D1.422 - Characterization of provocation-induced changes in transcription factors in the nasal mucosa of birch pollen-allergic and non-allergic individuals

Birch pollen (BP) is one of the major elicitors of pollinosis in Europe. Interaction of BP with airway epithelial cells results in an immune response, which can lead to allergic sensitization. Data on transcription factors (TFs) regulating the observed clusters of pro-inflammatory genes in BP-allergic individuals are still missing.

Our aim is to dissect the very early epithelial transcriptional responses to allergens in allergic versus non‑allergic nasal mucosae and correlation with the regulation of genes encoding junctional proteins, mast cell activation and functional barrier disruption.

Clinically allergic and non‑allergic donors were nasally challenged with BP extract or control and nasal mucosa samples were harvested at baseline, 15, 30, 60 and 120 minutes. Bulk RNA sequencing was performed, followed by hierarchical cluster analysis to identify shared temporal expression patterns and gene‑set enrichment analysis using TF target collections. Computational deconvolution was applied to infer immune‑cell composition over time. IL‑33 concentrations were quantified in nasal mucosae from the same donors. Previous data on transepithelial electrical resistance (TEER) in 16HBE14o‑ monolayers exposed to BP extract were integrated as a functional readout of barrier integrity.

In allergic donors, we identified an early responder gene cluster, peaking shortly after allergen exposure that was significantly enriched for AP‑1 targets, with rapid induction of FOS and FOSB, which was blunted in non‑allergic donors. Barrier‑related genes encoding claudins, cadherins, nectins showed marked, dynamic modulations in allergic mucosae, including transient down‑regulation at 30–60 minutes. Contrarily, non‑allergic donors exhibited only modest, largely monotonic changes. Deconvolution revealed a bell‑shaped kinetic of activated mast cells in the mucosa of the allergic donors after allergen challenge, with minimal changes in the non‑allergic ones. Consistently, BP extract reduced TEER in epithelial monolayers, indicating functional barrier disruption.

These data support a model in which allergen challenge in allergic nasal mucosae triggers early AP‑1 activation and enhanced IL‑33 production in epithelial cells, which contributes, directly and via mast cell activation, to junctional gene modulation and loss of barrier integrity. An AP‑1–IL‑33–mast cell axis may therefore link epithelial stress to barrier dysfunction in allergic patients and represents a promising target for therapeutic intervention.