Early mucosal type 1 immunity in pre-school wheezers as protective factor for development of asthma at school-age 3090

Description Allergy and asthma are defined by local type-2 immunity at the airway barrier. However, whether immunity type-specific epithelial phenotypes can predict the persistence of asthma at school-age, remains elusive. We analyzed nasal immunophenotypes (nasotypes; NT) by nasal transcriptomics from 265 children (79 healthy, 81 wheezers, 105 asthmatic) from the ALL-Age Asthma Cohort (ALLIANCE; DZL), median age 10.4 [1.1-20.3]. E-signatures were assigned in single-cell transcriptomics (scRNASeq) of primary 3D-airway cultures. Correlation analysis of secreted genes showed antagonistic expression between IFNG-correlated E1-NT (IDO,CSF3,CCL20), IL4-correlated E2-NT (POSTN,CCL26,CST1) and IL17C-correlated E3-NT (IL36G,KLK7,KRTDAP). E1/E2/E3 transcriptional programs were assigned to distinct cells in scRNASeq. E2-NT was highly expressed in asthmatic children (age>6) and correlated with type-2 parameters (total/specific IgE, FeNO, eosinophilia). Wheezers showed an early E1/E3-signature (age 1-3; N = 36), while E2-signature was activated from age 4 (N = 38). Multivariate models adjusted for sensitization and age (AUC=0.87) revealed E1-NT as protective (OR = 0.29;P<0.05) and E3-NT as risk factor (OR = 2.03;P<0.05) for asthma development at age 6. The assessment of the here identified three nasotypes, activated age- and disease-dependently, predicted to a high degree (AUC=0.87) the persistence of asthma with E1 showing protection from progression, but E3 independently predicting progression of disease. Funding Sources Supported by the German Center of Lung Research (DZL) funded by the Federal Ministry of Education and Research (BMBF), the Bavarian State Office for Health and Food Safety (LGL; K1-2497-GLB-20-V4) of the Bavarian State Ministry of Health and Care and by grants from Deutsche Forschungsgemeinschaft RTG2668 (Project A5, Project-ID: 435874434) to C.B. Schmidt-Weber.