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, MLK; 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

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, MLK 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

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Publication Type:: Journal Article
Citation:: Journal of Clinical Investigation, 2019, 129 (1)
Issue Date:: 2019-01-02

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Field	Value	Language
dc.contributor.author	Christenson, SA	en_US
dc.contributor.author	Van Den Berge, M	en_US
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538	en_US
dc.contributor.author	Inkamp, K	en_US
dc.contributor.author	Bhakta, N	en_US
dc.contributor.author	Bonser, LR	en_US
dc.contributor.author	Zlock, LT	en_US
dc.contributor.author	Barjaktarevic, IZ https://orcid.org/0000-0002-8096-0858	en_US
dc.contributor.author	Barr, RG	en_US
dc.contributor.author	Bleecker, ER	en_US
dc.contributor.author	Boucher, RC	en_US
dc.contributor.author	Bowler, RP	en_US
dc.contributor.author	Comellas, AP	en_US
dc.contributor.author	Curtis, JL	en_US
dc.contributor.author	Han, MLK	en_US
dc.contributor.author	Hansel, NN	en_US
dc.contributor.author	Hiemstra, PS	en_US
dc.contributor.author	Kaner, RJ	en_US
dc.contributor.author	Krishnanm, JA	en_US
dc.contributor.author	Martinez, FJ	en_US
dc.contributor.author	O'Neal, WK	en_US
dc.contributor.author	Paine, R	en_US
dc.contributor.author	Timens, W	en_US
dc.contributor.author	Wells, JM	en_US
dc.contributor.author	Spira, A	en_US
dc.contributor.author	Erle, DJ	en_US
dc.contributor.author	Woodruff, PG	en_US
dc.date.available	2018-10-19	en_US
dc.date.issued	2019-01-02	en_US
dc.identifier.citation	Journal of Clinical Investigation, 2019, 129 (1)	en_US
dc.identifier.issn	0021-9738	en_US
dc.identifier.uri	http://hdl.handle.net/10453/134044
dc.description.abstract	© 2019 American Society for Clinical Investigation. All rights reserved. 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.	en_US
dc.relation.ispartof	Journal of Clinical Investigation	en_US
dc.relation.isbasedon	10.1172/JCI121087	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Bronchi	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive	en_US
dc.subject.mesh	Psoriasis	en_US
dc.subject.mesh	Adrenal Cortex Hormones	en_US
dc.subject.mesh	Interleukin-17	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Drug Resistance	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.title	An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	129	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	129	en_US

Abstract:

© 2019 American Society for Clinical Investigation. All rights reserved. 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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/134044