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 FcεRI (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–FcεRI 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 FcεRI at high levels and the slow rate of dissociation of IgE from FcεRI.
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–FcεRI 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.
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, FcεRI (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.
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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.
- Fluorescence resonance energy transfer
(FRET). A quantum mechanical process by which excitation energy is transferred, without the emission of a photon, from a donor fluorophore to an acceptor fluorophore that is in close proximity. FRET can be used to determine inter- or intra-molecular distances (in the range of 10–100 Å).
- Extracellular membrane-proximal domain
(EMPD). A domain present in each heavy chain of a membrane immunoglobulin, located between the C-terminal domain of the soluble antibody (Cε4 in IgE) and the transmembrane sequence.
- Antigen-presenting cells
(APCs). Cells that can internalize and process antigen, and then display antigenic peptide fragments on their surface, together with molecules required to activate the cognate lymphocytes.
- Immunoreceptor tyrosine-based activation motif
(ITAM). A short peptide motif containing tyrosine residues that is found in the cytoplasmic tail of several signalling adaptor proteins and that is necessary to recruit proteins that are involved in triggering activating signalling proteins. The consensus sequence is Tyr-X-X-(Leu/Ile)-X6–8-Tyr-X-X-(Leu/Ile), where X denotes any amino acid.
- C-type (calcium dependent) lectin superfamily
A family of calcium-dependent carbohydrate-binding proteins. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain (CRD), which is highly conserved across this family. Calcium contributes to the structural maintenance of this domain and typically is essential for its carbohydrate-binding function.
- Follicular dendritic cell
(FDC). A cell type that is normally found only in the germinal centres of lymphoid tissue and that presents antigen to selected B cells and provides survival signals required for affinity maturation.
- RGD sequence
A peptide motif that consists of the amino acids arginine, glycine and aspartic acid, common to many ligands that bind integrins.
- Early phase of the allergic reaction
The biological and clinical consequences that occur within the first hour of crosslinking complexes of IgE with FcεRI (high-affinity Fc receptor for IgE) at the surface of mast cells and/or basophils by allergens. The clinical manifestations are characterized by tissue-specific effects, including constriction of the large airways in asthma, and 'wheal-and-flare' reactions in the skin. Generalized symptoms in multiple target organs can include oedema and pruritus (itching). Systemic manifestations can include angio-oedema, urticaria and, in severe cases, vascular collapse (anaphylaxis).
- Late phase of the allergic reaction
Clinical manifestations can be measurable (visible) two or more hours after allergen exposure, but may also appear much later. These manifestations peak at 6–9 hours after allergen exposure and will have resolved by 24–48 hours. 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.
- Class-switch recombination
(CSR). The process by which a heavy-chain variable region gene segment attached to one heavy-chain constant region gene segment in the expressed heavy-chain gene is recombined with a downstream constant region gene segment to express a new antibody class.
- Somatic hypermutation
(SHM). The process by which point mutations occur in the heavy- or light-chain variable region gene segments, resulting in a change in the expressed protein, which may alter the antigen (or allergen) affinity or specificity.
- Affinity maturation
The process by which B cells are selected for survival and proliferation on the basis of their affinity for antigen.
- Langerhans cells
Professional antigen-presenting dendritic cells localized in the skin epidermis.
- Facilitated antigen presentation
(FAP). Also known as facilitated allergen presentation, this is the process by which CD23 internalizes allergen–IgE complexes and recycles peptides complexed with MHC class II molecules to the cell surface for T-cell recognition.
- Epitope spreading
The process by which an antibody response to one epitope on an antigen leads to the production of antibodies specific for other epitopes on the same antigen, or for epitopes on entirely unrelated antigens. This results from the internalization of whole antigen and subsequent display of a range of peptides derived from that antigen, leading to the generation of T cells with different epitope specificities. Simultaneous processing of two unrelated antigens by an antigen-presenting cell can lead to the production of antibodies directed against both antigens.
A condition, mediated by IgE antibodies, of increased susceptibility to immediate hypersensitivity.
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