Journal article
An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup
The Journal of clinical investigation, Vol.129(1), pp.169-181
01/02/2019
DOI: 10.1172/JCI121087
PMCID: PMC6307967
PMID: 30383540
Abstract
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.
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.
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.
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.
ClinicalTrials.gov NCT01969344.
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.
Details
- Title: Subtitle
- An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup
- Creators
- Stephanie A Christenson - University of California, San FranciscoMaarten van den Berge - University Medical Center GroningenAlen Faiz - University Medical Center GroningenKai Inkamp - University Medical Center GroningenNirav Bhakta - University of California, San FranciscoLuke R Bonser - University of California, San FranciscoLorna T Zlock - University of California, San FranciscoIgor Z Barjaktarevic - University of California, Los AngelesR Graham Barr - Columbia UniversityEugene R Bleecker - University of ArizonaRichard C Boucher - University of North Carolina at Chapel HillRussell P Bowler - National Jewish HealthAlejandro P Comellas - University of IowaJeffrey L Curtis - University of MichiganMeiLan K Han - Louisiana State University SystemNadia N Hansel - Johns Hopkins UniversityPieter S Hiemstra - Radboud University NijmegenRobert J Kaner - Cornell UniversityJerry A Krishnanm - University of Illinois SystemFernando J Martinez - Cornell UniversityWanda K O'Neal - University of North Carolina at Chapel HillRobert Paine III - University of UtahWim Timens - University Medical Center GroningenJ Michael Wells - University of Alabama at BirminghamAvrum Spira - Boston UniversityDavid J Erle - University of California, San FranciscoPrescott G Woodruff - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.129(1), pp.169-181
- DOI
- 10.1172/JCI121087
- PMID
- 30383540
- PMCID
- PMC6307967
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- P30 ES005605 / NIEHS NIH HHS U19 AI077439 / NIAID NIH HHS U01 HL137880 / NHLBI NIH HHS R01 HL121774 / NHLBI NIH HHS I01 CX000911 / CSRD VA P30 DK072517 / NIDDK NIH HHS R01 HL122438 / NHLBI NIH HHS K24 HL137013 / NHLBI NIH HHS R01 HL138424 / NHLBI NIH HHS K23 HL123778 / NHLBI NIH HHS P30 ES006694 / NIEHS NIH HHS K24 HL138188 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS K12 HL119997 / NHLBI NIH HHS
- Language
- English
- Date published
- 01/02/2019
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; ICTS; Internal Medicine
- Record Identifier
- 9984361735902771
Metrics
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