Cited 50 times since 2018 (9.2 per year) source: EuropePMC The Journal of clinical investigation, Volume 129, Issue 1, 26 4 2018, Pages 169-181 An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup. Christenson SA, van den Berge M, Faiz A, Inkamp K, Bhakta N, Bonser LR, Zlock LT, Barjaktarevic IZ, Barr RG, Bleecker ER, Boucher RC, Bowler RP, Comellas AP, Curtis JL, Han MK, Hansel NN, Hiemstra PS, Kaner RJ, Krishnanm JA, Martinez FJ, O'Neal WK, Paine R, Timens W, Wells JM, Spira A, Erle DJ, Woodruff PG
Background
Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar "molecular phenotypes" may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype.
Methods
We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids.
Results
The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation.
Conclusion
These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy.
Trial registration
ClinicalTrials.gov NCT01969344.
Funding
Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C.
