CD23: An overlooked regulator of allergic disease

Abstract

Given the importance of immunoglobulin (Ig) E in mediating type I hypersensitivity, inhibiting IgE production would be a general way of controlling allergic disease. The low-affinity IgE receptor (FceRII or CD23) has long been proposed to be a natural regulator of IgE synthesis. In vivo research supporting this concept includes the observation that mice lacking CD23 have increased IgE production whereas mice overexpressing CD23 show strongly suppressed IgE responses. In addition, the finding that mice injected with monoclonal antibody directed against the coiled-coil stalk of CD23 have enhanced soluble CD23 release and increased IgE production demonstrates that full-length, trimeric CD23 is responsible for initiating an IgE inhibitory signal. The recent identification of ADAM10 (a disintegrin and metalloprotease) as the CD23 metalloprotease provides an alternative approach for designing therapies to combat allergic disease. Current data suggest that stabilizing cell-surface CD23 would be a natural means to decrease IgE synthesis and thus control type I hypersensitivity.

Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor FcεRI

“…The interaction between IgE and CD23 is critically involved in the allergic response at several stages, including allergen presentation, the regulation of IgE synthesis, and transport of IgE and immune complexes across epithelial barriers in the gut and airways (1,14,15,17,18). At the cell surface, mCD23 is trimeric (9,31,32), and sCD23 fragments shed from the membrane that contain sufficient stalk region are also trimeric (31), although the structure of the trimer has only been modeled either on the basis of the structures of other C-type lectins (25) or guided by NMR chemical shift data (6).…”

“…A single head domain binds to IgE-Fc with lower affinity (K A = 10 5 -10 6 M −1 ) than FcεRI (4)(5)(6)(7)(8), although avidity of the trimer can substantially enhance this interaction (7,(9)(10)(11). Membrane CD23 (mCD23) is cleaved from the cell surface by endogenous proteases such as ADAM10 (12,13) to yield soluble trimeric and monomeric forms (sCD23), which have been implicated in both positive and negative feedback mechanisms for the regulation of IgE synthesis by B cells that have switched to IgE production (1,7,8,(14)(15)(16). Both FcεRI and CD23 are also expressed on a range of antigenpresenting cells (APCs), where they play similar roles in trapping IgE-allergen complexes and promoting the allergic response (1,14,15), but the functional interplay-cooperation or competitionbetween these two receptors in the context of APCs is not well understood.…”

“…Membrane CD23 (mCD23) is cleaved from the cell surface by endogenous proteases such as ADAM10 (12,13) to yield soluble trimeric and monomeric forms (sCD23), which have been implicated in both positive and negative feedback mechanisms for the regulation of IgE synthesis by B cells that have switched to IgE production (1,7,8,(14)(15)(16). Both FcεRI and CD23 are also expressed on a range of antigenpresenting cells (APCs), where they play similar roles in trapping IgE-allergen complexes and promoting the allergic response (1,14,15), but the functional interplay-cooperation or competitionbetween these two receptors in the context of APCs is not well understood. CD23 expressed on B cells also has the potential to contribute to the clinically serious phenomenon of the spreading of allergic reactivity to unrelated allergens, through its ability to internalize IgE-allergen complexes irrespective of the allergen, in contrast to mIgE-mediated allergen-specific presentation through the B-cell receptor (1).…”

CD23-Dependent Transcytosis of IgE and Immune Complex across the Polarized Human Respiratory Epithelial Cells

“…The function of CD23 has been most extensively studied on B cells, where it is involved in IgE-mediated Ag capture and facilitated presentation to T cells or regulation of IgE homeostasis (17,26). There is a paucity of information on the link between engagement of CD23 on the airway epithelial cells and the functional outcome.…”

“…sCD23 also has IgE-binding activity (23), and its level is increased in allergies (24). CD23 is constitutively and inducibly expressed in variety of cell types, including B cells, eosinophils, monocytes, and Langerhans cells (16,18,25,26). More interestingly, CD23 has various functions, such as mediating B cell growth, enhancing IgE-mediated Ag presentation (27,28), and regulating IgE homeostasis (29)(30)(31)(32).…”