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Targeting the IgE molecule in allergic and asthmatic diseases: Review of the IgE molecule and clinical efficacy

2005; Elsevier BV; Volume: 115; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2004.12.1124

ISSN

1097-6825

Autores

Jill A. Poole, Ponpan Matangkasombut, Lanny J. Rosenwasser,

Tópico(s)

Food Allergy and Anaphylaxis Research

Resumo

Diseases such as allergic asthma and rhinitis continue to increase in the United States, affecting millions of persons.1Beasley R. Crane J. Lai C.K. Pearce N. Prevalence and etiology of asthma.J Allergy Clin Immunol. 2000; 105: S466-S472Abstract Full Text Full Text PDF PubMed Google Scholar It is well established that allergy contributes to the pathogenesis of most asthma, especially in children and young adults.2Burrows B. Martinez F.D. Halonen M. Barbee R.A. Cline M.G. Association of asthma with serum IgE levels and skin-test reactivity to allergens.N Engl J Med. 1989; 320: 271-277Crossref PubMed Scopus (1433) Google Scholar Despite current therapy (eg, inhaled corticosteroids, antileukotrienes, and bronchodilators), patients with moderate-to-severe asthma continue to remain symptomatic and experience frequent exacerbations of disease requiring oral corticosteroids, emergency department treatments, and hospitalizations. Allergic diseases are traditionally referred to as immediate or type 1 hypersensitivity reactions, with IgE as a critical factor. IgE is involved in allergic inflammation, especially in the early-phase response, but it might also be involved in the late-phase allergic response. A direct correlation between serum IgE levels and asthma exists.2Burrows B. Martinez F.D. Halonen M. Barbee R.A. Cline M.G. Association of asthma with serum IgE levels and skin-test reactivity to allergens.N Engl J Med. 1989; 320: 271-277Crossref PubMed Scopus (1433) Google Scholar, 3Sunyer J. Anto J.M. Sabria J. Roca J. Morell F. Rodriguez-Roisin R. et al.Relationship between serum IgE and airway responsiveness in adults with asthma.J Allergy Clin Immunol. 1995; 95: 699-706Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar As log IgE values increase, asthma prevalence increases linearly, even in patients who are categorized as having nonallergic asthma.2Burrows B. Martinez F.D. Halonen M. Barbee R.A. Cline M.G. Association of asthma with serum IgE levels and skin-test reactivity to allergens.N Engl J Med. 1989; 320: 271-277Crossref PubMed Scopus (1433) Google Scholar In addition, there is a significant, although lower, association in allergic rhinitis with IgE levels and positive skin test reactivity to pollens.2Burrows B. Martinez F.D. Halonen M. Barbee R.A. Cline M.G. Association of asthma with serum IgE levels and skin-test reactivity to allergens.N Engl J Med. 1989; 320: 271-277Crossref PubMed Scopus (1433) Google Scholar Recent advances in our understanding of the role of IgE in allergic inflammation have led to the development of an mAb to IgE that reduces IgE levels, thereby reducing allergic inflammation. This review aims to provide an overview of the basic science of the IgE molecule and the clinical efficacy of anti-IgE therapy in allergic and asthmatic diseases. In 1967, Ishizaka and Ishizaka4Ishizaka K. Ishizaka T. Identification of gamma-E-antibodies as a carrier of reaginic activity.J Immunol. 1967; 99: 1187-1198PubMed Google Scholar described a new antibody isotype, the IgE molecule. Since its discovery, IgE has been shown to be important in allergic diseases, as well as in immune responses to parasitic infection.5Yazdanbakhsh M. van den Biggelaar A. Maizels R.M. Th2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease.Trends Immunol. 2001; 22: 372-377Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 6Maizels N. Yin outwits yang at the IgE locus.Nat Immunol. 2003; 4: 7-8Crossref PubMed Scopus (6) Google Scholar, 7Maizels R.M. Yazdanbakhsh M. Immune regulation by helminth parasites: cellular and molecular mechanisms.Nat Rev Immunol. 2003; 3: 733-744Crossref PubMed Scopus (894) Google Scholar The IgE molecule is composed of 2 light chains and 2 heavy chains. The overall structure is similar to other classes of antibodies, but it is distinguished by the sequence of the ε-heavy chain constant region. As opposed to IgG, which contains 3 heavy chains, IgE contains 4 heavy chain constant domains (Cε1-Cε4).8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar The additional domain (Cε2) replaces the hinge region.9Sutton B.J. Gould H.J. The human IgE network.Nature. 1993; 366: 421-428Crossref PubMed Scopus (480) Google Scholar The allergen-binding site is located on the variable regions of the heavy and light chains. The Fc fragment of the IgE molecule is able to bind to 2 types of immunoglobulin Fc receptors, the high-affinity IgE receptor (FCεRI) and the low-affinity IgE receptor (FCεRII or CD23). The binding site for both the FCεRI and FCεRII is located in proximity to but on different parts of the Cε3 domain of the IgE molecule.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar, 10Vercelli D. Helm B. Marsh P. Padlan E. Geha R.S. Gould H. The B-cell binding site on human immunoglobulin E.Nature. 1989; 338: 649-651Crossref PubMed Scopus (128) Google Scholar, 11Nissim A. Schwarzbaum S. Siraganian R. Eshhar Z. Fine specificity of the IgE interaction with the low and high affinity Fc receptor.J Immunol. 1993; 150: 1365-1374PubMed Google Scholar, 12Presta L. Shields R. O'Connell L. Lahr S. Porter J. Gorman C. et al.The binding site on human immunoglobulin E for its high affinity receptor.J Biol Chem. 1994; 269: 26368-26373Abstract Full Text PDF PubMed Google Scholar IgE molecules are mainly produced by plasma cells in the mucosa-associated lymphoid tissue.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar Most of the IgE that is produced is bound by FcεRI expressed by mast cells and basophils.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar In nonallergic individuals the level of plasma IgE is 10,000- to 50,000-fold less than that of plasma IgG. Even in highly atopic individuals, the level of plasma IgE remains less than 1000-fold that of plasma IgG.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar The dimeric Fc fragment of the IgE antibody has full binding activity for FcεRI.14Basu M. Hakimi J. Dharm E. Kondas J.A. Tsien W.H. Pilson R.S. et al.Purification and characterization of human recombinant IgE-Fc fragments that bind to the human high affinity IgE receptor.J Biol Chem. 1993; 268: 13118-13127Abstract Full Text PDF PubMed Google Scholar, 15Keown M.B. Ghirlando R. Young R.J. Beavil A.J. Owens R.J. Perkins S.J. et al.Hydrodynamic studies of a complex between the Fc fragment of human IgE and a soluble fragment of the Fc epsilon RI alpha chain.Proc Natl Acad Sci U S A. 1995; 92: 1841-1845Crossref PubMed Scopus (32) Google Scholar, 16Keown M.B. Ghirlando R. Mackay G.A. Sutton B.J. Gould H.J. Basis of the 1:1 stoichiometry of the high affinity receptor Fc epsilon RI-IgE complex.Eur Biophys J. 1997; 25: 471-476Crossref PubMed Scopus (29) Google Scholar IgE antibody binds to FcεRI in the absence of antigen, and thus the receptor adopts the antigenic specificity of the prevalent IgE repertoire.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar Cross-linking of the receptor through antigen-antibody interaction leads to the initiation of a signal transduction cascade and downstream effects.17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar The major regulatory step in IgE synthesis is the regulation of IgE class-switch recombination. A comprehensive review of this subject has recently been done.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar Common for all isotype switching are the germline transcription of CH genes and the induction of activation-induced cytidine deaminase (AID) expression.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar, 14Basu M. Hakimi J. Dharm E. Kondas J.A. Tsien W.H. Pilson R.S. et al.Purification and characterization of human recombinant IgE-Fc fragments that bind to the human high affinity IgE receptor.J Biol Chem. 1993; 268: 13118-13127Abstract Full Text PDF PubMed Google Scholar, 15Keown M.B. Ghirlando R. Young R.J. Beavil A.J. Owens R.J. Perkins S.J. et al.Hydrodynamic studies of a complex between the Fc fragment of human IgE and a soluble fragment of the Fc epsilon RI alpha chain.Proc Natl Acad Sci U S A. 1995; 92: 1841-1845Crossref PubMed Scopus (32) Google Scholar, 16Keown M.B. Ghirlando R. Mackay G.A. Sutton B.J. Gould H.J. Basis of the 1:1 stoichiometry of the high affinity receptor Fc epsilon RI-IgE complex.Eur Biophys J. 1997; 25: 471-476Crossref PubMed Scopus (29) Google Scholar, 17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar, 18Chaudhuri J. Tian M. Khuong C. Chua K. Pinaud E. Alt F.W. Transcription-targeted DNA deamination by the AID antibody diversification enzyme.Nature. 2003; 422: 726-730Crossref PubMed Scopus (610) Google Scholar IgE class-switch recombination is accomplished through 2 pathways, the classical and alternative pathways.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar The classical or T cell–dependent pathway of IgE synthesis involves the presence of IL-4, IL-13, or both during ligation of the CD40-CD40 ligand (CD154) that leads to the induction of Cε germline transcription and induction of AID. In contrast, the alternative pathway does not require T-cell interaction but does require the presence of IL-4. For example, corticosteroids can induce IgE synthesis in the presence of IL-4 by upregulating CD40 ligand expression on T and B cells.19Jabara H.H. Ahern D.J. Vercelli D. Geha R.S. Hydrocortisone and IL-4 induce IgE isotype switching in human B cells.J Immunol. 1991; 147: 1557-1560PubMed Google Scholar, 20Jabara H.H. Brodeur S.R. Geha R.S. Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching.J Clin Invest. 2001; 107: 371-378Crossref PubMed Scopus (64) Google Scholar A second pathway to induce class switching to IgE exists when B cell–activating factor belonging to the TNF family and a proliferation-inducing ligand expressed on monocytes and dendritic cells (DCs) bind to their respective receptors on B cells in the presence of IL-4.21Litinskiy M.B. Nardelli B. Hilbert D.M. He B. Schaffer A. Casali P. et al.DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL.Nat Immunol. 2002; 3: 822-829Crossref PubMed Scopus (1019) Google Scholar In addition, EBV can nonspecifically induce IgE class switching, which is likely due to CD40 mimicry by virus-encoded latent membrane protein 1.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar, 22Jabara H.H. Schneider L.C. Shapira S.K. Alfieri C. Moody C.T. Kieff E. et al.Induction of germ-line and mature C epsilon transcripts in human B cells stimulated with rIL-4 and EBV.J Immunol. 1990; 145: 3468-3473PubMed Google Scholar A regulatory protein in the classical complement pathway, C4 binding protein has been shown to mimic the CD40 ligand.23Brodeur S.R. Angelini F. Bacharier L.B. Blom A.M. Mizoguchi E. Fujiwar A. et al.C4b-binding protein (C4BP) activates B cells through the CD40 receptor.Immunity. 2003; 18: 837-848Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar In the presence of IL-4, the interaction between this molecule and CD40 will induce transcription of germline Cε and expression of AID, thereby causing class switch to IgE.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar, 23Brodeur S.R. Angelini F. Bacharier L.B. Blom A.M. Mizoguchi E. Fujiwar A. et al.C4b-binding protein (C4BP) activates B cells through the CD40 receptor.Immunity. 2003; 18: 837-848Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar IgE class switching is negatively regulated by several mechanisms. Cytokines, such as IFN-γ and IL-21, inhibit IgE class switching, perhaps because of inhibition of the development of TH2 cells, the suppression of Cε germline transcription, or both.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar Various B-cell surface receptors (B-cell receptor, CD45, CTLA4, and CD23) inhibit IgE class switching through different mechanisms, such as altering the signal transduction cascade that leads to IgE class-switch recombination.13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar Several transcription factors, such as B-cell lymphoma 6 and inhibitor of DNA binding 2, can also inhibit IgE class switching. B-cell lymphoma 6 competitively inhibits signal transducer and activator of transcription 6 binding, thus repressing IL-4–induced Cε germline transcripts.24Harris M.B. Chang C.C. Berton M.T. Danial N.N. Zhang J. Kuehner D. et al.Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching.Mol Cell Biol. 1999; 19: 7264-7275Crossref PubMed Google Scholar Inhibitor of DNA binding 2 can also block Cε germline transcripts by skewing the cytokine profile to a TH1-type cytokine profile.25Sugai M. Gonda H. Kusunoki T. Katakai T. Yokota Y. Shimizu A. Essential role of Id2 in negative regulation of IgE class switching.Nat Immunol. 2003; 4: 25-30Crossref PubMed Scopus (109) Google Scholar FCεRI belongs to an antigen receptor superfamily that includes the B-cell receptor, T-cell receptor, and several IgG Fc receptor isotypes.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar As the name implies, the high-affinity IgE receptor binds with a high affinity to the IgE molecule, with an equilibrium dissociation constant or binding affinity of 10−9 to 10−10 M.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar FcεRI consists of 4 transmembrane polypeptides with the composition αβγ2.9Sutton B.J. Gould H.J. The human IgE network.Nature. 1993; 366: 421-428Crossref PubMed Scopus (480) Google Scholar This tetramer structure is only expressed on mast cells and basophils. An alternate form, an αγ2 trimer,17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar is expressed on a variety of other hematopoietic cell lines, including eosinophils,26Gounni A.S. Lamkhioued B. Delaporte E. Dubost A. Kinet J.P. Capron A. et al.The high-affinity IgE receptor on eosinophils: from allergy to parasites or from parasites to allergy?.J Allergy Clin Immunol. 1994; 94: 1214-1216Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar DCs, activated macrophages, and Langerhans cells.27Bieber T. de la Salle H. Wollenberg A. Hakimi J. Chizzonite R. Ring J. et al.Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI).J Exp Med. 1992; 175: 1285-1290Crossref PubMed Scopus (426) Google Scholar, 28Wang B. Rieger A. Kilgus O. Ochiai K. Maurer D. Fodinger D. et al.Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI.J Exp Med. 1992; 175: 1353-1365Crossref PubMed Scopus (335) Google Scholar, 29Maurer D. Ebner C. Reininger B. Fiebiger F. Kraft D. Kinet J.P. et al.The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation.J Immunol. 1995; 154: 6285-6290PubMed Google Scholar, 30Novak N. Kraft S. Bieber T. Unraveling the mission of FcepsilonRI on antigen-presenting cells.J Allergy Clin Immunol. 2003; 111: 38-44Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar The extracellular portion of the α chain binds to the Cε3 of the IgE molecule.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar, 17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar The β and γ chains are required for receptor transmembrane insertion and intracellular signal transduction.17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar Although the α subunit is highly N-glycosylated, glycosylation is not necessary for IgE binding.31Robertson M.W. Phage and Escherichia coli expression of the human high affinity immunoglobulin E receptor alpha-subunit ectodomain. Domain localization of the IgE-binding site.J Biol Chem. 1993; 268: 12736-12743Abstract Full Text PDF PubMed Google Scholar The extracellular region of the α chain contains 2 immunoglobulin domains (D1 and D2).17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar The crystal structure of the Fc fragment of human IgE bound to FcεRIα is known.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar The 2 immunoglobulin domains of FcγRIα are positioned at an acute angle to one another, forming a convex surface at the top of the molecule, and a marked cleft is enclosed by the 2 globular immunoglobulin domains.17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar Through the discovery of the crystal structure, it was revealed that one receptor binds one dimeric IgE-Fc molecule asymmetrically through interactions at 2 sites.32Garman S.C. Kinet J.P. Jardetzky T.S. Crystal structure of the human high-affinity IgE receptor.Cell. 1998; 95: 951-961Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar This is important because the interaction of one receptor with the IgE-Fc blocks the binding of a second receptor.17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar Two interaction sites exist for the IgE-Fc on the receptor surface, which explains how a 1:1 complex between antibody and receptor is formed.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar, 33Keown M.B. Henry A.J. Ghirlando R. Sutton B.J. Gould H.J. Thermodynamics of the interaction of human immunoglobulin E with its high-affinity receptor Fc epsilon RI.Biochemistry. 1998; 37: 8863-8869Crossref PubMed Scopus (30) Google Scholar The 2 Cε3 domains bind asymmetrically to distinct sites on the receptor: one is formed by the C-C′ loop in the receptor D2 domain, and the second is involved in the 4 solvent-exposed tryptophans (D1-D2 interface).8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar, 17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar Cross-linking of FcεRI with a multivalent antigen is critical in triggering cellular events, which include the release of mediators (histamine, newly synthesized leukotrienes, and IL-4).8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar, 13Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch recombination.Nat Rev Immunol. 2003; 3: 721-732Crossref PubMed Scopus (344) Google Scholar, 17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar Whereas other receptor types (hormone or cytokine receptors) dimerize and signal after binding a well-defined ligand, these Fc receptor types act as adaptors between highly variable antigen-binding sites and the intracellular signal transduction machinery.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar Flexible linkers between the antibody Fab and Fc arms appear necessary to accommodate the variable structures of Fab-antigen complexes and the need to cross-link 2 or more receptors to initiate signaling.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar, 17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar, 34Metzger H. The receptor with high affinity for IgE.Immunol Rev. 1992; 125: 37-48Crossref PubMed Scopus (222) Google Scholar, 35Kinet J.P. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology.Annu Rev Immunol. 1999; 17: 931-972Crossref PubMed Scopus (850) Google Scholar Therefore multivalent antigens can promote colocalization of receptors but cannot form specific contacts that dimerize FcRs.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar However, it remains unclear whether colocalization leads to a specific signaling structure or simply to membrane relocalization of the complex.8Garman 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 FcepsilonRI alpha.Nature. 2000; 406: 259-266Crossref PubMed Scopus (299) Google Scholar The FcεRI α chains do not aggregate in the absence of antigen, probably because of extensive glycosylation.17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar This glycosylation at the surfaces of the α chain prevents premature aggregation and permits interaction with the synthetic machinery.17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar, 36Letourneur O. Sechi S. Willette-Brown J. Robertson M.W. Kinet J.P. Glycosylation of human truncated Fc epsilon RI alpha chain is necessary for efficient folding in the endoplasmic reticulum.J Biol Chem. 1995; 270: 8249-8256Crossref PubMed Scopus (90) Google Scholar However, binding of multivalent antigen overcomes the intrinsic resistance of the α chains to interaction.17Turner H. Kinet J.P. Signalling through the high-affinity IgE receptor Fc epsilonRI.Nature. 1999; 402: B24-B30Crossref PubMed Scopus (616) Google Scholar Activation of the trimeric FcεRI on other leukocytes, such as monocytes, might also contribute to the pathogenesis of allergic diseases.37Saini S.S. MacGlashan D. How IgE upregulates the allergic response.Curr Opin Immunol. 2002; 14: 694-697Crossref PubMed Scopus (47) Google Scholar For example, activation of FcεRI prevents apoptosis of monocytes by induction of the anti-apoptotic ligands Bcl-2 and Bcl-xL and also protects from CD95 Fas-mediated apoptosis.37Saini S.S. MacGlashan D. How IgE upregulates the allergic response.Curr Opin Immunol. 2002; 14: 694-697Crossref PubMed Scopus (47) Google Scholar In addition, IL-10 production occurs after cross-linking FcεRI on monocytes.38Novak N. Bieber T. Katoh N. Engagement of Fc epsilon RI on human monocytes induces the production of IL-10 and prevents their differentiation in dendritic cells.J Immunol. 2001; 167: 797-804PubMed Google Scholar In monocyte cultures with IL-4 and GM-CSF, cross-linking FcεRI alters monocyte differentiation toward a macrophage species and away from a DC phenotype.38Novak N. Bieber T. Katoh N. Engagement of Fc epsilon RI on human monocytes induces the production of IL-10 and prevents their differentiation in dendritic cells.J Immunol. 2001; 167: 797-804PubMed Google Scholar Also, activation of FcεRI in atopic donors with high expression of FcεRI leads to the downstream activation of the proinflammatory transcription factor nuclear factor κB.39Kraft S. Katoh N. Novak N. Koch S. Bieber T. 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Lichtenstein L.M. et al.Down-regulation of human basophil IgE and FC epsilon RI alpha surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo.J Immunol. 1999; 162: 5624-5630PubMed Google Scholar This has been found true in clinical trials in which a reduction in serum IgE levels led to a reduction in FcεRI on circulating basophils.43Prussin C. Griffith D.T. Boesel K.M. Lin H. Foster B. Casale T.B. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression.J Allergy Clin Immunol. 2003; 112: 1147-1154Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar IgE is able to upregulate FcεRI expression by a number of mechanisms. IgE binding stabilizes the receptor at the cell surface, which prevents receptor internalization and degradation. In addition, IgE uses a preformed pool of receptors comprising recycled and recently synthesized receptors.44Borkowski T.A. Jouvin M.H. Lin S.Y. Kinet J.P. 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