Allergic individuals exposed to minute quantities of allergen experience an immediate response. Immediate hypersensitivity reflects the permanent sensitization of mucosal mast cells by allergen-specific IgE antibodies bound to their high-affinity receptors (FcepsilonRI). A combination of factors contributes to such long-lasting sensitization of the mast cells. They include the homing of mast cells to mucosal tissues, the local synthesis of IgE, the induction of FcepsilonRI expression on mast cells by IgE, the consequent downregulation of FcgammaR (through an insufficiency of the common gamma-chains), and the exceptionally slow dissociation of IgE from FcepsilonRI. To understand the mechanism of the immediate hypersensitivity phenomenon, we need explanations of why IgE antibodies are synthesized in preference to IgG in mucosal tissues and why the IgE is so tenaciously retained on mast cell-surface receptors. There is now compelling evidence that the microenvironment of mucosal tissues of allergic disease favors class switching to IgE; and the exceptionally high affinity of IgE for FcepsilonRI can now be interpreted in terms of the recently determined crystal structures of IgE-FcepsilonRI and IgG-FcgammaR complexes. The rate of local IgE synthesis can easily compensate for the rate of the antibody dissociation from its receptors on mucosal mast cells. Effective mechanisms ensure that allergic reactions are confined to mucosal tissues, thereby minimizing the risk of systemic anaphylaxis.

The distinguishing structural feature of immunoglobulin E (IgE), the antibody responsible for allergic hypersensitivity, is the C epsilon 2 domain pair that replaces the hinge region of IgG. The crystal structure of the IgE Fc (constant fragment) at a 2.6-A resolution has revealed these domains. They display a distinctive, disulfide-linked Ig domain interface and are folded back asymmetrically onto the C epsilon 3 and C epsilon 4 domains, which causes an acute bend in the IgE molecule. The structure implies that a substantial conformational change involving C epsilon 2 must accompany binding to the mast cell receptor Fc epsilon RI. This may be the basis of the exceptionally slow dissociation rate of the IgE-Fc epsilon RI complex and, thus, of the ability of IgE to cause persistent allergic sensitization of mast cells.

Of all the antibody classes, IgE displays a uniquely slow dissociation rate from, and high affinity for, its cell surface receptor FcεRI. The structural basis for these key determinants of IgE's ability to mediate allergic hypersensitivity is now revealed by the 3.4Å resolution crystal structure of human IgE-Fc (consisting of the Cε2, Cε3 and Cε4 domains) bound to the extracellular domains of the FcεRI α-chain. Comparison with free IgE-Fc (reported here at 1.9Å) shows that the antibody, which has a compact, bent structure prior to receptor engagement, becomes even more acutely bent in the complex. Thermodynamic analysis indicates that the interaction is entropically driven, which explains how the non-contacting Cε2 domains, in place of the flexible hinge region of IgG antibodies, contribute together with the conformational changes to IgE's unique binding properties.The global incidence of allergic disease has increased markedly in recent years and continues to rise. Asthma currently affects 22.2 million people in North America and 5.4 million in the UK where the rate of incidence, especially in children, is among the highest in the world 1 . Anaphylactic reactions to foods such as nuts, virtually unknown thirty years ago, are now relatively common. The reason for this increase is debated, but these and other allergic conditions (rhinitis, eczema etc.) are all mediated by IgE, and the viability of AUTHOR CONTRIBUTIONS MDH and AMD carried out the crystallographic analysis of the complex, and BD the crystallographic analysis of IgE-Fc; MDH, JEN, JH, AJB and RJO produced the proteins; SCB and JMM carried out the thermodynamic analysis; EG contributed to the analysis of the conformational changes; HJG, AJB and BJS planned and directed the project; MDH, AMD, JMM and BJS wrote the paper.Accession codes. Atomic coordinates and structure factors have been deposited in the Protein Data Bank with entry codes 2WQR for IgE-Fc and 2Y7Q for the complex. [6][7][8][9] . Particular interest has centered on the role of the Cε2 domains, which were shown to contribute to the slow dissociation rate 10 , by comparing the binding kinetics of the complete IgE-Fc (dimer Cε2-Cε3-Cε4 domains) with a sub-fragment lacking the Cε2 domains, here referred to as Fcε3-4. The Cε2 domains have no counterpart in IgG, all four subclasses of which have in their place hinge regions of various lengths and degrees of flexibility. Europe PMC Funders GroupEarly fluorescence resonance energy transfer (FRET) studies of labelled chimeric IgE indicated a more compact and bent structure than the extended, flexible Y-shaped IgG 11 , and later solution scattering studies of IgE-Fc were consistent with such a structure 12 . The crystal structure of IgE-Fc revealed for the first time the extent and nature of this bend 13 , made possible by the presence of the Cε2 domains. Surprisingly the molecule was found to be so acutely and asymmetrically bent, with the Cε2 domain pair folded back across the Cε3 domains, that one Cε2 domain even contacted the Cε4 domai...