Recruiting CD33 on mast cells to inhibit IgE-mediated mast cell-dependent anaphylaxis

Abstract

IgE-mediated activation of mast cells is a hallmark of an anaphylactic reaction to allergen. In this issue of the JCI, Duan et al. describe an approach for suppressing IgE-dependent mast cell activation, thereby suppressing anaphylaxis. Specifically, the authors show that delivery of liposomes containing both the specific antigen recognized by the mast cell-bound IgE and a high-affinity glycan ligand of the inhibitory receptor CD33 (CD33L) to targeted mast cells inhibits antigen-induced, FcεRI-dependent spleen tyrosine kinase (Syk) phosphorylation and downstream protein tyrosine kinase (PTK) phosphorylation, Ca++ flux, and β-hexosaminidase release (i.e., degranulation). However, this strategy only worked if both the antigen (reactive with the mast cell-bound IgE) and CD33L were on the same liposome. This approach promises to rapidly reduce IgE-dependent mast cell activation in response to challenge with offending allergens.

Figure 1. Recruitment of CD33 suppresses IgE/FcεRI signaling and mast cell activation.

(A) TNP-LPs stabilize the α–TNP-IgE–FcεRI complex in lipid rafts with Src kinases that initiate the FcεRI signaling cascade. Activation of this cascade results in extensive mast cell degranulation and mediator release. Duan et al. (6) suggest that CD33 has no detectable basal impact on FcεRI signaling, because it is not constitutively localized in the same microdomain as FcεRI, which localizes to lipid rafts. (B) TNP-LP-CD33L recruits CD33 to the α–TNP-IgE–FcεRI immunological synapse. Duan and colleagues (6) suggest that the cytoplasmic ITIMs of CD33 are phosphorylated by Src kinases and then recruit the tyrosine phosphatase SHP-1, which dephosphorylates Syk and other kinases, thereby dampening the FcεRI-mediated signaling cascade. This results in a marked reduction in mast cell degranulation and mediator release. (C) Monoclonal α-CD33 antibodies are proposed to block recruitment of CD33 to the IgE-FcεRI complex, thereby enabling mast cell degranulation and mediator release induced by TNP-LP-CD33L.