Soluble CD23 Monomers Inhibit and Oligomers Stimulate IGE Synthesis in Human B Cells

Abstract

The low affinity IgE receptor, CD23, is implicated in IgE regulation and the pathogenesis of allergic disease. CD23 is a type II integral membrane protein, comprising a lectin "head," N-terminal "stalk," and C-terminal "tail" in the extracellular sequence. Endogenous proteases cleave CD23 in the stalk and the tail to release soluble fragments that either stimulate or inhibit IgE synthesis in human B cells. The molecular basis of these paradoxical activities is not understood. We have characterized three fragments of CD23, monomeric derCD23, monomeric exCD23, and oligomeric lzCD23. We show that the monomers inhibit and the oligomer stimulates IgE synthesis in human B cells after heavy chain switching to IgE. CD23 fragments could be targets for therapeutic intervention in allergic disease.

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

“…4A may reflect the slightly lower affinity reported for sFcεRIα binding to Fcε3-4 compared with IgE-Fc (5, 21, 38)]. derCD23 can similarly cause almost complete displacement of sFcεRIα, although much higher concentrations are required, greater than 100 μM, to overcome its lower affinity (K D ∼ 10 −5 -10 −6 M) (4)(5)(6)(7)(8).…”

“…Although the affinity of derCD23 for IgE is considerably lower than that of FcεRI, avidity effects for trimeric CD23 can considerably enhance its ability to compete with FcεRI binding (7,(9)(10)(11). Indeed, a recombinant sCD23 species trimerized via a leucine-zipper motif, termed lzCD23, more effectively inhibited IgE binding to mast cells expressing FcεRI (10,11).…”

“…1), maximize the propensity for cross-linking of mIgE on B cells committed to IgE synthesis by trimeric sCD23, and also mCD23 on B cells by IgE or IgE-allergen complexes. We have hypothesized that through such interactions, the former leading to upregulation of IgE synthesis and the latter to down-regulation, CD23 contributes to the mechanism of IgE homeostasis (43), and this notion has received experimental support from studies with monomeric and oligomeric sCD23 species (7,8,16,44). The structure of the complex is also consistent with the cocross-linking of mCD21 and mIgE by trimeric sCD23 (proposed to enhance IgE up-regulation), because CD21 binds to the "tail" sequence that is, although only partially present in derCD23, located adjacent to the connection to the stalk (Fig.…”

“…In contrast, CD23 (FcεRII), expressed on B cells, consists of three C-type lectin "head" domains connected to the membrane by a trimeric α-helical coiled-coil "stalk" (3). 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).…”

“…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.…”