CD23 provides a noninflammatory pathway for IgE-allergen complexes

Background: Type I hypersensitivity is mediated by allergen-specific IgE, which sensitizes the high-affinity IgE receptor Fc epsilon RI on mast cells and basophils and drives allergic inflammation upon secondary allergen contact. CD23/Fc epsilon RII, the low-affinity receptor for IgE, is constitutively expressed on B cells and has been shown to regulate immune responses. Simultaneous binding of IgE to Fc epsilon RI and CD23 is blocked by reciprocal allosteric inhibition, suggesting that the 2 receptors exert distinct roles in IgE handling. Objective: We aimed to study how free IgE versus precomplexed IgE-allergen immune complexes (IgE-ICs) target the 2 IgE receptors Fc epsilon RI and CD23, and we investigated the functional implications of the 2 pathways. Methods: We performed binding and activation assays with human cells in vitro and IgE pharmacokinetics and anaphylaxis experiments in vivo. Results: We demonstrate that Fc epsilon RI preferentially binds free IgE and CD23 preferentially binds IgE-ICs. We further show that those different binding properties directly translate to distinct biological functions: free IgE initiated allergic inflammation through Fc epsilon RI on allergic effector cells, while IgE-ICs were noninflammatory because of reduced Fc epsilon RI binding and enhanced CD23-dependent serum clearance. Conclusion: We propose that IgE-ICs are noninflammatory through reduced engagement by Fc epsilon RI but increased targeting of the CD23 pathway.