VEGF-C enhances BALT and skews IgE responses towards a pathogenic, anaphylactic profile in mouse models of allergic asthma 2259494

Abstract Introduction Understanding how environmental allergens elicit bronchus-associated lymphoid tissue (BALT) is key to elucidating mechanisms of asthma pathophysiology; however, the extent to which different allergens elicit BALT and IgE responses is poorly understood. We previously reported that intratracheal administration of VEGF-C drives lymphangiogenesis and increases BALT and IgE, but their pathogenicity was unclear. Methods To investigate this, we exposed mice intratracheally to house dust mite, Alternaria, and ragweed allergens and assessed BALT via fluorescence microscopy. Additionally, we implemented NP-conjugated OVA to measure IgE affinity and to distinguish high affinity (anaphylactic) from low affinity (protective) IgE responses. Results All allergens induced BALT, with Alternaria eliciting a stronger response, suggesting differential immune activation and lymphoid tissue formation to environmental allergens. ELISA with NP2, NP7 and NP36 conjugated antigens showed that VEGF-C driven BALT increased the NP2-to-NP36 IgE ratio, indicating a skew towards high affinity anaphylactic IgE responses. Furthermore, following allergen inhalation, VEGF-C treated mice exhibited exacerbated hypothermia, associated with worse anaphylaxis. By contrast, no significant difference was observed between the control and VEGF-C treated groups upon intravenous allergen exposure, implying a lung-localized response. Indeed, VEGF-C treated mice showed increased airway hyperresponsiveness to increasing methacholine, indicative of exacerbated local reactivity. Finally, in B cells within the BALT, we identified Iε transcripts, a necessary event delineating B cells poised to IgE class switching. Conclusion Overall, these findings demonstrate that environmental allergens promote BALT and that VEGF-C enhances this process by driving local high affinity IgE production, anaphylaxis and airway hyperresponsiveness. These results suggest that BALT is not only a site for immune activation but also a local source of IgE-producing B cells. Funding Source Alper Fund & Nucleate DojoGrant Research Fellowship 2025 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)