The low level of expression of FcRI on mast cells from IgE-deficient mice could be markedly upregulated by incubation with IgE in vitro or by injection of IgE in vivo33 . . .
    • . . . Importantly, this IgE-mediated upregulation of FcRI expression leads to increased effector-cell functions, such as mast-cell mediator release and IgE-dependent antigen-presenting functions of DCs14, 33, 35, 36. . . .
    • . . . This early phase is insensitive to the protein-synthesis inhibitor cycloheximide33 . . .
    • . . . Later on, further receptor accumulation at the cell surface depends on a basal level of FcRI protein synthesis and becomes sensitive to cycloheximide33, 37 . . .
  34. MacGlashan, D. W., Jr. et al. Down-regulation of FcRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J. Immunol. 158, 1438-1445 , (1997) .
    • . . . Other studies confirmed similar effects of IgE on the levels of surface FcRI on basophils, mast cells, monocytes and DCs14, 34, 35, 36 . . .
    • . . . Conversely, the treatment of atopic patients with IgE-specific antibodies leads to decreased levels of serum IgE and of FcRI expression on basophils34 . . .
  35. Lantz, C. S. et al. IgE regulates mouse basophil FcRI expression in vivo. J. Immunol. 158, 2517-2521 , (1997) .
    • . . . Other studies confirmed similar effects of IgE on the levels of surface FcRI on basophils, mast cells, monocytes and DCs14, 34, 35, 36 . . .
    • . . . Importantly, this IgE-mediated upregulation of FcRI expression leads to increased effector-cell functions, such as mast-cell mediator release and IgE-dependent antigen-presenting functions of DCs14, 33, 35, 36. . . .
  36. Yano, K. et al. Production of macrophage inflammatory protein-1 by human mast cells: increased anti-IgE-dependent secretion after IgE-dependent enhancement of mast cell IgE-binding ability. Lab. Invest. 77, 185-193 , (1997) .
    • . . . Other studies confirmed similar effects of IgE on the levels of surface FcRI on basophils, mast cells, monocytes and DCs14, 34, 35, 36 . . .
  37. Borkowski, T. A., Jouvin, M. H., Lin, S. Y. & Kinet, J. P. Minimal requirements for IgE-mediated regulation of surface FcRI. J. Immunol. 167, 1290-1296 , (2001) .
    • . . . Initially, the accumulation comes from the use of a preformed receptor pool derived from recycled and recently synthesized receptors37 . . .
    • . . . Later on, further receptor accumulation at the cell surface depends on a basal level of FcRI protein synthesis and becomes sensitive to cycloheximide33, 37 . . .
    • . . . This stabilization mechanism applies to both 2 and 2 complexes37 . . .
  38. Wedemeyer, J., Tsai, M. & Galli, S. J. Roles of mast cells and basophils in innate and acquired immunity. Curr. Opin. Immunol. 12, 624-631 , (2000) .
    • . . . This is reflected by the release of preformed mediators such as histamine, heparin, neutral proteases and others, the generation of leukotrienes and prostaglandins, and the de novo synthesis of cytokines and chemokines upon crosslinking of FcRI-bound IgE by antigen38, 39 . . .
    • . . . This topic and the role of FcRI-bearing cells in host defence and asthma have been reviewed extensively elsewhere1, 38, 42 . . .
  39. Galli, S. J., Maurer, M. & Lantz, C. S. Mast cells as sentinels of innate immunity. Curr. Opin. Immunol. 11, 53-59 , (1999) .
    • . . . This is reflected by the release of preformed mediators such as histamine, heparin, neutral proteases and others, the generation of leukotrienes and prostaglandins, and the de novo synthesis of cytokines and chemokines upon crosslinking of FcRI-bound IgE by antigen38, 39 . . .
  40. Wershil, B. K., Mekori, Y. A., Murakami, T. & Galli, S. J. 125I-fibrin deposition in IgE-dependent immediate hypersensitivity reactions in mouse skin. Demonstration of the role of mast cells using genetically mast cell-deficient mice locally reconstituted with cultured mast cells. J. Immunol. 139, 2605-2614 , (1987) .
    • . . . Components of IgE-dependent late-phase responses, such as tissue swelling, fibrin deposition and leukocyte accumulation, also depend on FcRI-bearing mast cells and basophils40, 41 . . .
  41. Wershil, B. K., Wang, Z. S., Gordon, J. R. & Galli, S. J. Recruitment of neutrophils during IgE-dependent cutaneous late phase reactions in the mouse is mast cell-dependent. Partial inhibition of the reaction with antiserum against tumor necrosis factor-. J. Clin. Invest. 87, 446-453 , (1991) .
    • . . . Components of IgE-dependent late-phase responses, such as tissue swelling, fibrin deposition and leukocyte accumulation, also depend on FcRI-bearing mast cells and basophils40, 41 . . .
  42. Galli, S. J. et al. Mast cells as 'tunable' effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749-786 , (2005) .
    • . . . This topic and the role of FcRI-bearing cells in host defence and asthma have been reviewed extensively elsewhere1, 38, 42 . . .
    • . . . The role of mast cells in delayed-type hypersensitivity (DTH) reactions, such as cutaneous hypersensitivity (CHS) to contact allergens, has been controversial (see Ref. 42) . . .
  43. Asai, K. et al. Regulation of mast cell survival by IgE. Immunity 14, 791-800 , (2001) .
    • . . . Two studies43, 44 have shown that IgE alone — without antigen — can enhance mast-cell survival upon growth-factor deprivation . . .
    • . . . Whereas Kalesnikoff et al.44 observed IgE-induced FcRI signalling (activation of extracellular-signal regulated kinase (ERK), JUN N-terminal kinase (JNK), p38 and AKT (also known as PKB) signalling), and postulated that autocrine secretion of cytokines and induction of the anti-apoptotic protein B-cell lymphoma XL (BCL-XL) are responsible for the enhanced mast-cell survival, Asai et al.43 did not observe any of these signalling events . . .
  44. Kalesnikoff, J. et al. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14, 801-811.References 43 and 44 were the first to describe the anti-apoptotic effect of IgE binding to FcRI , (2001) .
    • . . . Two studies43, 44 have shown that IgE alone — without antigen — can enhance mast-cell survival upon growth-factor deprivation . . .
    • . . . Whereas Kalesnikoff et al.44 observed IgE-induced FcRI signalling (activation of extracellular-signal regulated kinase (ERK), JUN N-terminal kinase (JNK), p38 and AKT (also known as PKB) signalling), and postulated that autocrine secretion of cytokines and induction of the anti-apoptotic protein B-cell lymphoma XL (BCL-XL) are responsible for the enhanced mast-cell survival, Asai et al.43 did not observe any of these signalling events . . .
  45. Kitaura, J. et al. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the FcRI. Proc. Natl Acad. Sci. USA 100, 12911-12916.In this paper the authors show that different IgE clones have a different capacity for FcRI aggregation , (2003) .
    • . . . Interestingly, a later study confirmed that transplantation of an IgE-producing hybridoma into mice increased the number of gastric mast cells45. . . .
    • . . . Incubation with these IgE clones produces a broad range of FcRI-induced events, such as histamine synthesis and release, adhesion, migration and DNA synthesis, through the induction of signalling events that are known to occur after 'classical' FcRI crosslinking by IgE and antigen (such as activation of spleen tyrosine kinase (SYK))45, 46, 47, 48 . . .
  46. Tanaka, S., Takasu, Y., Mikura, S., Satoh, N. & Ichikawa, A. Antigen-independent induction of histamine synthesis by immunoglobulin E in mouse bone marrow-derived mast cells. J. Exp. Med. 196, 229-235 , (2002) .
    • . . . Incubation with these IgE clones produces a broad range of FcRI-induced events, such as histamine synthesis and release, adhesion, migration and DNA synthesis, through the induction of signalling events that are known to occur after 'classical' FcRI crosslinking by IgE and antigen (such as activation of spleen tyrosine kinase (SYK))45, 46, 47, 48 . . .
  47. Kitaura, J. et al. Regulation of highly cytokinergic IgE-induced mast cell adhesion by Src, Syk, Tec, and protein kinase C family kinases. J. Immunol. 174, 4495-4504 , (2005) .
    • . . . Incubation with these IgE clones produces a broad range of FcRI-induced events, such as histamine synthesis and release, adhesion, migration and DNA synthesis, through the induction of signalling events that are known to occur after 'classical' FcRI crosslinking by IgE and antigen (such as activation of spleen tyrosine kinase (SYK))45, 46, 47, 48 . . .
    • . . . Importantly, the effects of 'monomeric' IgE, other than FcRI upregulation, can be inhibited by hapten administration, which shows that these effects are due to low-level FcRI aggregation47, 50, 51 . . .
  48. Kitaura, J. et al. IgE- and IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion. Blood. 105, 3222-3229 , (2005) .
    • . . . Incubation with these IgE clones produces a broad range of FcRI-induced events, such as histamine synthesis and release, adhesion, migration and DNA synthesis, through the induction of signalling events that are known to occur after 'classical' FcRI crosslinking by IgE and antigen (such as activation of spleen tyrosine kinase (SYK))45, 46, 47, 48 . . .
  49. Kohno, M., Yamasaki, S., Tybulewicz, V. L. & Saito, T. Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen. Blood 105, 2059-2065 , (2005) .
    • . . . Autocrine IL-3 production, together with BCL-XL and BCL-2 upregulation, seems to be a major component of enhanced mast-cell survival by highly cytokinergic IgE49. . . .
  50. Kitaura, J. et al. Early divergence of Fc receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival. J. Immunol. 173, 4317-4323 , (2004) .
    • . . . Importantly, the effects of 'monomeric' IgE, other than FcRI upregulation, can be inhibited by hapten administration, which shows that these effects are due to low-level FcRI aggregation47, 50, 51 . . .
  51. Pandey, V., Mihara, S., Fensome-Green, A., Bolsover, S. & Cockcroft, S. Monomeric IgE stimulates NFAT translocation into the nucleus, a rise in cytosol Ca2+, degranulation, and membrane ruffling in the cultured rat basophilic leukemia-2H3 mast cell line. J. Immunol. 172, 4048-4058 , (2004) .
    • . . . Importantly, the effects of 'monomeric' IgE, other than FcRI upregulation, can be inhibited by hapten administration, which shows that these effects are due to low-level FcRI aggregation47, 50, 51 . . .
  52. Kraft, S. & Novak, N. Fc receptors as determinants of allergic reactions. Trends Immunol. 27, 88-95 , (2006) .
    • . . . In humans, trimeric FcRI 2 is expressed by professional APCs such as DCs (including epidermal Langerhans cells), monocytes and macrophages (for more detail see Refs 1,52) . . .
    • . . . The inhibition of FcRI function has led to various therapeutic approaches for allergies (for an overview see Ref. 52). . . .
  53. Maurer, D. et al. Fc receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation. J. Immunol. 161, 2731-2739 , (1998) .
    • . . . Maurer et al.19, 53, 54 showed that monocytes and DCs from allergic patients present birch-pollen allergen to T cells more efficiently when specific IgE is added, which leads to the channelling of IgE–FcRI-bound antigen into intracellular MHC-class-II-rich compartments and the presentation of antigen-derived peptides . . .
  54. Maurer, D. et al. Peripheral blood dendritic cells express FcRI as a complex composed of FcRI- and FcRI -chains and can use this receptor for IgE-mediated allergen presentation. J. Immunol. 157, 607-616 , (1996) .
    • . . . Maurer et al.19, 53, 54 showed that monocytes and DCs from allergic patients present birch-pollen allergen to T cells more efficiently when specific IgE is added, which leads to the channelling of IgE–FcRI-bound antigen into intracellular MHC-class-II-rich compartments and the presentation of antigen-derived peptides . . .
  55. Jurgens, M., Wollenberg, A., Hanau, D., de la Salle, H. & Bieber, T. Activation of human epidermal Langerhans cells by engagement of the high affinity receptor for IgE, FcRI. J. Immunol. 155, 5184-5189 , (1995) .
    • . . . FcRI crosslinking on monocytes, Langerhans cells and DCs from atopic patients can induce protein-tyrosine kinase activation, calcium mobilization and the activation of pro-inflammatory transcription factors such as nuclear factor-B (NF-B)19, 55, 56, 57 . . .
  56. Kraft, S., Novak, N., Katoh, N., Bieber, T. & Rupec, R. A. Aggregation of the high-affinity IgE receptor FcRI on human monocytes and dendritic cells induces NF-B activation. J. Invest. Dermatol. 118, 830-837 , (2002) .
    • . . . FcRI crosslinking on monocytes, Langerhans cells and DCs from atopic patients can induce protein-tyrosine kinase activation, calcium mobilization and the activation of pro-inflammatory transcription factors such as nuclear factor-B (NF-B)19, 55, 56, 57 . . .
    • . . . This leads to the production of several pro-inflammatory and chemotactic factors, such as tumour-necrosis factor (TNF), CC-chemokine ligand 2 (CCL2; also known as MCP1), IL-1, IL-8 and IL-16, which can support the inflammatory micromilieu in tissues of atopic patients56, 58, 59, 60 . . .
    • . . . The FcRI-induced cytokine production underlying these responses is mainly the result of activation of nuclear factor of activated T cells (NFAT), activator protein 1 (AP1) and NF-B transcription factors56, 113 . . .
  57. Kraft, S. et al. Enhanced expression and activity of protein-tyrosine kinases establishes a functional signaling pathway only in FcRIhigh Langerhans cells from atopic individuals. J. Invest. Dermatol. 119, 804-811 , (2002) .
    • . . . FcRI crosslinking on monocytes, Langerhans cells and DCs from atopic patients can induce protein-tyrosine kinase activation, calcium mobilization and the activation of pro-inflammatory transcription factors such as nuclear factor-B (NF-B)19, 55, 56, 57 . . .
  58. Reich, K. et al. Engagement of the FcRI stimulates the production of IL-16 in Langerhans cell-like dendritic cells. J. Immunol. 167, 6321-6329 , (2001) .
    • . . . This leads to the production of several pro-inflammatory and chemotactic factors, such as tumour-necrosis factor (TNF), CC-chemokine ligand 2 (CCL2; also known as MCP1), IL-1, IL-8 and IL-16, which can support the inflammatory micromilieu in tissues of atopic patients56, 58, 59, 60 . . .
    • . . . For example, IL-16 production induced by FcRI crosslinking on Langerhans cells from patients with atopic dermatitis could lead to the recruitment of CD4+ T cells, DCs and eosinophils to skin sites of allergen exposure58. . . .
  59. Novak, N. et al. FcRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J. Allergy Clin. Immunol. 113, 949-957 , (2004) .
    • . . . This leads to the production of several pro-inflammatory and chemotactic factors, such as tumour-necrosis factor (TNF), CC-chemokine ligand 2 (CCL2; also known as MCP1), IL-1, IL-8 and IL-16, which can support the inflammatory micromilieu in tissues of atopic patients56, 58, 59, 60 . . .
  60. Novak, N. et al. A reducing microenvironment leads to the generation of FcRIhigh inflammatory dendritic epidermal cells (IDEC). J. Invest. Dermatol. 119, 842-849 , (2002) .
    • . . . This leads to the production of several pro-inflammatory and chemotactic factors, such as tumour-necrosis factor (TNF), CC-chemokine ligand 2 (CCL2; also known as MCP1), IL-1, IL-8 and IL-16, which can support the inflammatory micromilieu in tissues of atopic patients56, 58, 59, 60 . . .
  61. Novak, N. et al. Characterization of FcRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J. Allergy Clin. Immunol. 114, 364-370 , (2004) .
    • . . . Langerhans cells can help to produce a TH2-cell phenotype, which is seen in the initial phases of atopic dermatitis, whereas another DC subtype that is present only in established inflammatory skin lesions produces IL-12 and IL-18 upon FcRI crosslinking and might support the development of the TH1-cell phenotype, which is usually seen in chronic atopic dermatitis lesions61, 62 . . .
    • . . . In addition, it was found recently that FcRI ligation on plasmacytoid DCs decreases their capacity to secrete interferon- (IFN) and IFN upon Toll-like receptor 9 (TLR9) stimulation, thereby decreasing their TH1-cell-polarizing capacity61, 63. . . .
  62. Grewe, M. et al. Analysis of the cytokine pattern expressed in situ in inhalant allergen patch test reactions of atopic dermatitis patients. J. Invest. Dermatol. 105, 407-410 , (1995) .
    • . . . Langerhans cells can help to produce a TH2-cell phenotype, which is seen in the initial phases of atopic dermatitis, whereas another DC subtype that is present only in established inflammatory skin lesions produces IL-12 and IL-18 upon FcRI crosslinking and might support the development of the TH1-cell phenotype, which is usually seen in chronic atopic dermatitis lesions61, 62 . . .
  63. Schroeder, J. T. et al. TLR9- and FcRI-mediated responses oppose one another in plasmacytoid dendritic cells by down-regulating receptor expression. J. Immunol. 175, 5724-5731 , (2005) .
    • . . . In addition, it was found recently that FcRI ligation on plasmacytoid DCs decreases their capacity to secrete interferon- (IFN) and IFN upon Toll-like receptor 9 (TLR9) stimulation, thereby decreasing their TH1-cell-polarizing capacity61, 63. . . .
  64. Biedermann, T. et al. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J. Exp. Med. 192, 1441-1452 , (2000) .
    • . . . First, using mast-cell-deficient mice, Biedermann et al.64 showed that mast-cell-derived TNF and CXC-chemokine ligand 2 (CXCL2; also known as MIP2; the functional analogue of human IL-8) are essential for the recruitment of polymorphonuclear leukocytes into CHS lesions . . .
  65. Bryce, P. J. et al. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20, 381-392.This is an interesting study on the antigen-independent role of IgE, FcRI and mast cells in cutaneous hypersensitivity , (2004) .
    • . . . More recently, Bryce et al.65 showed that IgE-, mast-cell- and FcR-deficient mice (which lack FcRI and FcRIII), but not FcRIII-deficient mice, had markedly decreased CHS reactions and a reduced cellular infiltrate (in particular neutrophils) . . .
    • . . . The defect in IgE-deficient mice seems to occur in the sensitization phase and is characterized by decreased levels of the mast-cell-derived cytokines mast-cell protease 6 (MCP6), IL-1, TNF and CCL2, which could explain why the migration of epidermal Langerhans cells upon sensitization in IgE-deficient mice is much less pronounced65 . . .
  66. Ott, V. L., Cambier, J. C., Kappler, J., Marrack, P. & Swanson, B. J. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nature Immunol. 4, 974-981 , (2003) .
    • . . . Leukotriene B4 (LTB4) that is produced after antigen-dependent FcRI crosslinking attracts CD8+ effector T cells66, although it is not clear whether LTB4 is produced by low-level FcRI aggregation through monomeric IgE . . .
  67. Meng, H. et al. Mast cells induce T-cell adhesion to human fibroblasts by regulating intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. J. Invest. Dermatol. 105, 789-796 , (1995) .
    • . . . The induction of expression of vascular cell-adhesion molecule 1 (VCAM1) on endothelial cells or selectins and intercellular adhesion molecule 1 (ICAM1) on leukocytes, for example through mast-cell-derived TNF, is another possibility67, 68. . . .
  68. Walsh, L. J., Trinchieri, G., Waldorf, H. A., Whitaker, D. & Murphy, G. F. Human dermal mast cells contain and release tumor necrosis factor , which induces endothelial leukocyte adhesion molecule 1. Proc. Natl Acad. Sci. USA 88, 4220-4224 , (1991) .
    • . . . The induction of expression of vascular cell-adhesion molecule 1 (VCAM1) on endothelial cells or selectins and intercellular adhesion molecule 1 (ICAM1) on leukocytes, for example through mast-cell-derived TNF, is another possibility67, 68. . . .
  69. Dombrowicz, D. et al. Role of the high affinity immunoglobulin E receptor in bacterial translocation and intestinal inflammation. J. Exp. Med. 193, 25-34 , (2001) .
    • . . . Comparable antigen-independent effects could also contribute to the protection of FcRI-deficient mice from trinitrobenzene sulphonic acid (TNBS)-induced colitis, a model of inflammatory bowel disease69 . . .
  70. Turner, H. & Kinet, J. P. Signalling through the high-affinity IgE receptor FcRI. Nature 402, B24-B30 , (1999) .
    • . . . The - and -chains of FcRI contain ITAMs, which after tyrosine phosphorylation bind the SH2 domains of protein tyrosine kinases (PTKs), mainly the SRC family kinases LYN and FYN, as well as SYK1, 70, 73 (Fig. 3) . . .
    • . . . In turn, this leads to diacylglycerol (DAG) production and inositol-1,4,5-trisphosphate (InsP3)-induced Ca2+ mobilization70. . . .
  71. Rivera, J. & Gilfillan, A. M. Molecular regulation of mast cell activation. J. Allergy Clin. Immunol. 117, 1214-1225 , (2006) .
  72. Gilfillan, A. M. & Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nature Rev. Immunol. 6, 218-230 , (2006) .
    • . . . The mitogen-activated protein kinase (MAPK) ERK signalling cascade is activated through the primary pathway by the adaptor LAT, which recruits GRB2 and the guanine-nucleotide-exchange factor son-of-sevenless homologue (SOS), which ultimately activates RAS72 . . .
  73. Parravicini, V. et al. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nature Immunol. 3, 741-748.This is the first study to separate FcRI signalling into two distinct pathways , (2002) .
    • . . . The - and -chains of FcRI contain ITAMs, which after tyrosine phosphorylation bind the SH2 domains of protein tyrosine kinases (PTKs), mainly the SRC family kinases LYN and FYN, as well as SYK1, 70, 73 (Fig. 3) . . .
    • . . . Newer studies have identified a complementary pathway initiated by FcRI through FYN and the adaptor growth-factor-receptor-bound protein 2 (GRB2)-associated binding protein 2 (GAB2)73, 81 . . .
    • . . . In FYN-deficient cells, PI3K activity and degranulation are impaired, whereas Ca2+ signalling is only moderately affected73 . . .
    • . . . By contrast, Ca2+ signalling is inhibited in LYN-deficient cells, whereas degranulation is increased, which indicates a negative effect of the LYN pathway on the FYN pathway73, 80 . . .
  74. El-Hillal, O., Kurosaki, T., Yamamura, H., Kinet, J. P. & Scharenberg, A. M. Syk kinase activation by a Src kinase-initiated activation loop phosphorylation chain reaction. Proc. Natl Acad. Sci. USA 94, 1919-1924 , (1997) .
    • . . . SYK binding to FcRI then leads to LYN-dependent tyrosine phosphorylation and activation of SYK74 . . .
  75. Pivniouk, V. I. et al. SLP-76 deficiency impairs signaling via the high-affinity IgE receptor in mast cells. J. Clin. Invest. 103, 1737-1743 , (1999) .
    • . . . Among the many substrates for SYK are the adaptor proteins linker for activation of T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kDa (SLP76)75, 76 . . .
  76. Saitoh, S. et al. LAT is essential for FcRI-mediated mast cell activation. Immunity 12, 525-535 , (2000) .
    • . . . Among the many substrates for SYK are the adaptor proteins linker for activation of T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kDa (SLP76)75, 76 . . .
  77. Kawakami, Y. et al. Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation. J. Immunol. 165, 1210-1219 , (2000) .
    • . . . These adaptors then participate in the assembly of large signalling complexes that include other molecules such as the PTK Bruton's tyrosine kinase (BTK), which activates phospholipase C (PLC) cooperatively with SYK77, 78, 79 . . .
  78. Fluckiger, A. C. et al. Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation. EMBO J. 17, 1973-1985 , (1998) .
    • . . . These adaptors then participate in the assembly of large signalling complexes that include other molecules such as the PTK Bruton's tyrosine kinase (BTK), which activates phospholipase C (PLC) cooperatively with SYK77, 78, 79 . . .
    • . . . FcRIIB recruits SHIP through its ITIM to the plasma membrane, where SHIP degrades PtdIns(3,4,5)P3 to PtdIns(4,5)P2, ultimately leading to reduced BTK activation and PLC-mediated Ca2+ mobilization through the aforementioned mechanisms78, 79, 119, 120 . . .
  79. Scharenberg, A. M. et al. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent calcium signaling pathway: a target for SHIP-mediated inhibitory signals. EMBO J. 17, 1961-1972 , (1998) .
    • . . . These adaptors then participate in the assembly of large signalling complexes that include other molecules such as the PTK Bruton's tyrosine kinase (BTK), which activates phospholipase C (PLC) cooperatively with SYK77, 78, 79 . . .
    • . . . FcRIIB recruits SHIP through its ITIM to the plasma membrane, where SHIP degrades PtdIns(3,4,5)P3 to PtdIns(4,5)P2, ultimately leading to reduced BTK activation and PLC-mediated Ca2+ mobilization through the aforementioned mechanisms78, 79, 119, 120 . . .
  80. Nishizumi, H. & Yamamoto, T. Impaired tyrosine phosphorylation and Ca2+ mobilization, but not degranulation, in lyn-deficient bone marrow-derived mast cells. J. Immunol. 158, 2350-2355 , (1997) .
    • . . . However, studies from LYN-deficient bone-marrow-derived mast cells (BMMCs), which showed normal degranulation, indicated that there is compensation by other molecules in LYN-deficient cells or that a second pathway is involved in degranulation80 . . .
    • . . . By contrast, Ca2+ signalling is inhibited in LYN-deficient cells, whereas degranulation is increased, which indicates a negative effect of the LYN pathway on the FYN pathway73, 80 . . .
  81. Gu, H. et al. Essential role for Gab2 in the allergic response. Nature 412, 186-190 , (2001) .
    • . . . Newer studies have identified a complementary pathway initiated by FcRI through FYN and the adaptor growth-factor-receptor-bound protein 2 (GRB2)-associated binding protein 2 (GAB2)73, 81 . . .
  82. Zhang, J., Berenstein, E. H., Evans, R. L. & Siraganian, R. P. Transfection of Syk protein tyrosine kinase reconstitutes high affinity IgE receptor-mediated degranulation in a Syk-negative variant of rat basophilic leukemia RBL-2H3 cells. J. Exp. Med. 184, 71-79 , (1996) .
    • . . . Both pathways require SYK activation, as both Ca2+ mobilization and degranulation are abolished in SYK-deficient mast cells82, 83. . . .
  83. Costello, P. S. et al. Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells. Oncogene 13, 2595-2605 , (1996) .
    • . . . Both pathways require SYK activation, as both Ca2+ mobilization and degranulation are abolished in SYK-deficient mast cells82, 83. . . .
  84. Lin, S., Cicala, C., Scharenberg, A. M. & Kinet, J. P. The FcRI subunit functions as an amplifier of FcRI-mediated cell activation signals. Cell 85, 985-995 , (1996) .
    • . . . Tetrameric FcRI induced markedly increased FcRI and SYK tyrosine phosphorylation compared with trimeric FcRI, which lacks the -chain, as well as a more rapid and increased Ca2+ mobilization84 . . .
  85. Furumoto, Y., Nunomura, S., Terada, T., Rivera, J. & Ra, C. The FcRI immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IB kinase phosphorylation and mast cell cytokine production. J. Biol. Chem. 279, 49177-49187 , (2004) .
    • . . . Loss of Tyr219 phosphorylation leads to reductions in receptor-associated LYN, Ca2+ mobilization, degranulation and cytokine synthesis85, 86 . . .
    • . . . The middle, non-canonical tyrosine (Tyr225) has some inhibitory effect on FcRI-induced signalling through the activation of SH2-domain-containing inositol-5-phosphatase (SHIP)85 . . .
  86. On, M., Billingsley, J. M., Jouvin, M. H. & Kinet, J. P. Molecular dissection of the FcR signaling amplifier. J. Biol. Chem. 279, 45782-45790 , (2004) .
    • . . . Loss of Tyr219 phosphorylation leads to reductions in receptor-associated LYN, Ca2+ mobilization, degranulation and cytokine synthesis85, 86 . . .
  87. Xiao, W. et al. Positive and negative regulation of mast cell activation by Lyn via the FcRI. J. Immunol. 175, 6885-6892 , (2005) .
    • . . . Xiao et al.87 suggested that this might be a negative-feedback mechanism that occurs during high-intensity stimulation of FcRI. . . .
  88. Parekh, A. B. & Penner, R. Store depletion and calcium influx. Physiol. Rev. 77, 901-930 , (1997) .
    • . . . The current that carries Ca2+ is known as ICRAC (calcium-release-activated calcium current)88. . . .
  89. Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220-1223 , (2006) .
    • . . . We called it CRACM1 (Ref. 89) and others have named it ORAI1 (Ref. 90) . . .
  90. Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179-185 , (2006) .
    • . . . We called it CRACM1 (Ref. 89) and others have named it ORAI1 (Ref. 90) . . .
  91. Yeromin, A. V. et al. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443, 226-229 , (2006) .
    • . . . This transmembrane protein multimerizes to form a SOC and cooperates with the intracellular Ca2+ sensor stromal interaction molecule 1 (STIM1) to mediate the store-operated Ca2+ influx91, 92, 93, 94. . . .
  92. Vig, M. et al. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16, 2073-2079 , (2006) .
    • . . . This transmembrane protein multimerizes to form a SOC and cooperates with the intracellular Ca2+ sensor stromal interaction molecule 1 (STIM1) to mediate the store-operated Ca2+ influx91, 92, 93, 94. . . .
  93. Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230-233 , (2006) .
    • . . . This transmembrane protein multimerizes to form a SOC and cooperates with the intracellular Ca2+ sensor stromal interaction molecule 1 (STIM1) to mediate the store-operated Ca2+ influx91, 92, 93, 94. . . .
  94. Peinelt, C. et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nature Cell Biol. 8, 771-773 , (2006) .
    • . . . This transmembrane protein multimerizes to form a SOC and cooperates with the intracellular Ca2+ sensor stromal interaction molecule 1 (STIM1) to mediate the store-operated Ca2+ influx91, 92, 93, 94. . . .
  95. Ammit, A. J. et al. Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma. FASEB J. 15, 1212-1214 , (2001) .
    • . . . Increased S1P levels are present in the airways of asthmatic subjects following localized antigen challenge, which correlates with an increase in airway inflammation95 . . .
  96. Prieschl, E. E., Csonga, R., Novotny, V., Kikuchi, G. E. & Baumruker, T. The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fc receptor I triggering. J. Exp. Med. 190, 1-8 , (1999) .
    • . . . Furthermore, external application of S1P to mast cells induces mediator release96 . . .
    • . . . In addition, mast cells activated by FcRI crosslinking release S1P96, 97, which then binds to the extracellular sphingosine receptors S1P1 and S1P2 and further transactivates mast cells . . .
    • . . . This balance has been shown in particular for FcRI (Ref. 96) . . .
  97. Jolly, P. S. et al. Transactivation of sphingosine-1-phosphate receptors by FcRI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199, 959-970 , (2004) .
    • . . . In addition, mast cells activated by FcRI crosslinking release S1P96, 97, which then binds to the extracellular sphingosine receptors S1P1 and S1P2 and further transactivates mast cells . . .
    • . . . This creates a positive-feedback loop, which amplifies the allergic reaction by enhancing the migration of mast cells to sites of inflammation (mainly through S1P1) and their degranulation response (mainly through S1P2)97. . . .
  98. Choi, O. H., Kim, J. H. & Kinet, J. P. Calcium mobilization via sphingosine kinase in signalling by the FcRI antigen receptor. Nature 380, 634-636 , (1996) .
    • . . . FcRI crosslinking induces sphingosine-kinase activity98 . . .
    • . . . Although initially it was believed that sphingosine kinases, mainly through sphingosine kinase 1 (SPHK1), regulate Ca2+ release from intracellular stores98, 100, 101, Olivera et al.102 showed that SPHK2 is the main regulator of intracellular S1P levels in mast cells and drives FcRI-induced PKC and NF-B activation, degranulation, lipid-mediator production and cytokine synthesis . . .
    • . . . The role of upstream PTK activity in the activation of sphingosine kinases has previously been investigated with controversial results98, 101 . . .
  99. Hait, N. C., Oskeritzian, C. A., Paugh, S. W., Milstien, S. & Spiegel, S. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim. Biophys. Acta 1758, 2016-2026 , (2006) .
    • . . . This activity is responsible for a dynamic balance between sphingosine and S1P, the 'sphingolipid rheostat', with high levels of sphingosine being associated with certain signals, such as apoptosis, and high levels of S1P being associated with opposite signals, such as cell proliferation99 . . .
  100. Lee, H. S. et al. Antigen-induced Ca2+ mobilization in RBL-2H3 cells: role of I(1,4,5)P3 and S1P and necessity of I(1,4,5)P3 production. Cell Calcium 38, 581-592 , (2005) .
    • . . . Although initially it was believed that sphingosine kinases, mainly through sphingosine kinase 1 (SPHK1), regulate Ca2+ release from intracellular stores98, 100, 101, Olivera et al.102 showed that SPHK2 is the main regulator of intracellular S1P levels in mast cells and drives FcRI-induced PKC and NF-B activation, degranulation, lipid-mediator production and cytokine synthesis . . .
  101. Melendez, A. J. & Khaw, A. K. Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J. Biol. Chem. 277, 17255-17262 , (2002) .
    • . . . Although initially it was believed that sphingosine kinases, mainly through sphingosine kinase 1 (SPHK1), regulate Ca2+ release from intracellular stores98, 100, 101, Olivera et al.102 showed that SPHK2 is the main regulator of intracellular S1P levels in mast cells and drives FcRI-induced PKC and NF-B activation, degranulation, lipid-mediator production and cytokine synthesis . . .
    • . . . The role of upstream PTK activity in the activation of sphingosine kinases has previously been investigated with controversial results98, 101 . . .
  102. Olivera A, M. K. et al. The sphingosine kinase-sphingosine-1-phosphate-axis is a determinant of mast cell function and anaphylaxis. Immunity 8 March 2007.This is a well carried out and extensive study clarifying the role of SPHK1and SPHK2 in FcRI signalling , .
    • . . . Although initially it was believed that sphingosine kinases, mainly through sphingosine kinase 1 (SPHK1), regulate Ca2+ release from intracellular stores98, 100, 101, Olivera et al.102 showed that SPHK2 is the main regulator of intracellular S1P levels in mast cells and drives FcRI-induced PKC and NF-B activation, degranulation, lipid-mediator production and cytokine synthesis . . .
    • . . . Although SPHK2 regulates FcRI-induced Ca2+ mobilization, this effect is due to the regulation of extracellular Ca2+ influx and not Ca2+ release from ER stores102 . . .
    • . . . Although SPHK2 seems to be the main intracellular S1P regulator in mast cells, experiments using SPHK1-deficient mice indicate that SPHK1 regulates extracellular S1P in vivo (probably not produced by mast cells, as mast-cell-deficient mice have normal S1P levels102), thereby affecting mast-cell responsiveness and anaphylaxis. . . .
  103. Mathes, C., Fleig, A. & Penner, R. Calcium release-activated calcium current (ICRAC) is a direct target for sphingosine. J. Biol. Chem. 273, 25020-25030 , (1998) .
    • . . . This could occur by a reduced suppression of sphingosine on ICRAC103 through increased conversion to S1P . . .
  104. Urtz, N. et al. Early activation of sphingosine kinase in mast cells and recruitment to FcRI are mediated by its interaction with Lyn kinase. Mol. Cell. Biol. 24, 8765-8777 , (2004) .
    • . . . LYN has a role in the early recruitment of SPHK1 to FcRI through direct interaction, allowing its fast subsequent activation, and FYN may be responsible for prolonged sphingosine-kinase activation104, 105. . . .
  105. Olivera, A. et al. IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J. Biol. Chem. 281, 2515-2525 , (2006) .
    • . . . LYN has a role in the early recruitment of SPHK1 to FcRI through direct interaction, allowing its fast subsequent activation, and FYN may be responsible for prolonged sphingosine-kinase activation104, 105. . . .
  106. Tam, S. Y. et al. RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nature Immunol. 5, 844-852.This study identified a new negative regulator of FcRI signalling , (2004) .
    • . . . By screening for genes that are activated after FcRI crosslinking, Tam et al.106 identified RAB guanine-nucleotide-exchange factor 1 (RABGEF1) as a novel negative regulator of FcRI-induced signalling . . .
  107. Liu, Y., Zhu, M., Nishida, K., Hirano, T. & Zhang, W. An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response. J. Exp. Med. 204, 93-103 , (2007) .
    • . . . N-RAS, activated by RAS guanyl-nucleotide-releasing protein 1 (RASGRP1), might modulate degranulation through the distal complementary pathway through class I PI3K and PKC (Ref. 107) . . .
  108. Tkaczyk, C. et al. NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and FcRI aggregation. Blood 104, 207-214 , (2004) .
    • . . . FcRI crosslinking leads to rapid LYN- and SYK-dependent phosphorylation of NTAL108, 109 . . .
  109. Brdicka, T. et al. Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling. J. Exp. Med. 196, 1617-1626 , (2002) .
    • . . . FcRI crosslinking leads to rapid LYN- and SYK-dependent phosphorylation of NTAL108, 109 . . .
  110. Zhu, M., Liu, Y., Koonpaew, S., Granillo, O. & Zhang, W. Positive and negative regulation of FcRI-mediated signaling by the adaptor protein LAB/NTAL. J. Exp. Med. 200, 991-1000 , (2004) .
    • . . . As NTAL resides in different microdomains to LAT and the residual Ca2+ mobilization and degranulation observed in LAT-deficient BMMCs is further reduced in BMMCs deficient in both LAT and NTAL110, 111, NTAL might be the LAT counterpart for the complementary FYN pathway . . .
  111. Volna, P. et al. Negative regulation of mast cell signaling and function by the adaptor LAB/NTAL. J. Exp. Med. 200, 1001-1013 , (2004) .
    • . . . As NTAL resides in different microdomains to LAT and the residual Ca2+ mobilization and degranulation observed in LAT-deficient BMMCs is further reduced in BMMCs deficient in both LAT and NTAL110, 111, NTAL might be the LAT counterpart for the complementary FYN pathway . . .
  112. Zhu, M., Rhee, I., Liu, Y. & Zhang, W. Negative regulation of FcRI-mediated signaling and mast cell function by the adaptor protein LAX. J. Biol. Chem. 281, 18408-18413 , (2006) .
    • . . . Another structurally related molecule, LAX (linker for activation of X cells, where X denotes an as-yet-unidentified cell), has been proposed as a negative regulator of FcRI signalling112 . . .
  113. Kitaura, J. et al. Akt-dependent cytokine production in mast cells. J. Exp. Med. 192, 729-740 , (2000) .
    • . . . The FcRI-induced cytokine production underlying these responses is mainly the result of activation of nuclear factor of activated T cells (NFAT), activator protein 1 (AP1) and NF-B transcription factors56, 113 . . .
  114. Klemm, S. et al. The Bcl10-Malt1 complex segregates FcRI-mediated nuclear factorB activation and cytokine production from mast cell degranulation. J. Exp. Med. 203, 337-347 , (2006) .
    • . . . Recently, Klemm et al.114 showed that the caspase-recruitment-domain-containing protein B-cell lymphoma 10 (BCL-10) and the paracaspase mucosa-associated-lymphoid tissue lymphoma-translocation protein 1 (MALT1) are part of this missing link . . .
  115. Ruland, J., Duncan, G. S., Wakeham, A. & Mak, T. W. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19, 749-758 , (2003) .
    • . . . BCL-10 and MALT1 can directly bind to each other, and the two proteins cooperate in the assembly of a complex that mediates signal-specific activation of IKK in T-cell receptor signalling115 . . .
  116. Bruhns, P., Fremont, S. & Daeron, M. Regulation of allergy by Fc receptors. Curr. Opin. Immunol. 17, 662-669 , (2005) .
    • . . . FcRI-mediated mast-cell and basophil effector functions are regulated by inhibitory cell-surface receptors (for a review of inhibitory receptors in allergy see Refs 116,117) . . .
  117. Katz, H. R. Inhibitory receptors and allergy. Curr. Opin. Immunol. 14, 698-704 , (2002) .
    • . . . FcRI-mediated mast-cell and basophil effector functions are regulated by inhibitory cell-surface receptors (for a review of inhibitory receptors in allergy see Refs 116,117) . . .
    • . . . The low-affinity IgG receptor FcRIIB binds allergen-specific IgG and, upon co-aggregation with allergen-specific IgE bound to FcRI, it shuts off FcRI signalling and effector functions in mast cells and basophils117 . . .
    • . . . FcRIIB has a broader tissue distribution than FcRI, including B cells, and can also inhibit responses induced by IgG receptors117 . . .
    • . . . FcRIIB-deficient mice undergo increased FcRI-mediated anaphylaxis, and they have higher immunoglobulin levels (including IgG1, which can cause anaphylactic responses in mice) and reduced nasal allergen tolerance, indicating that FcRIIB also has a suppressive role in the sensitization phase, by inhibiting B-cell receptor activation and by downregulating APC function117, 118. . . .
  118. Watanabe, T. et al. Roles of FcRIIB in nasal eosinophilia and IgE production in murine allergic rhinitis. Am. J. Respir. Crit. Care Med. 169, 105-112 , (2004) .
    • . . . FcRIIB-deficient mice undergo increased FcRI-mediated anaphylaxis, and they have higher immunoglobulin levels (including IgG1, which can cause anaphylactic responses in mice) and reduced nasal allergen tolerance, indicating that FcRIIB also has a suppressive role in the sensitization phase, by inhibiting B-cell receptor activation and by downregulating APC function117, 118. . . .
  119. Bolland, S., Pearse, R. N., Kurosaki, T. & Ravetch, J. V. SHIP modulates immune receptor responses by regulating membrane association of Btk. Immunity 8, 509-516 , (1998) .
    • . . . FcRIIB recruits SHIP through its ITIM to the plasma membrane, where SHIP degrades PtdIns(3,4,5)P3 to PtdIns(4,5)P2, ultimately leading to reduced BTK activation and PLC-mediated Ca2+ mobilization through the aforementioned mechanisms78, 79, 119, 120 . . .
  120. Ono, M., Bolland, S., Tempst, P. & Ravetch, J. V. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcRIIB. Nature 383, 263-266 , (1996) .
    • . . . FcRIIB recruits SHIP through its ITIM to the plasma membrane, where SHIP degrades PtdIns(3,4,5)P3 to PtdIns(4,5)P2, ultimately leading to reduced BTK activation and PLC-mediated Ca2+ mobilization through the aforementioned mechanisms78, 79, 119, 120 . . .
  121. Isnardi, I. et al. Two distinct tyrosine-based motifs enable the inhibitory receptor FcRIIB to cooperatively recruit the inositol phosphatases SHIP1/2 and the adapters Grb2/Grap. J. Biol. Chem. 279, 51931-51938 , (2004) .
    • . . . More recently, it has been postulated that SHIP exerts its inhibitory function through the adaptor docking protein 1 (DOK1), which then binds a RAS GTPase-activating protein that suppresses Ca2+ mobilization and ERK activation through an unknown mechanism121, 122 . . .
  122. Kepley, C. L. et al. Co-aggregation of FcRII with FcRI on human mast cells inhibits antigen-induced secretion and involves SHIP-Grb2-Dok complexes. J. Biol. Chem. 279, 35139-35149 , (2004) .
    • . . . More recently, it has been postulated that SHIP exerts its inhibitory function through the adaptor docking protein 1 (DOK1), which then binds a RAS GTPase-activating protein that suppresses Ca2+ mobilization and ERK activation through an unknown mechanism121, 122 . . .
  123. Cherwinski, H. M. et al. The CD200 receptor is a novel and potent regulator of murine and human mast cell function. J. Immunol. 174, 1348-1356 , (2005) .
    • . . . Antibodies specific for CD200R — a receptor for CD200 (also known as OX2) and an immunoglobulin superfamily member — suppress FcRI-induced mast-cell degranulation and cutaneous anaphylaxis, although the mechanism remains unknown123 . . .
  124. Pasquier, B. et al. Identification of FcRI as an inhibitory receptor that controls inflammation: dual role of FcR ITAM. Immunity 22, 31-42.This is an interesting study that describes a negative effect of FcRI signalling on FcRI signalling , (2005) .
    • . . . The IgA receptor FcRI, which associates with the -chain of FcRI and therefore is an ITAM-containing receptor, can inhibit FcRI-induced mast-cell degranulation124 . . .
    • . . . FcRI-specific antibody Fab fragments downregulate the severity of airway inflammation and bronchial hyper-reactivity in a mouse model of asthma124 . . .
  125. Fleming, T. J. et al. Negative regulation of FcRI-mediated degranulation by CD81. J. Exp. Med. 186, 1307-1314 , (1997) .
    • . . . Antibodies specific for the tetraspanin molecules CD63 and CD81 suppress FcRI-induced mast-cell degranulation125, 126, 127 . . .
  126. Kitani, S., Berenstein, E., Mergenhagen, S., Tempst, P. & Siraganian, R. P. A cell surface glycoprotein of rat basophilic leukemia cells close to the high affinity IgE receptor (FcRI). Similarity to human melanoma differentiation antigen ME491. J. Biol. Chem. 266, 1903-1909 , (1991) .
    • . . . Antibodies specific for the tetraspanin molecules CD63 and CD81 suppress FcRI-induced mast-cell degranulation125, 126, 127 . . .
  127. Nishikata, H., Oliver, C., Mergenhagen, S. E. & Siraganian, R. P. The rat mast cell antigen AD1 (homologue to human CD63 or melanoma antigen ME491) is expressed in other cells in culture. J. Immunol. 149, 862-870 , (1992) .
    • . . . Antibodies specific for the tetraspanin molecules CD63 and CD81 suppress FcRI-induced mast-cell degranulation125, 126, 127 . . .
  128. Hemler, M. E. Specific tetraspanin functions. J. Cell Biol. 155, 1103-1107 , (2001) .
    • . . . Tetraspanins do not have known extracellular ligands or intrinsic signalling capacity, but form membrane-localized networks with each other, other tetraspanins, or other plasma-membrane proteins such as -integrins128, 129 . . .
  129. Boucheix, C. & Rubinstein, E. Tetraspanins. Cell. Mol. Life Sci. 58, 1189-1205 , (2001) .
    • . . . Tetraspanins do not have known extracellular ligands or intrinsic signalling capacity, but form membrane-localized networks with each other, other tetraspanins, or other plasma-membrane proteins such as -integrins128, 129 . . .
  130. Kraft, S. et al. Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo. J. Exp. Med. 201, 385-396 , (2005) .
    • . . . We found recently that CD63-specific antibody potently suppresses in vivo anaphylaxis and inhibits the complementary GAB2–PI3K pathway in mast cells while leaving FcRI-proximal events and Ca2+ mobilization intact130. -Integrin-mediated adhesion of mast cells is known to enhance their secretory function131 . . .
    • . . . An inhibition of positive signals derived from integrins might explain the suppressive effect of the CD63-specific antibody, although the inhibition of adhesion by CD63-specific antibody could also be a secondary effect of targeting the GAB2–PI3K signalling pathway, which is used by integrins and FcRI (Ref. 130) . . .
  131. Hamawy, M. M., Swieter, M., Mergenhagen, S. E. & Siraganian, R. P. Reconstitution of high affinity IgE receptor-mediated secretion by transfecting protein tyrosine kinase pp125FAK. J. Biol. Chem. 272, 30498-30503 , (1997) .
    • . . . We found recently that CD63-specific antibody potently suppresses in vivo anaphylaxis and inhibits the complementary GAB2–PI3K pathway in mast cells while leaving FcRI-proximal events and Ca2+ mobilization intact130. -Integrin-mediated adhesion of mast cells is known to enhance their secretory function131 . . .
  132. Soler, M. et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur. Respir. J. 18, 254-261 , (2001) .
    • . . . Monoclonal antibodies specific for IgE are an effective adjunct therapy for asthma132, 133, 134 . . .
  133. Holgate, S. T., Djukanovic, R., Casale, T. & Bousquet, J. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin. Exp. Allergy 35, 408-416 , (2005) .
    • . . . Monoclonal antibodies specific for IgE are an effective adjunct therapy for asthma132, 133, 134 . . .
  134. Busse, W. et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J. Allergy Clin. Immunol. 108, 184-190 , (2001) .
    • . . . Monoclonal antibodies specific for IgE are an effective adjunct therapy for asthma132, 133, 134 . . .
  135. Casale, T. B. et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. JAMA 286, 2956-2967 , (2001) .
    • . . . Furthermore, there are encouraging results from clinical studies using IgE-specific antibody as a treatment for allergic rhinitis (Ref. 135, among others) and peanut allergy136 . . .
  136. Leung, D. Y. et al. Effect of anti-IgE therapy in patients with peanut allergy. N. Engl. J. Med. 348, 986-993 , (2003) .
    • . . . Furthermore, there are encouraging results from clinical studies using IgE-specific antibody as a treatment for allergic rhinitis (Ref. 135, among others) and peanut allergy136 . . .
    • . . . This novel approach might not only work for cat allergy, but also provides proof of principle for other allergies such as peanut allergies, which can be life-threatening and for which no effective allergen desensitization protocol exists136 . . .
  137. Djukanovic, R. et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am. J. Respir. Crit. Care Med. 170, 583-593 , (2004) .
    • . . . IgE-specific antibody leads to a reduction of free IgE molecules in the sera of allergic individuals, and of FcRI levels on basophils, mast cells and DCs137, 138 . . .
  138. Prussin, C. et al. Omalizumab treatment downregulates dendritic cell FcRI expression. J. Allergy Clin. Immunol. 112, 1147-1154 , (2003) .
    • . . . IgE-specific antibody leads to a reduction of free IgE molecules in the sera of allergic individuals, and of FcRI levels on basophils, mast cells and DCs137, 138 . . .
  139. Belostotsky, R. & Lorberboum-Galski, H. Apoptosis-inducing human-origin Fc-Bak chimeric proteins for targeted elimination of mast cells and basophils: a new approach for allergy treatment. J. Immunol. 167, 4719-4728 , (2001) .
    • . . . A different strategy using a chimeric fusion protein consisting of one IgE C3 domain and the pro-apoptotic molecule BCL-2 antagonist/killer (BAK) selectively targets and destroys FcRI-expressing cells, such as basophils and mast cells, by the induction of apoptosis139. . . .
  140. Strait, R. T., Morris, S. C. & Finkelman, F. D. IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcRIIb cross-linking. J. Clin. Invest. 116, 833-841 , (2006) .
    • . . . Putatively, allergen desensitization could be based on the production of allergen-specific IgG, which intercepts allergens and engages FcRIIB, thereby turning off specific-IgG-expressing B cells and IgE-mediated responses by mast cells and basophils140 . . .
  141. Tam, S. W., Demissie, S., Thomas, D. & Daeron, M. A bispecific antibody against human IgE and human FcRII that inhibits antigen-induced histamine release by human mast cells and basophils. Allergy 59, 772-780 , (2004) .
    • . . . Tam et al.141 used a bispecific antibody consisting of a human-specific IgE Fab' fragment crosslinked to a human-specific FcRII Fab' fragment to suppress IgE–FcRI-induced basophil and mast-cell degranulation . . .
  142. Zhu, D., Kepley, C. L., Zhang, M., Zhang, K. & Saxon, A. A novel human immunoglobulin Fc-Fc bifunctional fusion protein inhibits FcRI-mediated degranulation. Nature Med. 8, 518-521 , (2002) .
    • . . . Zhu et al.142 reported that a chimeric molecule consisting of the Fc portion of human IgG1 fused to the Fc portion of human IgE inhibits FcRI-induced degranulation . . .
  143. Kinet, J. P. A new strategy to counter allergy. N. Engl. J. Med. 353, 310-312 , (2005) .
    • . . . Recently, they refined the chimeric molecule such that it contains human IgG1 Fc and the cat allergen Fel d1 (Refs 143,144) (Fig. 4) . . .
    • . . . Modified with permission from Ref. 143 © (2005) Massachusetts Medical Society. . . .
  144. Zhu, D. et al. A chimeric human-cat fusion protein blocks cat-induced allergy. Nature Med. 11, 446-449.This study uses FcRIIB-mediated inhibition of FcRI signalling to develop a novel targeted strategy for the treatment of allergy , (2005) .
    • . . . Recently, they refined the chimeric molecule such that it contains human IgG1 Fc and the cat allergen Fel d1 (Refs 143,144) (Fig. 4) . . .
    • . . . Zhu and colleagues144 report a strategy that takes advantage of the natural capacity of FcRIIB to inhibit the allergenic activity of FcRI . . .
  145. Kono, H. et al. FcRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum. Mol. Genet. 14, 2881-2892 , (2005) .
    • . . . Although the chimeric molecule by itself cannot activate mast-cell degranulation, it might be harmful in a subgroup of patients in which activating FcRIIA prevails over FcRIIB, as in the case of polymorphisms of the FCGRIIB gene145. . . .
  146. Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875-878 , (2002) .
    • . . . For example, the recent finding of an involvement of mast cells in autoimmune diseases146 raises the question of a possible role for FcRI in some of these diseases . . .
  147. Windmiller, D. A. & Backer, J. M. Distinct phosphoinositide 3-kinases mediate mast cell degranulation in response to G-protein-coupled versus FcRI receptors. J. Biol. Chem. 278, 11874-11878 , (2003) .
  148. Laffargue, M. et al. Phosphoinositide 3-kinase is an essential amplifier of mast cell function. Immunity 16, 441-451 , (2002) .
  149. Ali, K. et al. Essential role for the p110 phosphoinositide 3-kinase in the allergic response. Nature 431, 1007-1011.This is a study that provides convincing evidence for the essential role of p110 PI3K in mast cells and allergy , (2004) .
  150. Cantley, L. C. & Neel, B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl Acad. Sci. USA 96, 4240-4245 , (1999) .
  151. Castells, M. C. et al. gp49B1-v3 interaction inhibits antigen-induced mast cell activation. Nature Immunol. 2, 436-442 , (2001) .
  152. Daheshia, M., Friend, D. S., Grusby, M. J., Austen, K. F. & Katz, H. R. Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J. Exp. Med. 194, 227-234 , (2001) .
  153. Lu-Kuo, J. M., Fruman, D. A., Joyal, D. M., Cantley, L. C. & Katz, H. R. Impaired kit- but not FcRI-initiated mast cell activation in the absence of phosphoinositide 3-kinase p85 gene products. J. Biol. Chem. 275, 6022-6029 , (2000) .
  154. Abramson, J., Licht, A. & Pecht, I. Selective inhibition of the FcRI-induced de novo synthesis of mediators by an inhibitory receptor. EMBO J. 25, 323-334 , (2006) .
  155. Guthmann, M. D., Tal, M. & Pecht, I. A secretion inhibitory signal transduction molecule on mast cells is another C-type lectin. Proc. Natl Acad. Sci. USA 92, 9397-9401 , (1995) .
  156. Licht, A., Pecht, I. & Schweitzer-Stenner, R. Regulation of mast cells' secretory response by co-clustering the Type 1 Fc receptor with the mast cell function-associated antigen. Eur. J. Immunol. 35, 1621-1633 , (2005) .
  157. Ortega, E., Schneider, H. & Pecht, I. Possible interactions between the Fc receptor and a novel mast cell function-associated antigen. Int. Immunol. 3, 333-342 , (1991) .
  158. Xu, R., Abramson, J., Fridkin, M. & Pecht, I. SH2 domain-containing inositol polyphosphate 5'-phosphatase is the main mediator of the inhibitory action of the mast cell function-associated antigen. J. Immunol. 167, 6394-6402 , (2001) .
  159. Colonna, M. et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 186, 1809-1818 , (1997) .
  160. Lienard, H., Bruhns, P., Malbec, O., Fridman, W. H. & Daeron, M. Signal regulatory proteins negatively regulate immunoreceptor-dependent cell activation. J. Biol. Chem. 274, 32493-32499 , (1999) .
  161. Bachelet, I., Munitz, A., Moretta, A., Moretta, L. & Levi-Schaffer, F. The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells. J. Immunol. 175, 7989-7995 , (2005) .
  162. Yotsumoto, K. et al. Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and MAIR-II, regulate mast cell and macrophage activation. J. Exp. Med. 198, 223-233 , (2003) .
  163. Alvarez-Errico, D. et al. IREM-1 is a novel inhibitory receptor expressed by myeloid cells. Eur. J. Immunol. 34, 3690-3701 , (2004) .
  164. Alvarez-Errico, D., Sayos, J. & Lopez-Botet, M. The IREM-1 (CD300f) inhibitory receptor associates with the p85 subunit of phosphoinositide 3-kinase. J. Immunol. 178, 808-816 , (2007) .
Expand