Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes

Baines, Katherine J.; Simpson, Jodie L.; Wood, Lisa G.; Scott, Rodney J.; Fibbens, Naomi L.; Powell, Heather; Cowan, Douglas C.; Taylor, D. Robin; Cowan, Jan O.; Gibson, Peter G.

doi:10.1016/j.jaci.2013.12.1091

Cited by 184 publications

(210 citation statements)

References 30 publications

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“…Although there was a significant correlation between the IL-13-induced signature, a (8,30 Ethics Committees of the recruiting centres. All participants gave written informed consent.…”

mentioning

confidence: 98%

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Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

Rossios

Pavlidis

Hoda

et al. 2018

Journal of Allergy and Clinical Immunology

179

136

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Background: Sputum analysis in asthma is used to define airway inflammatory processes and may guide therapy. Objective: To determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared to mildmoderate non-smoking asthmatics (MMA). Methods: Induced sputum was obtained from non-smoking SA (SAn), smokers/ex-smokers with SA (SAsm), MMA and healthy non-smoking controls. Differential cell counts, microarray analysis of cell pellets and SOMAscan analysis of sputum analytes was performed. CRID3 was used to inhibit the inflammasome in a mouse model of severe asthma. Results: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in SA compared to MMA. 42 genes probes were upregulated (>2-fold) in SAn compared to MMA including IL-1R family and NRLP3 inflammasome members (FDR<0.05). The inflammasome proteins NLRP1, NLRP3 and NLRC4 were associated with neutrophilic asthma and with sputum IL--13-induced Th2 signature and IL1RL1 mRNA expression. These differences were sputum-specific since no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsies in SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics (ADEPT) cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma.Conclusion: IL1RL1 gene expression is associated with eosinophilic SA whilst NLRP3 inflammasome expression is highest in neutrophilic SA. Th2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation may represent interacting pathways in SA.Imperial College of Science, Technology and Medicine We enclose a revised version of the above manscript entitled 'Sputum transcriptomics reveal upregulation of IL-1 receptor family members in severe asthma' by Rossios and collagues.We have responded to the Reviewer's comments in a point by point manner below and have incorporated the changes requested.We hope that the manuscript is now acceptable for publication. Responses to CommentsImperial College of Science, Technology and Medicine EDITOR'S SPECIFIC COMMENTS: Thank you for your thoughtful revision of this manuscript. However, I agree with Reviewer 2 in that adjusting for cell composition will allow you to determine whether your results are driven largely by differences in cellular composition or by true differences in gene expression. This will affect the interpretation of your results and provide important biological insight. Response: we have added this detail as detailed in response to Reviewers 1 and 2 below. COMMENTS FROM REVIEWER #1:The authors have addressed most of my original comments and have rewritten some sections of the manuscript to increase overall clarity. Response: We thank the Reviewer for their helpful comments which have improved the paper considerably.The one issue they did not address is...

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“…Although there was a significant correlation between the IL-13-induced signature, a (8,30 Ethics Committees of the recruiting centres. All participants gave written informed consent.…”

mentioning

confidence: 98%

“…Inflammasome activation in bronchial brushings or biopsies was not observed inflammasome activation in severe asthma (8,30 Supplementary Methods.…”

mentioning

confidence: 99%

Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

Rossios

Pavlidis

Hoda

et al. 2018

Journal of Allergy and Clinical Immunology

179

136

View full text Add to dashboard Cite

show abstract

“…Neutrophilic inflammation may play some role, but its meaning may differ on whether it is seen with or without eosinophils (84,85). Biopsy studies showed patients without eosinophilic inflammation have a thinner SBM, suggesting an alternative pathology, whereas studies by Wenzel and colleagues (42) and Baines and colleagues (86) showed differences in gene expression in sputum from patients with neutrophilic versus eosinophilic asthma. These studies argue for a role for neutrophilic inflammation in some asthmatic phenotypes.…”

Section: Type 2 Lo Asthmamentioning

confidence: 91%

Evolving Concepts of Asthma

Gauthier

Ray

Wenzel

2015

Am J Respir Crit Care Med

224

138

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“…Eosinophilic asthmatics display raised IL-5 and IL-13 levels in their sputum supernatant 43 and a peculiar gene signature in sputum cells 48 compared to healthy subjects. Interestingly, sputum cells from eosinophilic asthmatics cultured for 24 hours were shown to produce greater levels of IL-4 but less tumour necrosis factor (TNF)-α compared to those of healthy subjects 49 .…”

Section: Mechanisms Leading To Airway Eosinophilia In Asthmamentioning

confidence: 99%