Systemic IgE promotes allergic rhinitis by licensing Th2-to-Tfh conversion and local IgE production.

Although systemic allergen-specific IgE is an essential biomarker for allergic rhinitis (AR), its mechanistic contribution to symptom development remains unclear. Here, using mouse models, we investigated how systemic antigen-specific IgE influences AR symptoms and local type 2 inflammation. Mice were adoptively sensitized with ovalbumin (OVA)-specific IgE (OVA-IgE) and/or in vitro-differentiated OVA-specific Th2 (OVA-Th2) cells, followed by repeated intranasal OVA exposure. AR symptoms (sneezing) and the appearance of IgE-producing cells in the cervical lymph nodes (cLNs) and nasopharynx-associated lymphoid tissue were observed only in mice that received both OVA-Th2 cells and OVA-IgE. These responses were absent in recipients lacking factors required for IgE production, Rag2-/-, Aid-/-, and Stat6-/- mice, or in mice receiving OVA-Th2 cells deficient in IL-4-producing T follicular helper (Tfh) cell differentiation. Notably, when IgE-independent mast cell activation was induced by repeated intranasal administration of compound 48/80 in mice that had received OVA-Th2 cells, subsequent OVA challenge elicited OVA-specific AR symptoms and induced IgE-producing cells in the cLNs. Single-cell RNA sequencing revealed that systemic OVA-IgE facilitated the differentiation of OVA-Th2 cells into Tfh cells upon OVA challenge. Together, systemic IgE-mediated mast cell/basophil activation promoted Th2-to-Tfh differentiation and local IgE production, thereby contributing to the AR symptoms.