IgE-sensitized mast cells release extracellular vesicles that transfer IgE and spread allergic sensitization.

Abstract

Elevated IgE levels are linked to allergic conditions. IgE binding to FcεRI sensitizes mast cells (MCs), and allergen-induced cross-linking of IgE-bound FcεRI triggers MC activation. Extracellular vesicles (EVs), implicated in intercellular communication, are coreleased during IgE-mediated MC degranulation. Although extensive research has examined MC activation, the effects of IgE sensitization alone on MCs remain less understood. We sought to investigate how IgE sensitization of MCs, without inducing degranulation, affects the quantity, molecular composition, and potential functions of released EVs. EVs from IgE-sensitized cultured MCs or present in human plasma were isolated by differential ultracentrifugation and quantified by nanoparticle tracking. The molecular composition of MC EVs was analyzed by proteomics, lipidomics, and biochemical assays. Naive MCs were incubated with IgE-containing EVs, and IgE transfer from EVs to recipient cells was tested by flow cytometry, immunoblotting, and cell activation. IgE sensitization altered quantity and composition of MC EVs. EVs derived from IgE-sensitized MCs exhibited distinct molecular signatures compared to EVs from degranulated MCs. Unlike EVs released during degranulation, these EVs displayed surface-exposed IgE capable of binding antigen and transferred functional IgE complexes to previously unsensitized MCs, thereby conferring activation potential. IgE sensitization of MCs induces the release of IgE-containing EVs with distinct molecular signatures, demonstrating that IgE binding has functional consequences and revealing a previously unrecognized mechanism for the dissemination of IgE. This study advances our understanding of MC biology and highlights EVs from IgE-sensitized MCs as amplifiers of allergic sensitization, immune cell communication, and potential biomarkers in allergic diseases.