An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup.

TitleAn airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup.
Publication TypePublication
Year2019
AuthorsChristenson SA, van den Berge M, Faiz A, Inkamp K, Bhakta N, Bonser LR, Zlock LT, Barjaktarevic IZ, R Barr G, 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, J Wells M, Spira A, Erle DJ, Woodruff PG
JournalJ Clin Invest
Volume129
Issue1
Pagination169-181
Date Published2019 01 02
ISSN1558-8238
KeywordsAdrenal Cortex Hormones, Aged, Aged, 80 and over, Bronchi, Drug Resistance, Female, Gene Expression Regulation, Humans, Interleukin-17, Male, Middle Aged, Psoriasis, Pulmonary Disease, Chronic Obstructive
Abstract

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.

DOI10.1172/JCI121087
Alternate JournalJ Clin Invest
PubMed ID30383540
PubMed Central IDPMC6307967
Grant ListK23 HL116657 / HL / NHLBI NIH HHS / United States
P30 ES005605 / ES / NIEHS NIH HHS / United States
P30 ES006694 / ES / NIEHS NIH HHS / United States
P30 DK072517 / DK / NIDDK NIH HHS / United States
R01 HL121774 / HL / NHLBI NIH HHS / United States
K08 HL123940 / HL / NHLBI NIH HHS / United States
I01 CX000911 / CX / CSRD VA / United States
U19 AI077439 / AI / NIAID NIH HHS / United States
U01 HL137880 / HL / NHLBI NIH HHS / United States
R01 HL122438 / HL / NHLBI NIH HHS / United States
P30 DK054759 / DK / NIDDK NIH HHS / United States
K24 HL138188 / HL / NHLBI NIH HHS / United States
R01 HL138424 / HL / NHLBI NIH HHS / United States
K23 HL123778 / HL / NHLBI NIH HHS / United States
K12 HL119997 / HL / NHLBI NIH HHS / United States
K24 HL137013 / HL / NHLBI NIH HHS / United States
MS#: 
MS081
Manuscript Full Title: 
An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup.
Manuscript Lead/Corresponding Author Affiliation: 
Clinical Center: San Francisco (University of California at San Francisco)
ECI: 
Manuscript Status: 
Published and Public