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  • Review Article
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New developments in FcεRI regulation, function and inhibition

Nature Reviews Immunology volume 7, pages 365–378 (2007)Cite this article

Key Points

  • FcεRI is a multimeric immune Fc receptor that binds IgE with high affinity. It has a tetrameric structure on the surface of mast cells and basophils, consisting of one IgE-binding α-chain, one β-chain and two γ-chains for signal transduction. Human antigen-presenting cells and eosinophils express trimeric FcεRI, which lacks the β-chain.

  • Cell-surface expression of FcεRI requires co-expression of γ-chains with the α-chain in humans, and both β- and γ-chains with the α-chain in rodents. Cell-surface expression of FcεRI is positively regulated by its ligand IgE. In humans, cell-surface expression is also regulated positively by the full-length β-chain and negatively by an alternatively spliced truncated β-chain variant.

  • FcεRI is a key structure in IgE-mediated acute- and late-phase allergic reactions. Antigen-independent effects of IgE binding to FcεRI are responsible for increased mast-cell survival and might have a role in contact hypersensitivity and colitis. FcεRI on antigen-presenting cells has a role in efficient IgE-mediated antigen presentation, as well as in the release of pro-inflammatory mediators and in T-helper-cell polarization.

  • FcεRI signal transduction leads to mast-cell and basophil effector responses such as degranulation, and lipid-mediator and cytokine synthesis. It is a complex process that can be separated into a primary pathway mediated by the protein tyrosine kinase LYN, the adaptor linker for activation of T cells (LAT) and Ca2+ mobilization, and a complementary pathway mediated by the protein tyrosine kinase FYN, the adaptor growth-factor-receptor-bound protein 2 (GRB2)-associated binding protein 2 (GAB2) and phosphoinositide 3-kinase (PI3K).

  • The FcεRI Ca2+ activation signal is mediated by inositol-1,4,5-trisphosphate (InsP3), which results in the release of Ca2+ from intracellular stores, followed by the activation of store-operated calcium channels leading to extracellular Ca2+ influx. Sphingosine kinase 2 and its product sphingosine 1-phosphate are also involved in the regulation of extracellular Ca2+ influx.

  • FcεRI signalling and effector functions are under the tight control of inhibitory receptors, which are characterized by immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and by other cell-surface structures such as tetraspanins. The inhibitory receptor FcγRIIB, upon allergen-specific IgG binding and co-ligation with FcεRI, mediates a negative-feedback loop that inhibits FcεRI signalling at the level of the PI3K product phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Enhancement of FcγRIIB-mediated inhibition is of considerable interest for the development of novel therapeutic approaches.

Abstract

The high-affinity Fc receptor for IgE (FcεRI), 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 FcεRI. The first area relates to FcεRI-mediated biological responses that are antigen independent. The second area encompasses the biological relevance of the distinct signalling pathways that are activated by FcεRI; and the third area relates to the accumulated evidence for the tight control of FcεRI signalling through a broad array of inhibitory mechanisms, which are being developed into promising therapeutic approaches.

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Figure 1: Composition of the FcεRI complex (tetrameric and trimeric structures) and biological functions.
Figure 2: Regulation of human FcεRI cell-surface expression by mast cells and basophils.
Figure 3: Simplified model of FcεRI signalling.
Figure 4: Principle of antigen-specific FcεRI inhibition by a chimeric molecule consisting of an important cat allergen and IgG-Fc.

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References

  1. Kinet, J. P. The high-affinity IgE receptor (FcεRI): from physiology to pathology. Annu. Rev. Immunol. 17, 931–972 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Letourneur, O., Sechi, S., Willette-Brown, J., Robertson, M. W. & Kinet, J. P. Glycosylation of human truncated FcεRI α chain is necessary for efficient folding in the endoplasmic reticulum. J. Biol. Chem. 270, 8249–8256 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Wurzburg, B. A., Garman, S. C. & Jardetzky, T. S. Structure of the human IgE–Fc Cε 3–Cε4 reveals conformational flexibility in the antibody effector domains. Immunity 13, 375–385 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Wan, T. et al. The crystal structure of IgE Fc reveals an asymmetrically bent conformation. Nature Immunol. 3, 681–686 (2002).

    Article  CAS  Google Scholar 

  5. Mackay, G. A. et al. Mutagenesis within human FcεRIα differentially affects human and murine IgE binding. J. Immunol. 168, 1787–1795 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Garman, S. C., Kinet, J. P. & Jardetzky, T. S. Crystal structure of the human high-affinity IgE receptor. Cell 95, 951–961 (1998).

    Article  CAS  PubMed  Google Scholar 

  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 FcεRIα. Nature 406, 259–266 (2000). This study describes the interaction of IgE with FcεRI and provides valuable information for the design of inhibitors of IgE binding to FcεRI.

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  9. Hasegawa, S. et al. Functional expression of the high affinity receptor for IgE (FcεRI) in human platelets and its' intracellular expression in human megakaryocytes. Blood 93, 2543–2551 (1999).

    CAS  PubMed  Google Scholar 

  10. Gounni, A. S. et al. Human neutrophils express the high-affinity receptor for immunoglobulin E (FcεRI): role in asthma. FASEB J. 15, 940–949 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  12. Fiebiger, E., Tortorella, D., Jouvin, M. H., Kinet, J. P. & Ploegh, H. L. Cotranslational endoplasmic reticulum assembly of FcεRI controls the formation of functional IgE-binding receptors. J. Exp. Med. 201, 267–277 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Geiger, E. et al. IL-4 induces the intracellular expression of the α chain of the high-affinity receptor for IgE in in vitro-generated dendritic cells. J. Allergy Clin. Immunol. 105, 150–156 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Novak, N. et al. Evidence for a differential expression of the FcεRIγ chain in dendritic cells of atopic and nonatopic donors. J. Clin. Invest. 111, 1047–1056 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Toru, H. et al. Induction of the high-affinity IgE receptor (FcεRI) on human mast cells by IL-4. Int. Immunol. 8, 1367–1373 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Xia, H. Z. et al. Effect of recombinant human IL-4 on tryptase, chymase, and Fcε receptor type I expression in recombinant human stem cell factor-dependent fetal liver-derived human mast cells. J. Immunol. 159, 2911–2921 (1997).

    CAS  PubMed  Google Scholar 

  17. Hasegawa, M. et al. Regulation of the human FcεRIα-chain distal promoter. J. Immunol. 170, 3732–3738 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Maurer, D. et al. Expression of functional high affinity immunoglobulin E receptors (FcεRI) on monocytes of atopic individuals. J. Exp. Med. 179, 745–750 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Sihra, B. S., Kon, O. M., Grant, J. A. & Kay, A. B. Expression of high-affinity IgE receptors (FcεRI) 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).

    Article  CAS  PubMed  Google Scholar 

  21. Semper, A. E. et al. Surface expression of FcεRI 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  23. Ryan, J. J., Kinzer, C. A. & Paul, W. E. Mast cells lacking the high affinity immunoglobulin E receptor are deficient in FcεRIγ messenger RNA. J. Exp. Med. 182, 567–574 (1995).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  27. Blank, U. et al. Complete structure and expression in transfected cells of high affinity IgE receptor. Nature 337, 187–189 (1989).

    Article  CAS  PubMed  Google Scholar 

  28. Blank, U., Ra, C. S. & Kinet, J. P. Characterization of truncated α chain products from human, rat, and mouse high affinity receptor for immunoglobulin E. J. Biol. Chem. 266, 2639–2646 (1991).

    CAS  PubMed  Google Scholar 

  29. Donnadieu, E., Jouvin, M. H. & Kinet, J. P. A second amplifier function for the allergy-associated FcεRI-β subunit. Immunity 12, 515–523 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Donnadieu, E. et al. Competing functions encoded in the allergy-associated FceRIβ gene. Immunity 18, 665–674 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Quarto, R., Kinet, J. P. & Metzger, H. Coordinate synthesis and degradation of the α-, β- and γ-subunits of the receptor for immunoglobulin E. Mol. Immunol. 22, 1045–1051 (1985).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yamaguchi, M. et al. IgE enhances mouse mast cell FcεRI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions. J. Exp. Med. 185, 663–672 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. MacGlashan, D. W., Jr. et al. Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J. Immunol. 158, 1438–1445 (1997).

    CAS  PubMed  Google Scholar 

  35. Lantz, C. S. et al. IgE regulates mouse basophil FcεRI expression in vivo. J. Immunol. 158, 2517–2521 (1997).

    CAS  PubMed  Google Scholar 

  36. Yano, K. et al. Production of macrophage inflammatory protein-1α 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).

    CAS  PubMed  Google Scholar 

  37. Borkowski, T. A., Jouvin, M. H., Lin, S. Y. & Kinet, J. P. Minimal requirements for IgE-mediated regulation of surface FcεRI. J. Immunol. 167, 1290–1296 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  39. Galli, S. J., Maurer, M. & Lantz, C. S. Mast cells as sentinels of innate immunity. Curr. Opin. Immunol. 11, 53–59 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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-α. J. Clin. Invest. 87, 446–453 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Galli, S. J. et al. Mast cells as 'tunable' effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Asai, K. et al. Regulation of mast cell survival by IgE. Immunity 14, 791–800 (2001).

    Article  CAS  PubMed  Google Scholar 

  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 (2001). References 43 and 44 were the first to describe the anti-apoptotic effect of IgE binding to FcεRI.

    Article  CAS  PubMed  Google Scholar 

  45. Kitaura, J. et al. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the FcεRI. Proc. Natl Acad. Sci. USA 100, 12911–12916 (2003). In this paper the authors show that different IgE clones have a different capacity for FcεRI aggregation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  48. Kitaura, J. et al. IgE− and IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion. Blood. 105, 3222–3229 (2005).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  50. Kitaura, J. et al. Early divergence of Fcε receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival. J. Immunol. 173, 4317–4323 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  52. Kraft, S. & Novak, N. Fc receptors as determinants of allergic reactions. Trends Immunol. 27, 88–95 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Maurer, D. et al. Fcε 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).

    CAS  PubMed  Google Scholar 

  54. Maurer, D. et al. Peripheral blood dendritic cells express FcεRI as a complex composed of FcεRIα- and FcεRI γ-chains and can use this receptor for IgE-mediated allergen presentation. J. Immunol. 157, 607–616 (1996).

    CAS  PubMed  Google Scholar 

  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, FcεRI. J. Immunol. 155, 5184–5189 (1995).

    CAS  PubMed  Google Scholar 

  56. Kraft, S., Novak, N., Katoh, N., Bieber, T. & Rupec, R. A. Aggregation of the high-affinity IgE receptor FcεRI on human monocytes and dendritic cells induces NF-κB activation. J. Invest. Dermatol. 118, 830–837 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Kraft, S. et al. Enhanced expression and activity of protein-tyrosine kinases establishes a functional signaling pathway only in FcεRIhigh Langerhans cells from atopic individuals. J. Invest. Dermatol. 119, 804–811 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Reich, K. et al. Engagement of the FcεRI stimulates the production of IL-16 in Langerhans cell-like dendritic cells. J. Immunol. 167, 6321–6329 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Novak, N. et al. FcεRI 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).

    Article  CAS  PubMed  Google Scholar 

  60. Novak, N. et al. A reducing microenvironment leads to the generation of FcεRIhigh inflammatory dendritic epidermal cells (IDEC). J. Invest. Dermatol. 119, 842–849 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Novak, N. et al. Characterization of FcεRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J. Allergy Clin. Immunol. 114, 364–370 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  63. Schroeder, J. T. et al. TLR9- and FcεRI-mediated responses oppose one another in plasmacytoid dendritic cells by down-regulating receptor expression. J. Immunol. 175, 5724–5731 (2005).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bryce, P. J. et al. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20, 381–392 (2004). This is an interesting study on the antigen-independent role of IgE, FcεRI and mast cells in cutaneous hypersensitivity.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  68. Walsh, L. J., Trinchieri, G., Waldorf, H. A., Whitaker, D. & Murphy, G. F. Human dermal mast cells contain and release tumor necrosis factor α, which induces endothelial leukocyte adhesion molecule 1. Proc. Natl Acad. Sci. USA 88, 4220–4224 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Turner, H. & Kinet, J. P. Signalling through the high-affinity IgE receptor FcεRI. Nature 402, B24–B30 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Rivera, J. & Gilfillan, A. M. Molecular regulation of mast cell activation. J. Allergy Clin. Immunol. 117, 1214–1225 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Gilfillan, A. M. & Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nature Rev. Immunol. 6, 218–230 (2006).

    Article  CAS  Google Scholar 

  73. Parravicini, V. et al. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nature Immunol. 3, 741–748 (2002). This is the first study to separate FcεRI signalling into two distinct pathways.

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Saitoh, S. et al. LAT is essential for FcεRI-mediated mast cell activation. Immunity 12, 525–535 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  81. Gu, H. et al. Essential role for Gab2 in the allergic response. Nature 412, 186–190 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  84. Lin, S., Cicala, C., Scharenberg, A. M. & Kinet, J. P. The FcεRIβ subunit functions as an amplifier of FcεRIγ-mediated cell activation signals. Cell 85, 985–995 (1996).

    Article  CAS  PubMed  Google Scholar 

  85. Furumoto, Y., Nunomura, S., Terada, T., Rivera, J. & Ra, C. The FcεRIβ immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IκB kinase phosphorylation and mast cell cytokine production. J. Biol. Chem. 279, 49177–49187 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. On, M., Billingsley, J. M., Jouvin, M. H. & Kinet, J. P. Molecular dissection of the FcRβ signaling amplifier. J. Biol. Chem. 279, 45782–45790 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Xiao, W. et al. Positive and negative regulation of mast cell activation by Lyn via the FcεRI. J. Immunol. 175, 6885–6892 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Parekh, A. B. & Penner, R. Store depletion and calcium influx. Physiol. Rev. 77, 901–930 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Vig, M. et al. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16, 2073–2079 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Peinelt, C. et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nature Cell Biol. 8, 771–773 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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 Fcε receptor I triggering. J. Exp. Med. 190, 1–8 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jolly, P. S. et al. Transactivation of sphingosine-1-phosphate receptors by FcεRI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199, 959–970 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Choi, O. H., Kim, J. H. & Kinet, J. P. Calcium mobilization via sphingosine kinase in signalling by the FcεRI antigen receptor. Nature 380, 634–636 (1996).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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 (doi:10.1016/j.immuni.2007.02.008). This is a well carried out and extensive study clarifying the role of SPHK1and SPHK2 in FcεRI signalling.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  104. Urtz, N. et al. Early activation of sphingosine kinase in mast cells and recruitment to FcεRI are mediated by its interaction with Lyn kinase. Mol. Cell. Biol. 24, 8765–8777 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  106. Tam, S. Y. et al. RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nature Immunol. 5, 844–852 (2004). This study identified a new negative regulator of FcεRI signalling.

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 FcεRI aggregation. Blood 104, 207–214 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhu, M., Liu, Y., Koonpaew, S., Granillo, O. & Zhang, W. Positive and negative regulation of FcεRI-mediated signaling by the adaptor protein LAB/NTAL. J. Exp. Med. 200, 991–1000 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhu, M., Rhee, I., Liu, Y. & Zhang, W. Negative regulation of FcεRI-mediated signaling and mast cell function by the adaptor protein LAX. J. Biol. Chem. 281, 18408–18413 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Kitaura, J. et al. Akt-dependent cytokine production in mast cells. J. Exp. Med. 192, 729–740 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Klemm, S. et al. The Bcl10–Malt1 complex segregates FcεRI-mediated nuclear factorκB activation and cytokine production from mast cell degranulation. J. Exp. Med. 203, 337–347 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  116. Bruhns, P., Fremont, S. & Daeron, M. Regulation of allergy by Fc receptors. Curr. Opin. Immunol. 17, 662–669 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Katz, H. R. Inhibitory receptors and allergy. Curr. Opin. Immunol. 14, 698–704 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Watanabe, T. et al. Roles of FcγRIIB in nasal eosinophilia and IgE production in murine allergic rhinitis. Am. J. Respir. Crit. Care Med. 169, 105–112 (2004).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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 FcγRIIB. Nature 383, 263–266 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Isnardi, I. et al. Two distinct tyrosine-based motifs enable the inhibitory receptor FcγRIIB to cooperatively recruit the inositol phosphatases SHIP1/2 and the adapters Grb2/Grap. J. Biol. Chem. 279, 51931–51938 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Kepley, C. L. et al. Co-aggregation of FcγRII with FcεRI on human mast cells inhibits antigen-induced secretion and involves SHIP–Grb2–Dok complexes. J. Biol. Chem. 279, 35139–35149 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  124. Pasquier, B. et al. Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM. Immunity 22, 31–42 (2005). This is an interesting study that describes a negative effect of FcαRI signalling on FcεRI signalling.

    CAS  PubMed  Google Scholar 

  125. Fleming, T. J. et al. Negative regulation of FcεRI-mediated degranulation by CD81. J. Exp. Med. 186, 1307–1314 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 (FcεRI). Similarity to human melanoma differentiation antigen ME491. J. Biol. Chem. 266, 1903–1909 (1991).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  128. Hemler, M. E. Specific tetraspanin functions. J. Cell Biol. 155, 1103–1107 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Boucheix, C. & Rubinstein, E. Tetraspanins. Cell. Mol. Life Sci. 58, 1189–1205 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  135. Casale, T. B. et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial. JAMA 286, 2956–2967 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Leung, D. Y. et al. Effect of anti-IgE therapy in patients with peanut allergy. N. Engl. J. Med. 348, 986–993 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  138. Prussin, C. et al. Omalizumab treatment downregulates dendritic cell FcεRI expression. J. Allergy Clin. Immunol. 112, 1147–1154 (2003).

    Article  CAS  PubMed  Google Scholar 

  139. Belostotsky, R. & Lorberboum-Galski, H. Apoptosis-inducing human-origin Fcε–Bak chimeric proteins for targeted elimination of mast cells and basophils: a new approach for allergy treatment. J. Immunol. 167, 4719–4728 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. Strait, R. T., Morris, S. C. & Finkelman, F. D. IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcγRIIb cross-linking. J. Clin. Invest. 116, 833–841 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Tam, S. W., Demissie, S., Thomas, D. & Daeron, M. A bispecific antibody against human IgE and human FcγRII that inhibits antigen-induced histamine release by human mast cells and basophils. Allergy 59, 772–780 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Zhu, D., Kepley, C. L., Zhang, M., Zhang, K. & Saxon, A. A novel human immunoglobulin Fcγ–Fcε bifunctional fusion protein inhibits FcεRI-mediated degranulation. Nature Med. 8, 518–521 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Kinet, J. P. A new strategy to counter allergy. N. Engl. J. Med. 353, 310–312 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Zhu, D. et al. A chimeric human–cat fusion protein blocks cat-induced allergy. Nature Med. 11, 446–449 (2005). This study uses FcγRIIB-mediated inhibition of FcεRI signalling to develop a novel targeted strategy for the treatment of allergy.

    Article  CAS  PubMed  Google Scholar 

  145. Kono, H. et al. FcγRIIB 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).

    Article  CAS  PubMed  Google Scholar 

  146. Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875–878 (2002).

    Article  CAS  PubMed  Google Scholar 

  147. Windmiller, D. A. & Backer, J. M. Distinct phosphoinositide 3-kinases mediate mast cell degranulation in response to G-protein-coupled versus FcεRI receptors. J. Biol. Chem. 278, 11874–11878 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Laffargue, M. et al. Phosphoinositide 3-kinase γ is an essential amplifier of mast cell function. Immunity 16, 441–451 (2002).

    Article  CAS  PubMed  Google Scholar 

  149. Ali, K. et al. Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature 431, 1007–1011 (2004). This is a study that provides convincing evidence for the essential role of p110δ PI3K in mast cells and allergy.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Castells, M. C. et al. gp49B1–αvβ3 interaction inhibits antigen-induced mast cell activation. Nature Immunol. 2, 436–442 (2001).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lu-Kuo, J. M., Fruman, D. A., Joyal, D. M., Cantley, L. C. & Katz, H. R. Impaired kit- but not FcεRI-initiated mast cell activation in the absence of phosphoinositide 3-kinase p85α gene products. J. Biol. Chem. 275, 6022–6029 (2000).

    Article  CAS  PubMed  Google Scholar 

  154. Abramson, J., Licht, A. & Pecht, I. Selective inhibition of the FcεRI-induced de novo synthesis of mediators by an inhibitory receptor. EMBO J. 25, 323–334 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Licht, A., Pecht, I. & Schweitzer-Stenner, R. Regulation of mast cells' secretory response by co-clustering the Type 1 Fcε receptor with the mast cell function-associated antigen. Eur. J. Immunol. 35, 1621–1633 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Ortega, E., Schneider, H. & Pecht, I. Possible interactions between the Fcε receptor and a novel mast cell function-associated antigen. Int. Immunol. 3, 333–342 (1991).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Alvarez-Errico, D. et al. IREM-1 is a novel inhibitory receptor expressed by myeloid cells. Eur. J. Immunol. 34, 3690–3701 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Alvarez-Errico, D., Sayos, J. & Lopez-Botet, M. The IREM-1 (CD300f) inhibitory receptor associates with the p85α subunit of phosphoinositide 3-kinase. J. Immunol. 178, 808–816 (2007).

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Pathology, Laboratory of Allergy and Immunology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine 945, 71 Avenue Louis Pasteur, Boston, 02215, Massachusetts, USA

    Stefan Kraft & Jean-Pierre Kinet

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Glossary

Immunoreceptor tyrosine-based activation motif

(ITAM). A structural motif containing tyrosine residues, found in the cytoplasmic tails of several signalling molecules. The motif has the form Tyr-X-X-(Leu/Ile), where X denotes any amino acid, and the tyrosine is a target for phosphorylation by SRC tyrosine kinases and subsequent binding of proteins containing SH2 domains.

SRC homology 2 (SH2) domain

A protein domain that is commonly found in signal-transduction molecules. It interacts specifically with phosphotyrosine-containing peptides.

Immediate-type allergic reaction

The IgE-mediated 'type I' immune reaction that occurs within minutes to a few hours of allergen exposure, which can be localized (for example, acute rhinoconjunctivitis, acute asthma attack, urticaria and food allergy) or systemic (anaphylaxis). In this reaction, preformed IgE antibodies bound to FcεRI on mast cells and basophils are crosslinked by allergen, which leads to the release of preformed mediators (for example, histamine), proteolytic enzymes and proteoglycans, as well as lipid mediators and cytokines. These events cause vasodilatation, oedema, fever and bronchoconstriction, leading to the aforementioned clinical conditions.

Late-phase allergic reactions

These reactions are the long-term consequence of mast-cell and/or basophil activation by IgE and allergen. Clinical manifestations can be measurable (visible) two or more hours after allergen exposure but might appear much later. These manifestations peak at 6–9 hours after allergen exposure and have resolved by 24–48 hours. The reactions are characterized by oedema and the infiltration of T helper 2 cells and eosinophils. Tissue reactions are characterized by oedema, pain, warmth and erythema (redness). Reactions in the lungs are characterized by airway narrowing and mucus hypersecretion.

Anaphylaxis

The generalized release of histamine and other inflammatory mediators following systemic induction of mast-cell degranulation by an allergen. Anaphylaxis can cause bronchospasm, cardiovascular collapse and death.

Plasmacytoid DCs

A subset of DCs that was named 'plasmacytoid' because their appearance under the microscope is similar to that of plasmablasts. In humans, these DCs can be derived from lineage-negative haematopoietic stem cells from the peripheral blood. These DCs are the main producers of type I interferons in response to viral infections. They express high levels of CD123 (IL-3 receptor α-chain), high levels of MHC class II, and lack expression of CD11c.

Delayed-type hypersensitivity

(DTH). A cellular immune response to antigen that develops over ∼24–72 hours with the infiltration of T cells and monocytes, and is dependent on the production of T-helper-1-specific cytokines.

Knockdown

Reduction of expression of a gene of interest, for example through the use of short oligonucleotides, such as small interfering RNA or morpholino oligonucleotides, with sequence complementarity to a gene or a messenger RNA.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several inhibitory receptors, such as FcγRIIB and paired immunoglobulin-like receptor B (PIRB). The prototype six-amino-acid ITIM sequence is (Ile/Val/Leu/Ser)-X-Tyr-X-X-(Leu/Val), where X denotes any amino acid. Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family tyrosine kinases, which provides a docking site for the recruitment of cytoplasmic phosphatases that have an SRC homology 2 (SH2) domain.

Allergen desensitization

Activation of the immune system with increasing doses of allergens, to which a specific individual is allergic. Allergen desensitization is being used for allergies to pollen, mites, cats and insect stings. The therapy usually takes 6 months to 1 year to become effective and injections are usually required for several years.

Tetraspanins

A family of transmembrane proteins that have four transmembrane domains and two extracellular domains of different sizes, which are defined by several conserved amino acids in the transmembrane domains. Their function is not known clearly, but they seem to interact with many other transmembrane proteins and to form large multimeric protein networks.

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Kraft, S., Kinet, JP. New developments in FcεRI regulation, function and inhibition. Nat Rev Immunol 7, 365–378 (2007). https://doi.org/10.1038/nri2072

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