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

Stephanie A. Christenson, Maarten Van Den Berge, Alen Faiz, Kai Inkamp, Nirav Bhakta, Luke R. Bonser, Lorna T. Zlock, Igor Z. Barjaktarevic, R. Graham Barr, Eugene R. Bleecker, Richard C. Boucher, Russell P. Bowler, Alejandro P. Comellas, Jeffrey L. Curtis, Mei Lan K. Han, Nadia Hansel, Pieter S. Hiemstra, Robert J. Kaner, Jerry A. Krishnanm, Fernando J. Martinez & 7 others Wanda K. O'Neal, Robert Paine, Wim Timens, J. Michael Wells, Avrum Spira, David J. Erle, Prescott G. Woodruff

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numberCI121087
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
StatePublished - Jan 2 2019

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Interleukin-17
Chronic Obstructive Pulmonary Disease
Steroids
Adrenal Cortex Hormones
Inflammation
Airway Obstruction
Phenotype
Smoking Cessation
Transcriptome
Psoriasis
Neutrophils
Thorax
Therapeutics
Smoking
Macrophages
Placebos

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Christenson, S. A., Van Den Berge, M., Faiz, A., Inkamp, K., Bhakta, N., Bonser, L. R., ... Woodruff, P. G. (2019). An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup. Journal of Clinical Investigation, 129(1), [CI121087]. https://doi.org/10.1172/JCI121087

An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup. / Christenson, Stephanie A.; Van Den Berge, Maarten; Faiz, Alen; Inkamp, Kai; Bhakta, Nirav; Bonser, Luke R.; Zlock, Lorna T.; Barjaktarevic, Igor Z.; Barr, R. Graham; Bleecker, Eugene R.; Boucher, Richard C.; Bowler, Russell P.; Comellas, Alejandro P.; Curtis, Jeffrey L.; Han, Mei Lan K.; Hansel, Nadia; Hiemstra, Pieter S.; Kaner, Robert J.; Krishnanm, Jerry A.; Martinez, Fernando J.; O'Neal, Wanda K.; Paine, Robert; Timens, Wim; Wells, J. Michael; Spira, Avrum; Erle, David J.; Woodruff, Prescott G.

In: Journal of Clinical Investigation, Vol. 129, No. 1, CI121087, 02.01.2019.

Research output: Contribution to journalArticle

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, N, Hiemstra, PS, Kaner, RJ, Krishnanm, JA, Martinez, FJ, O'Neal, WK, Paine, R, Timens, W, Wells, JM, Spira, A, Erle, DJ & Woodruff, PG 2019, 'An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup', Journal of Clinical Investigation, vol. 129, no. 1, CI121087. https://doi.org/10.1172/JCI121087
Christenson, Stephanie A. ; Van Den Berge, Maarten ; Faiz, Alen ; Inkamp, Kai ; Bhakta, Nirav ; Bonser, Luke R. ; Zlock, Lorna T. ; Barjaktarevic, Igor Z. ; Barr, R. Graham ; Bleecker, Eugene R. ; Boucher, Richard C. ; Bowler, Russell P. ; Comellas, Alejandro P. ; Curtis, Jeffrey L. ; Han, Mei Lan K. ; Hansel, Nadia ; Hiemstra, Pieter S. ; Kaner, Robert J. ; Krishnanm, Jerry A. ; Martinez, Fernando J. ; O'Neal, Wanda K. ; Paine, Robert ; Timens, Wim ; Wells, J. Michael ; Spira, Avrum ; Erle, David J. ; Woodruff, Prescott G. / An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 1.
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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.",
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T1 - An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup

AU - Christenson, Stephanie A.

AU - Van Den Berge, Maarten

AU - Faiz, Alen

AU - Inkamp, Kai

AU - Bhakta, Nirav

AU - Bonser, Luke R.

AU - Zlock, Lorna T.

AU - Barjaktarevic, Igor Z.

AU - Barr, R. Graham

AU - Bleecker, Eugene R.

AU - Boucher, Richard C.

AU - Bowler, Russell P.

AU - Comellas, Alejandro P.

AU - Curtis, Jeffrey L.

AU - Han, Mei Lan K.

AU - Hansel, Nadia

AU - Hiemstra, Pieter S.

AU - Kaner, Robert J.

AU - Krishnanm, Jerry A.

AU - Martinez, Fernando J.

AU - O'Neal, Wanda K.

AU - Paine, Robert

AU - Timens, Wim

AU - Wells, J. Michael

AU - Spira, Avrum

AU - Erle, David J.

AU - Woodruff, Prescott G.

PY - 2019/1/2

Y1 - 2019/1/2

N2 - 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.

AB - 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.

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