Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD.

Faiz, A; Pavlidis, S; Kuo, C-H; Rowe, A; Hiemstra, PS; Timens, W; Berg, M; Wisman, M; Guo, Y-K; Djukanović, R; Sterk, P; Meyer, KB; Nawijn, MC; Adcock, I; Chung, KF; van den Berge, M

Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD.

Pavlidis, S Kuo, C-H Rowe, A Hiemstra, PS Timens, W Berg, M Wisman, M Guo, Y-K Djukanović, R Sterk, P Meyer, KB Nawijn, MC Adcock, I Chung, KF van den Berge, M

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Publisher:: BMJ PUBLISHING GROUP
Publication Type:: Journal Article
Citation:: Thorax, 2023, 78, (4), pp. 335-343
Issue Date:: 2023

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Field	Value	Language
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Pavlidis, S
dc.contributor.author	Kuo, C-H
dc.contributor.author	Rowe, A
dc.contributor.author	Hiemstra, PS
dc.contributor.author	Timens, W
dc.contributor.author	Berg, M
dc.contributor.author	Wisman, M
dc.contributor.author	Guo, Y-K
dc.contributor.author	Djukanović, R
dc.contributor.author	Sterk, P
dc.contributor.author	Meyer, KB
dc.contributor.author	Nawijn, MC
dc.contributor.author	Adcock, I
dc.contributor.author	Chung, KF
dc.contributor.author	van den Berge, M
dc.date.accessioned	2023-09-28T01:15:53Z
dc.date.available	2022-10-27
dc.date.available	2023-09-28T01:15:53Z
dc.date.issued	2023
dc.identifier.citation	Thorax, 2023, 78, (4), pp. 335-343
dc.identifier.issn	0040-6376
dc.identifier.issn	1468-3296
dc.identifier.uri	http://hdl.handle.net/10453/172353
dc.description.abstract	RATIONALE: Severe asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3). OBJECTIVE: We examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity. METHODS: Using gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types. MEASUREMENTS AND MAIN RESULTS: Bronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA. CONCLUSION: Sputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	BMJ PUBLISHING GROUP
dc.relation.ispartof	Thorax
dc.relation.isbasedon	10.1136/thorax-2021-217736
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences
dc.subject.classification	Respiratory System
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.classification	3202 Clinical sciences
dc.subject.mesh	Humans
dc.subject.mesh	Administration, Inhalation
dc.subject.mesh	Adrenal Cortex Hormones
dc.subject.mesh	Adrenergic beta-2 Receptor Agonists
dc.subject.mesh	Asthma
dc.subject.mesh	Biomarkers
dc.subject.mesh	Bronchodilator Agents
dc.subject.mesh	Drug Therapy, Combination
dc.subject.mesh	Mast Cells
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Th2 Cells
dc.subject.mesh	Th2 Cells
dc.subject.mesh	Mast Cells
dc.subject.mesh	Humans
dc.subject.mesh	Asthma
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Adrenal Cortex Hormones
dc.subject.mesh	Bronchodilator Agents
dc.subject.mesh	Drug Therapy, Combination
dc.subject.mesh	Administration, Inhalation
dc.subject.mesh	Adrenergic beta-2 Receptor Agonists
dc.subject.mesh	Biomarkers
dc.subject.mesh	Humans
dc.subject.mesh	Administration, Inhalation
dc.subject.mesh	Adrenal Cortex Hormones
dc.subject.mesh	Adrenergic beta-2 Receptor Agonists
dc.subject.mesh	Asthma
dc.subject.mesh	Biomarkers
dc.subject.mesh	Bronchodilator Agents
dc.subject.mesh	Drug Therapy, Combination
dc.subject.mesh	Mast Cells
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Th2 Cells
dc.title	Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD.
dc.type	Journal Article
utslib.citation.volume	78
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
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
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2023-09-28T01:15:47Z
pubs.issue	4
pubs.publication-status	Published online
pubs.volume	78
utslib.citation.issue	4

Abstract:

RATIONALE: Severe asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3). OBJECTIVE: We examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity. METHODS: Using gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types. MEASUREMENTS AND MAIN RESULTS: Bronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA. CONCLUSION: Sputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.

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http://hdl.handle.net/10453/172353