Nasal Epithelial Immune Signatures Are Associated With Age-Dependent Asthma Trajectories in Early Life.
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Jakwerth Constanze A, Illi Sabina, Charles Helen, Oelsner Madlen, Gabr Amr A, Zissler Ulrich M, Erb Anna, Feuerherd Martin, Drost Felix, Büttner Maren, Schubert Benjamin, Maison Nicole, Omony Jimmy, Weckmann Markus, Grychtol Ruth, Dittrich Anna-Maria, Foth Svenja, Skevaki Chrysanthi, Trojan Tobias, van Koningsbruggen-Rietschel Silke, Hansen Gesine, Bahmer Thomas, Rabe Klaus F, Brinkmann Folke, Kopp Matthias Volkmar, Protzer Ulrike, Chaker Adam M, Schaub Bianca, von Mutius Erika, Schmidt-Weber Carsten B, ALLIANCE Study Group as part of the German Center for Lung Research (DZL)
Аннотация
METHODS: Nasal epithelial transcriptomes from 265 children and young adults (79 healthy, 81 wheezers, 105 asthmatics; median age 10.4 [1.1-20.3] years) from the All Age Asthma Cohort (ALLIANCE) cohort were analyzed using a hypothesis-driven candidate approach based on predefined cytokine axes. Transcriptional signatures were mapped to epithelial cells by scRNA-sequencing. Asthma-outcome associations were assessed in age- and sensitization-adjusted multivariate models.
RESULTS: The candidate approach identified three antagonistic epithelial immune programs: an interferon-associated (E1; IDO1, CSF3, CCL20), a type-2-associated (E2; POSTN, CCL26, CST1), and a type-17-associated program (E3; IL36G, KLK7, KRTDAP). These programs were detected across basal, ciliated, and secretory epithelial cells. In early childhood (1-3 years), wheezers predominantly exhibited E1/E3-dominant epithelial profiles (n = 36). Age-group-specific comparisons showed higher E2 and lower E1/E3 expression in wheezers aged 4-6 years (n = 38) than in those aged 1-3 years (n = 36). E2 dominance correlated with IgE, FeNO, and eosinophilia (p < 0.01). In multivariate models assessing asthma outcome at age 6, E1 expression was inversely associated with asthma persistence (OR = 0.15, p < 0.05), whereas E3 expression was associated with disease progression (OR = 4.93, p < 0.05). The combined epithelial signature discriminated asthma outcomes with high accuracy (AUC = 0.90), independent of allergic sensitization.
CONCLUSION: Early-life wheeze reflects distinct airway epithelial immune programs characterized by age-associated patterns in epithelial immune activity. Nasal epithelial transcriptional signatures capture molecular trajectories associated with asthma persistence and may enable early risk stratification.
TRIAL REGISTRATION: All-Age-Asthma (ALLIANCE) cohort: clinicaltrials.gov: NCT02496468; adult arm: NCT02419274.