Adult non-cystic fibrosis bronchiectasis is characterised by airway luminal Th17 pathway activation

Abstract

Background: Non-cystic fibrosis (CF) bronchiectasis is characterised by chronic airway infection and neutrophilic inflammation, which we hypothesised would be associated with Th17 pathway activation.

Methods: Th17 pathway cytokines were quantified in bronchoalveolar lavage fluid (BALF), and gene expression of IL-17A, IL-1β, IL-8 and IL-23 determined from endobronchial biopsies (EBx) in 41 stable bronchiectasis subjects and 20 healthy controls. Relationships between IL-17A levels and infection status, important clinical measures and subsequent Pseudomonas aeruginosa infection were determined.

Results: BALF levels of all Th17 cytokines (median (IQR) pg/mL) were significantly higher in bronchiectasis than control subjects, including IL-17A (1.73 (1.19, 3.23) vs. 0.27 (0.24, 0.35), 95% CI 1.05 to 2.21, p<0.0001) and IL-23 (9.48 (4.79, 15.75) vs. 0.70 (0.43, 1.79), 95% CI 4.68 to 11.21, p<0.0001). However, BALF IL-17A levels were not associated with clinical measures or airway microbiology, nor predictive of subsequent P. aeruginosa infection. Furthermore, gene expression of IL-17A in bronchiectasis EBx did not differ from control. In contrast, gene expression (relative to medians of controls) in bronchiectasis EBx was significantly higher than control for IL1β (4.12 (1.24, 8.05) vs 1 (0.13, 2.95), 95% CI 0.05 to 4.07, p = 0.04) and IL-8 (3.75 (1.64, 11.27) vs 1 (0.54, 3.89), 95% CI 0.32 to 4.87, p = 0.02) and BALF IL-8 and IL-1α levels showed significant relationships with clinical measures and airway microbiology. P. aeruginosa infection was associated with increased levels of IL-8 while Haemophilus influenzae was associated with increased IL-1α.

Conclusions and clinical relevance: Established adult non-CF bronchiectasis is characterised by luminal Th17 pathway activation, however this pathway may be relatively less important than activation of non-antigen-specific innate neutrophilic immunity.

Fig 1. Airway luminal but not mucosal levels of IL-17A are significantly increased in adult non-CF bronchiectasis compared with healthy control subjects.

(A) Bronchoalveolar lavage fluid levels of IL-17A comparing bronchiectasis (n = 41) and healthy control (n = 20) subjects; (B) Gene expression of IL-17A in endobronchial biopsies from bronchiectasis (n = 34) and healthy control (n = 20) subjects. (Cont—control, BE—bronchiectasis; Box and whisker plots display median and interquartile ranges; p values are by Mann-Whitney U test).

Fig 2. Bronchoalveolar lavage fluid levels of Th17 pathway cytokines and chemokines are significantly increased in adult non-CF bronchiectasis.

(A) All Th17 pathway mediators are significantly increased in non-CF bronchiectasis (n = 41) compared with healthy control (n = 20) subjects. (B) Bronchoalveolar lavage fluid levels of IL-17A correlate strongly with all Th17 pathway mediators, but most strongly with IL-23 (n = 61). (Cont—control, BE—bronchiectasis; Box and whisker plots display median and interquartile ranges; p values are by Mann-Whitney U test).

Fig 3. Airway luminal and bronchial mucosal levels of IL-8 are increased in non-CF bronchiectasis and relate to airway microbiology.

(A) Bronchoalveolar lavage IL-8 levels are significantly increased in bronchiectasis subjects according to concurrent BALF infection by P. aeruginosa (n = 9) compared to H. influenzae (n = 11), normal respiratory flora only (n = 14) and healthy controls (n = 20). (B) Gene expression of IL-8 is significantly increased in endobronchial biopsy tissue from adult non-CF bronchiectasis (n = 34) than control (n = 20) subjects. (Cont—control, BE—bronchiectasis; Box and whisker plots display median and interquartile ranges; p values by Mann-Whitney U test).