The Airway Transcriptome in Type 2 Cytokine Biomarker-High and -Low Severe Asthma.

Severe asthma is a heterogeneous disease. The mechanisms driving airway pathology when type 2 (T2) cytokine activity is suppressed remain poorly understood. This study aimed to provide insight by identifying the airway molecular pathways of T2 biomarker-high and -low severe asthma. We analysed clinical and transcriptomic data from bronchial biopsies and brushes in the UK Refractory Asthma Stratification Programme multi-centre severe asthma cohort (18 corticosteroid-resistant T2 biomarker-high [T2-high], 23 T2 biomarker-intermediate [T2-intermediate], 11 T2 biomarker-low [T2-low]) plus 20 healthy controls pre- and post-treatment with high-dose inhaled corticosteroids (ICS). Many genes dysregulated in asthma vs. health were concordantly dysregulated in healthy subjects receiving ICS. Severe asthma as a whole, independent of confounding by ICS, was characterised by upregulation of mucins, CEACAM5, typical T2-genes (POSTN, CLCA1, CCL26), epithelial mast cell genes, and CPA4. T2-high severe asthma demonstrated upregulated T2-dependent genes, epithelial barrier and keratin genes, adaptive immune responses, and impaired ciliary function. T2-low asthma showed upregulated Th1- and IL-17-associated genes (IDO1, CXCL10, GBP1, LAG3), interferon-γ signalling, neuroimmune pathways, airway smooth muscle-related genes, and neutrophil enrichment. T2-intermediate asthma exhibited a mixed molecular profile sharing features of T2-high and T2-low endotypes, with selective expression of the pathogen defence and antiviral response genes. The results were validated using bronchoscopy data from the U-BIOPRED Consortium. This study defines airway molecular endotypes of severe asthma associated with T2 biomarker high and low phenotypes, independent of corticosteroid effects. These findings offer insights for severe asthma management and the development of targeted biologic therapies.