The spreading epidemic of allergies and asthma has heightened interest in IgE, the central player in the allergic response. The activity of IgE is associated with a network of proteins; prominent among these are its two principal receptors, FcRI (high-affinity Fc receptor for IgE) and CD23, as well as galectin-3 and several co-receptors for CD23, notably CD21 and various integrins. Here, we review recent progress in uncovering the structures of these proteins and their complexes, and in our understanding of how IgE exerts its effects and how its expression is regulated. The information that has emerged suggests new therapeutic directions for combating allergic disease.
Summary
Remarkable progress has been made in recent years on the structural determination of proteins in the IgE network and on the functions and regulation of IgE. This is beginning to feed into IgE-targeted therapies for allergy.
The shape of the IgE molecule differs dramatically from that of IgG. X-ray and nuclear magnetic resonance studies have also revealed conformational changes that occur on IgE binding to its high-affinity receptor Fc
RI (high-affinity Fc receptor for IgE) on mast cells and antigen-presenting cells, events that lead, respectively, to sensitization (and the immediate hypersensitivity reaction) and the facilitation of allergen presentation.
The structural data also provide clues to the unique nature of the high-affinity IgE–Fc
RI interaction, and indicate possibilities for blocking the interaction; validation of IgE as a target is demonstrated by the success of the IgE-specific monoclonal antibody omalizumab in the treatment of asthma.
The presence of an unusually long extracellular membrane-proximal domain in membrane IgE may also determine its ability to act as an antigen receptor on B cells and to respond to particular antigens (allergens).
The trimeric structure of the C-type lectin, low-affinity IgE receptor CD23, and its susceptibility to cleavage by ADAM10 (a disintegrin and metalloproteinase 10) at the cell surface, provide important clues to the mechanism of IgE homeostasis.
CD23 has multiple ligands, including IgE, CD21 and various integrins, enabling it to carry out several other functions, including IgE-dependent antigen presentation and cellular cytotoxicity.
IgE is transported to mucosal tissues by CD23 and is also synthesized by the resident B cells. Its concentration is maintained in the tissue by the number of mast cells that express Fc
RI at high levels and the slow rate of dissociation of IgE from Fc
RI.
Class switching to IgE and affinity maturation of the antibodies occur in mucosal tissues, and this may limit the ability of IgE antibodies to mediate systemic anaphylaxis.
Various mechanisms contrive to suppress the production of IgE synthesis to tolerable levels, as well as limiting its anatomical distribution. Some mechanisms operate at the level of class-switch recombination, others at the level of survival of the IgE-switched cells.
IgE transport in both directions through the gastrointestinal epithelium may be involved in early sensitization to allergens. Studies of the mechanism of early sensitization may suggest means of preventing the development of allergic disease.
Small molecule inhibitors of the IgE–Fc
RI interaction may supersede IgE-specific antibodies, but the combination of this approach with immunotherapy may be required for more effective therapeutic intervention in allergy and asthma.
Forty years ago, in February 1968, the name of the fifth and final class of human antibody, IgE, was officially adopted at a meeting under the auspices of the World Health Organization Immunoglobulin Reference Laboratory, held in Lucerne, Switzerland. The year before this, a series of papers had been published marking the culmination of studies by the Ishizakas in the USA, Bennich and Johansson in Sweden, and Humphrey and Stanworth in the UK. These established unequivocally that this new class of antibody was the factor capable of transferring sensitivity to allergens. The history of the discovery of IgE has been related by Stanworth
1.
IgE is thought to have evolved in mammals as the first line of defence against pathogens
2. But modern civilization has engendered a large increase in the cost:benefit ratio of this mechanism, such that a large and increasing proportion of the population — now around one in three — suffers from allergies
3. It has emerged that IgE acts as part of a protein network
4, which includes its two principal receptors,
FcRI (high-affinity Fc receptor for IgE) and
CD23, as well as the IgE- and Fc
RI-binding protein
galectin-3. In addition, the function of CD23 is extended by several co-receptors. These comprise the complement receptors
CD21 (also known as CR2),
M2-integrin (otherwise known as CD18/CD11b or CR3) and
X2-integrin (also known as CD18/CD11c or CR4); the vitronectin receptor (also known as
V3-integrin); and
V5-integrin. Here, we review the remarkable progress of the past several years on the structural determination of these proteins and of the complexes formed between them, and on the functions and regulation of IgE in the context of the extended protein network. The success of the IgE-specific antibody, omalizumab (Xolair; Novartis Pharmaceuticals Ltd), in the treatment of asthma and other allergic diseases demonstrates the virtues of targeting IgE for therapy
5. We expect that a deeper understanding of the IgE network will lead to a new generation of IgE-targeted therapies.
Structures and interactions in the IgE network
The IgE molecule. IgE shares the same basic molecular architecture as antibodies of other classes, with two identical heavy chains and two identical light chains, but, as illustrated in
Fig. 1, the heavy
-chain contains one more domain than the heavy
-chain of IgG. The pair of C
3 and C
4 domains are homologous in sequence, and similar in quaternary structure, to the pair of C
2 and C
3 domains of IgG, so that it is the pair of C
2 domains, located in the position equivalent to that occupied by the flexible hinge region of IgG, that is the most obvious distinguishing feature of IgE. Initially it was thought that this 'extra' domain pair might simply act as a spacer between the antigen-binding Fab 'arms' and the C
3–C
4 part of the Fc region (Fc
3-4), but elegant studies using
fluorescence resonance energy transfer (FRET) determined that the distance between the N- and C-termini of the molecule was less than half that expected for an extended Y-shaped structure (6.9 Ã… compared with 17.5 Ã…)
6; furthermore, this was also true for the IgE molecule bound to Fc
RI (Refs
6,
7).
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FIGURE 1 | The domain structures of IgE and IgG.
Schematic representations of the polypeptide and domain structures of human IgE and IgG1, showing the intra- and inter-domain disulphide bridges, and the sites of N-linked glycosylation.
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When the crystal structure of the complete IgE-Fc, including the C
2 domains, was determined, the molecule was found to be even more acutely bent than had been anticipated, with the C
2 domains folded back and making extensive contact with the C
3 domains, and even touching the C
4 domains
8 (
Fig. 2a, b). The structure was entirely consistent with X-ray and neutron scattering data obtained in solution
9, showing that this compact, bent conformation was indeed its native structure, and was markedly different from the extended and flexible structure of IgG
7. Nevertheless, within this overall compact structure, IgE displays considerable conformational flexibility both in tertiary (intra-domain) and quaternary (inter-domain) structure. Comparison of crystal structures of Fc
3-4 alone and in complex with Fc
RI (Ref.
10) (see below) show that the C
3 domains can adopt 'closed' (
Fig. 2c) or 'open' (
Fig. 2d) conformations by rotating relative to C
4. The asymmetrically bent IgE-Fc (
Fig. 2a, b), with its C
2 domains packed against the two C
3 domains, has one C
3 domain in the 'open' conformation, while the other is 'closed', and this structural asymmetry explains a key feature of the interaction with Fc
RI, as we discuss later.
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FIGURE 2 | The structures of IgE-Fc fragments.
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These structural features of IgE-Fc must also apply to the membrane form of the IgE molecule, which together with the signalling chains Ig
and Ig
constitutes the receptor for antigen on B cells committed to IgE synthesis. Each heavy chain of all membrane IgE molecules contains an additional
extracellular membrane-proximal domain (EMPD) between the C
4 domain and the transmembrane sequence, although there are at least two isoforms with EMPDs of different length,
short (14 amino acids) and
long (66 amino acids)
11. Nothing is known of the three-dimensional structure of the EMPDs, which contain inter-
-chain disulphide bridges, nor the way in which IgE and its Fab regions are presented at the cell surface, but the two isoforms associate with different glycoforms of Ig
and, together with other accessory proteins, form functionally distinct antigen receptors
12. Whatever the position of the IgE molecule in this complex, the binding site for Fc
RI is accessible to receptors expressed on another cell surface; the implications of this interaction for allergic disease have yet to be explored
13.
The high-affinity receptor FcRI and its interaction with IgE. Fc
RI is expressed as an
2 tetramer on mast cells and basophils, and as an
2 trimer on human but not mouse
antigen-presenting cells (APCs), monocytes, eosinophils, platelets and smooth-muscle cells, but its distribution is even wider than this
14, 15. The two extracellular domains of the
-chain (sFc
RI
) contain the IgE binding function, whereas the signalling motifs (
immunoreceptor tyrosine-based activation motifs (ITAMs)) are located in the intracellular sequences of the
- and
-chains. Although the quaternary arrangement of the chains is not known, X-ray analyses of sFc
RI
in several different crystal forms have revealed that the two domains are folded back on each other exposing a hydrophobic 'ridge' (
Fig. 3a) that was subsequently found to be the IgE binding site. Part of this ridge is formed by the CC' loop of the
2 domain, a segment that strikingly is the only region to exhibit conformational variation among the different unliganded sFc
RI
structures
16, 17.
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FIGURE 3 | The structure of the FcRI -chain and its complex with IgE.
a | The structure of the extracellular domains of the FcRI -chain (Protein Data Bank (PDB) ID: 1F6A), taken from the crystal structure of the Fc3-4–FcRI -chain complex, with the superimposed structure of free FcRI -chain (PDB ID: 1J87) showing only the region (shown in red) in which the structures differ. This is the CC' loop region, which displays conformational flexibility even within uncomplexed structures determined in different crystal forms. The structural change involves the edge -strand moving from one face of the immunoglobulin fold to the other. b | The structure of the high-affinity complex between Fc3-4 and the extracellular domains of the FcRI -chain, showing the extensive interaction surface and engagement of both C3 domains in the 'open' conformation (PDB ID: 1F6A). The connection to the membrane is at the C-terminal end of the 2 domain. c | Schematic representation of the entire IgE molecule bound to the extracellular domains of the FcRI -chain, according to the structural information from the Fc3-4 complex and the bent IgE-Fc structure. The - and -chains of FcRI, with their immunoreceptor tyrosine-based activation motifs (ITAMs), are also shown.
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The first view of the complex of Fc
RI with IgE came from the Fc
3-4–sFc
RI
structure
18, which showed how the two C
3 domains of IgE open up and how each contributes a sub-site of predominantly hydrophobic interaction surface (
Fig. 3b). The location of this binding site clearly accounts for the observed 1:1 stoichiometry despite the presence of two identical
-chains, and the extensive hydrophobic buried surface explains the high affinity (K
a 10
10 M
-1). In IgE (or IgE-Fc) with its C
2 domains, one of the C
3 domains is already in an open configuration and therefore accessible for receptor binding, as described above, whereas the other is not. The conformational changes that are necessary to allow IgE engagement using both sub-sites must therefore also include the C
2 domains, and the effect of their presence on the kinetics of the interaction — a reduction in both the on-rate and off-rate of IgE binding — have been quantified
19, 20. The kinetics are biphasic
19, consistent with the involvement of two sub-sites. It may be necessary for these extensive structural changes in IgE, and the CC' loop of the receptor, to occur in a concerted way to allow IgE disengagement. This would account in part for the exceptionally slow dissociation rate compared to IgG from its structurally homologous receptors
20.
The crystal structure of the Fc
3-4 complex, the acute bend in the IgE-Fc, and the fact that there is very little flexibility expected between the N-terminal end of the C
2 domains and the Fab regions, leads to a picture of the receptor-bound IgE molecule (
Fig. 3c) that is remarkably similar to that drawn 16 years ago based on the FRET studies
7. Therefore, it is likely that there are orientational constraints on the ligands, and location of allergenic epitopes that can effectively crosslink two or more receptor-bound IgE molecules and trigger cell activation. These effects are currently under investigation
21. However, the first crystal structure of an allergen–IgE complex, that of the dimeric
-lactoglobulin bound by two Fab regions of IgE, shows how the relative position of the two epitopes in this case enables crosslinking to occur
22.
The low-affinity receptor CD23, its soluble fragments and IgE interactions. CD23 is distinguished structurally from almost all other immunoglobulin receptors as it belongs to the
C-type (calcium dependent) lectin superfamily. In the membrane-bound form of CD23, three lectin domain 'heads' are spaced from the membrane by a triple
-helical coiled-coil 'stalk' (
Fig. 4a). However, the stalk region is susceptible to proteolysis, leading to the release of various soluble fragments (soluble CD23) that have activities that depend on their oligomeric state. The principal endogenous protease that releases soluble CD23 has recently been identified as
ADAM10 (a disintegrin and metalloproteinase 10)
23, 24. Subsequently, smaller soluble fragments of CD23 are generated of various sizes; those containing stalk sequences form trimers in a concentration-dependent manner or on IgE binding, whereas those lacking any stalk region are monomeric
25. In addition to promoting oligomerization, however, the stalk region probably has other functions, as a peptide at the base of the stalk region has been implicated in binding to MHC class II molecules
26. In the human form, but not the mouse form, the lectin head domains of CD23 additionally have a C-terminal 'tail' sequence (
Fig. 4a). IgE-binding activity is contained within the head, but the name 'low affinity' is a misnomer; although the affinity of a single head for IgE-Fc is low (K
a 10
6–10
7M
-1), the avidity effect achieved with the trimer leads to an affinity (K
a 10
8–10
9M
-1) approaching the high-affinity of Fc
RI (Refs
25,
27).
The short (N-terminal) intracellular sequence of CD23 exists in two splice variants that differ in their first seven (CD23a) or six (CD23b) amino-acid residues. They are differentially expressed: CD23a is expressed by antigen-activated B cells before differentiation into antibody-secreting plasma cells, whereas CD23b expression is induced by interleukin-4 (IL-4) on a variety of inflammatory cells, B cells and, importantly, epithelial cells. The region that differs between the two splice forms accounts for their distinct activities, and the crucial residues within this region have been identified
28, 29.
Surprisingly for a lectin, the ability of CD23 to bind IgE does not involve binding to carbohydrate
30. However, in addition to IgE, a second CD23 binding ligand (although evolutionarily, this was probably the primary binding partner for CD23) that does bind CD23 in a carbohydrate-dependent manner has been subsequently identified as CD21 (Refs
31,
32). As CD21 is expressed by B cells,
follicular dendritic cells (FDCs), activated T cells and basophils, adhesion pairing between these two molecules may have important consequences for allergy. Furthermore, the ability of CD23 to bind both IgE and CD21 links the IgE antibody and complement systems, with consequences for IgE regulation, as described later.
The structure of the CD23 monomeric lectin domain has been determined by both NMR (nuclear magnetic resonance) and X-ray crystallographic analysis
27, 33, and although both analyses confirm the C-type lectin fold, the structures differ in the calcium-binding regions (
Fig. 4b). Although CD23 appears to retain the two sites that are found in most other members of the family (on the basis of sequence homology), the NMR structure shows calcium occupancy at one site, whereas the X-ray structure shows calcium bound only at the other. Differences in the structures elsewhere point to a domain with a considerable degree of plasticity. The NMR analysis also located the binding sites for both IgE (using monomeric C
3) and CD21 (N-terminal domains 1 and 2)
27. The isolated C
3 domain was used because IgE-Fc containing both C
3 domains formed complexes of very high molecular weight
27. The CD21 site is incompletely represented in the NMR and crystal structures; the full C-terminal tail region was not present in the construct used in the NMR study, and although it was present in that used for the X-ray analysis, it was not visible in the structure, implying flexibility of this region. However, the IgE and CD21 binding sites are clearly distant from each other (
Fig. 4b), consistent with earlier evidence from site-directed mutagenesis
34, 35. Further studies showed that both could bind simultaneously
27. A model for trimerization of the heads was also proposed based on the NMR data, which brings the three CD21 binding sites close together adjacent to the stalk and leaves the three IgE binding sites positioned around the periphery of the trimer of heads.
However, the interaction of CD23 with CD21 involves not only domains 1 and 2 of CD21, but also domains 5–8, which interact with CD23 in a carbohydrate-dependent manner
32. CD21 consists of a tandem array of 15 or 16 short consensus repeats, a domain with a 6-stranded
-barrel structure that is a constituent of many complement-related proteins. The crystal structure of domains 1 and 2 of CD21 is known
36, and the whole molecule adopts an extended, flexible structure that is approximately 40 nm long
37 (
Fig. 5a). CD21 could clearly make extensive, multi-point attachments to the CD23 trimer, perhaps to the head as well as to the tail. However, we are still far from understanding the details of this interaction.
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FIGURE 5 | Mechanisms of IgE regulation by CD23.
a | Positive and negative regulation of IgE synthesis by human CD23. In this model, positive regulation of IgE synthesis is a result of the co-ligation of membrane IgE and CD21 on a human B cell committed to IgE synthesis by soluble CD23 released from membrane-bound CD23. IgE synthesis is thereby upregulated via synergistic signalling between the membrane IgE–Ig–Ig complex and the CD21–CD19 complex. (Soluble CD23 trimerizes in a concentration-dependent manner and on IgE binding, as shown here.) Negative regulation of IgE synthesis occurs by the co-ligation of IgE and CD23 on the membrane by allergen–IgE complexes. Competition between CD21 and CD23 for membrane IgE thus leads to homeostasis. b | A possible model for the formation of a signalling platform involving co-ligation of membrane IgE and CD21 by soluble CD23. It is known that: monomeric soluble CD23 binds simultaneously to a single C3 domain of IgE and one molecule of CD21; IgE-Fc can bind two molecules of monomeric soluble CD23; and soluble CD23 is trimeric at the high concentrations that probably exist in tissues in allergic inflammation and on binding to IgE-Fc. Thus, trimeric soluble CD23 (shown in red) can bind three molecules of IgE (via the C3 domain; shown in green) and three molecules of CD21 (shown in yellow). Furthermore, IgE can link two molecules of soluble trimeric CD23. This may lead to the formation of an extended network, creating a signalling platform for the survival and differentiation of IgE-committed B cells. c | In this scheme, IgE binding to mouse membrane CD23 trimers (which lack the C-terminal tails that in human CD23 trimers bind CD21) interferes with the upregulation of IgE class switching induced by interleukin-4 (IL-4) and CD40 ligand (CD40L). As CD23 trimers are unstable in the B-cell membrane, their unravelling allows ADAM10 (a disintegrin and metalloproteinase 10) to cleave the stalk region, releasing soluble CD23. This cleavage of membrane CD23 allows IgE synthesis to proceed by default. The binding of IgE, or certain CD23-specific IgG antibodies that bind to the lectin head domain (such as lumiliximab), stabilize the trimer and thereby enhance negative signalling. Although the negative signalling pathway of CD23 is unknown, IL-4 and CD40L act through STAT6 (signal transducer and activator of transcription 6) and NF-B (nuclear factor-B), respectively, to stimulate C germline gene transcription and class switching to IgE. EMPD, extracellular membrane-proximal domain; IL-4R, IL-4 receptor. Modified with permission from Ref. 85 © (2007) Current Science Inc.
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The binding site for CD23 in IgE-Fc is not precisely mapped either, but lies in the C
3 domains distinct from the Fc
RI site
38, away from the local symmetry axis of the Fc, and consistent with the observed 2:1 stoichiometry of binding
25. The ability of IgE to engage two molecules of CD23, and the dual binding activity of CD23, suggests a model for the formation of extensive arrays in the cell membrane involving co-crosslinking of membrane IgE and CD21 by trimeric soluble CD23 (Ref.
27). The significance of the equilibrium shown in
Fig. 5a, and the extended membrane complex (schematically indicated for one possible array in
Fig. 5b) are discussed below.
The wider network. The IgE network extends beyond the two principal receptors. A protein known originally as
-binding protein, but now known as galectin-3, has the ability to bind to both IgE and Fc
RI via
-galactose-containing oligosaccharide chains, thereby activating mast cells or basophils by crosslinking receptor-bound IgE, Fc
RI or both
39. Galectin-3 consists of a single carbohydrate-recognition domain (CRD) with an N-terminal region of proline-, glycine- and tyrosine-rich repeats through which it readily forms pentamers in complex with oligosaccharides
40; it therefore has a unique architecture and oligomerization propensity within the family of galectins, which otherwise contain just one or two CRDs and most commonly form dimers. The crystal structure of the CRD displays the canonical fold of this family, namely a sandwich of 5- and 6-stranded
-sheets, with the oligosaccharide binding site lying within a shallow surface groove
41.
Similarly, CD23 has been shown to interact with several integrins, including
M2-integrin in humans
42 and mice
43,
X2-integrin
42,
V3-integrin
44 and, most recently,
V5-integrin
45. The region of CD23 involved in the interaction with
V5-integrin has been located, and is distinct from the IgE and CD21 binding sites but close to the stalk region (
Fig. 4b). It includes two adjacent basic residues in a tripeptide motif, Arg-Lys-Cys, located on an exposed disulphide-bonded loop, and is recognized by a site on the integrin
-chain that is distinct from the
RGD sequence binding site of the integrin
45. No further details of these interactions are known.
Functions of IgE
We now consider the essential features of IgE function involving interactions between members of the protein network and the role of the different cells that express these proteins.
Immediate hypersensitivity: mast cells and basophils. Both IgE and mast cells are concentrated in the mucosal tissues, and so IgE antibodies are among the first defence molecules that an invading pathogen will encounter. The hallmark of an allergic response, which is mediated by the IgE–Fc
RI complex on mast cells, is immediate hypersensitivity. This reveals itself in characteristic signs and symptoms in the different target organs of allergy, the skin (atopic dermatitis or eczema), the nose (rhinitis), the lungs (asthma) and the gut (food allergic reactions)
4, 15. Crosslinking of IgE–Fc
RI complexes on the mast-cell surface by allergens leads, within minutes, to the so-called
'early phase' of the allergic reaction, which involves mast-cell degranulation and the synthesis of lipid mediators. Cytokines and chemokines liberated in this early phase initiate the '
late phase', which peaks some hours later and involves the recruitment and activation of inflammatory cells at sites sensitive to allergen. Similarly, but without overt symptoms, allergens activate the IgE-sensitized APCs, which in turn promote IgE production by B cells to replenish the IgE consumed in the allergic reaction, thereby maintaining mast-cell and APC sensitization (
Fig. 6).
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FIGURE 6 | Pump priming of the allergic response by allergens.
IgE is synthesized and secreted by B cells that have undergone heavy-chain class switching from IgM to IgE. The IgE binds to FcRI on mast cells and antigen-presenting cells (APCs) (a) and sensitizes these cells to allergens. Omalizumab inhibits the binding of IgE to FcRI on mast cells and APCs (b). Allergen binding to IgE triggers mast-cell degranulation to cause an allergic response (c). Allergen binding to the APC leads to the presentation of allergenic peptides to T helper 2 (TH2) cells (d). The allergen-activated TH2 cells secrete interleukin-4 (IL-4) (e) to maintain the TH2-cell lineage and recruit more TH cells into this lineage (e). The TH2 cells also secrete IL-13 and express CD40 ligand (CD40L), which together with IL-4 stimulates heavy-chain class switching to IgE (f). The allergen-activated mast cells contribute to the production of IL-4 and IL-13 (and express CD40L), which may also stimulate heavy-chain class switching to IgE (g). IL-4, IL-13 and CD40L also stimulate the expression of CD23 and the release of soluble CD23 (h). In humans, soluble trimeric CD23 upregulates IgE synthesis and secretion through interaction with CD21 (i). Thus, allergen acts in pump priming of the allergic response.
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The processes of mast-cell and APC recruitment and IgE production in the mucosal tissues are central to the functions of IgE, and no less so in guarding against systemic anaphylaxis. Mast-cell precursors are generated in the bone marrow and migrate to mucosal tissue before expressing Fc
RI (Ref.
46). The receptor is highly expressed (
500,000 copies per cell) on tissue mast cells, probably as a result of IgE-mediated upregulation of Fc
RI expression
15, 47. The concentrations of IgE required for the upregulation of Fc
RI in the mucosal tissues, which are higher than those normally present in the circulation, may derive from IgE synthesis by local B cells
48. The rate of this process is more than sufficient to maintain saturation of the Fc
RI molecules on the mast cells
4, 48, and any excess IgE is preferentially directed into secretions, rather than entering the circulation
49, 50. Local IgE synthesis is important for the function of IgE, as is discussed later.
Cytokinergic IgE activation of mast cells. Recent work has revealed that certain monomeric IgE molecules have the ability to activate mast-cell signalling in the absence of crosslinking by allergen through some of the same pathways as allergen–IgE complexes. The reported activities vary from the most 'highly cytokinergic', corresponding to full mast-cell activation (degranulation) at one extreme to the most 'poorly cytokinergic' (enhanced mast-cell survival) at the other. Although cytokinergic IgE molecules were shown to be monomeric in solution, on the cell membrane they form clusters and thereby crosslink Fc
RI and activate mast-cell signalling. The effective concentrations of IgE on the cell surface exceed those in solution by many orders of magnitude, and their orientation may further promote self association. The structural determinants of cytokinergic activity are under investigation. It is not yet clear whether these IgE molecules act in the same manner
in vivo, and if so what the physiological consequences might be. This subject is discussed in greater detail in two recent reviews
15, 51.
Local IgE synthesis: B cells and plasma cells. In allergy and asthma, the populations of B cells and plasma cells in the respiratory tract mucosa are heavily biased towards the production of IgE. Approximately 4% of the B cells and 12–19% of the plasma cells express IgE in the nasal mucosa of patients with rhinitis, compared with 1% and <1 healthy="" in="" respectively="" subjects="" sup="">
521>
. The concentration of IgE in the serum of healthy individuals is 10
times less than that of IgG. IgE-expressing plasma cells in the bone marrow are comparably sparse
, suggesting that, in individuals with rhinitis, the nasal mucosa is a major source of IgE. Local production of IgE may account for the generally higher allergen-specific fraction (up to a half) in the tissue than in the blood, where allergen-specific IgE may stem wholly or partly from other sources
.
We acknowledge the support of the Medical Research Council (UK), The Wellcome Trust and Asthma UK for our work in this field. We also thank K. Kirwan, A. Davies and R. Beavil for help with preparation of the original figures.
Hannah Gould received her Ph.D. from Harvard University, USA, and carried out postdoctoral research at The National Institute for Medical Research, University College London, UK, and Imperial College London, UK. She joined the Biophysics Department of King's College London, UK, in 1980, and is now Professor of Biophysics and a member of the Medical Research Council (MRC) & Asthma UK Centre in Allergic Mechanisms of Asthma. Her interests in IgE biology include the mechanism of gene regulation at the immunoglobulin loci, the structure and function of proteins of the IgE network, and more recently the application of IgE antibodies to the immunotherapy of cancer.
Brian Sutton received his D.Phil. from the University of Oxford, UK, and continued his postdoctoral research there in the Laboratory of Molecular Biophysics. He joined King's College London in 1987 and began collaborating with Hannah Gould in studies of the IgE network. He is currently Professor of Molecular Biophysics, Head of the Structural Biology Section and a member of the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma. His research focuses on understanding the molecular mechanisms of allergy and asthma, and applying structure-based approaches to develop new therapeutic agents.