Structure of the CD23 molecule showing the binding sites for IgE (green) and CD21 (blue).

The structure of the low-affinity human immunoglobulin E (IgE) receptor CD23, revealed on page 751, accounts for its provocative behavior. Hibbert and colleagues show that soluble CD23 (sCD23) can simultaneously bind IgE and the complement receptor CD21 on B cells. This binding dexterity helps explain how CD23 and IgE cooperate to ramp up the synthesis of more IgE.

The production of IgE—the signature antibody of allergic diseases—is enhanced when sCD23 (which is cleaved from the surface of activated B cells by endogenous or pathogen-derived proteases) binds to CD21 on other B cells. But it was not clear why sCD23 binding to CD21 enhanced the production of IgE but not other antibody isotypes, as CD21 is present on all B cells.The group used NMR spectroscopy to show that sCD23 can bind to both IgE and CD21 simultaneously, as their binding sites are nonoverlapping. This dual binding capacity allows sCD23 to link IgE and CD21 on the surface of B cells. How this linkage triggers IgE production is not yet known, but the process is likely to be similar to one initiated by the complement component C3d. C3d, when covalently linked to antigen, brings together the B cell receptor (immunoglobulin M) and CD21. This assemblage recruits the CD21-associated signaling molecule CD19, which synergizes with the B cell receptor to increase activation and proliferation of the cell.

Once IgE levels are high, a trimeric membrane–bound form of CD23 helps turn off IgE production, possibly by stabilizing the molecule and preventing its cleavage. The next challenge, according to senior author James McDonnell, will be to study CD23-mediated IgE regulation in animal models of allergic disease. In the meantime, these data might provide a structural basis for the development of novel inhibitors of allergic disease.