Gene expression of airway epithelial interleukin (IL)-17 response distinguishes a biologically, radiographically, and clinically distinct chronic obstructive pulmonary disease (COPD) subgroup of patients who may benefit from personalized therapy, according to a study published in the Journal of Clinical Investigation.
Investigators examined a dataset of bronchial airway epithelial (BAE) brushings collected from patients with asthma during bronchoscopy for a genomic signature of airway epithelial IL-17 response. The IL-17 genomic signature was fit to a cross-sectional study of ever-smokers with (n=85) and without (n=152) COPD. Determining that the signature specifically identified IL-17 associated inflammation by its response to other airway epithelial adaptive immune responses (type 1 and 2), the investigators tested the associations between this IL-17 signature and rich phenotypic data collected in two independent COPD studies (GLUCOLD: n=79 and SPIROMICS: n=47). Using whole transcriptome profiling of IL-17, the researchers characterized airway epithelial response to IL-17.
The gene signature characterized in the BAE dataset was higher in former smokers (mean of the zero-centered log2 gene expression, 0.29±0.46) compared with current smokers (–0.42±0.48, P <2.21*10-16) and was associated with older age (⍴ =.19, P =.004). In patients with COPD compared with ever-smokers without COPD (ie, those with preserved lung function, 0.21±0.66 and –0.12±0.51, respectively, P =1.34*10-5), the signature increased, even after adjustment for smoking status and age (P =6.2*10-6). Higher gene signature was associated with lower forced expiratory volume in 1 second (FEV1)% predicted across all participants and in participants with only COPD (associated with a 5.5 ml decrease in FEV1, P =.04), suggesting the association occurred with increasing COPD severity. In SPIROMICS, the investigators also found an association between higher IL-17 signature and slightly greater airway obstruction in COPD (P =.038, after adjustments for smoking and age). After adjustments for multiple comparisons, this was not significant.
The IL-17 response is associated with increases in airway neutrophils and macrophages and is related to worse clinical outcomes in current and former smokers. This research shows, for the first time in a longitudinal randomized controlled trial, an association between IL-17 inflammatory signature and poor corticosteroid responsiveness. The investigators hypothesize that predicting which patient populations will respond to therapies targeting IL-17 or associated inflammatory pathways could be more useful than predicting which patients will not respond to corticosteroids.
Disclosures: Two authors declare a patent pending related to this work. Please see the reference for a full list of disclosures.
Christenson SA, van den Berge M, Faiz A, et al. An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup [published online November 1, 2018]. J Clin Invest. doi:10.1172/jci121087