Sputum Gene Expression Reveals Dysregulation of Mast Cells and Basophils in Eosinophilic COPD

Natasha A Winter,1– 3 Peter G Gibson,1– 5 Vanessa M McDonald,1,2,4,6 Michael Fricker1– 4 1National Health and Medical Research Council Centre for Research Excellence in Severe Asthma, Newcastle, NSW, Australia; 2The Priority Research Centre for Health Lungs, The University of Newcastle, Newcastle, NSW, Australia; 3School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia; 4Hunter Medical Research Institute, Newcastle, NSW, Australia; 5Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia; 6School of Nursing and Midwifery, The University of Newcastle, Newcastle, NSW, AustraliaCorrespondence: Michael FrickerThe Priority Research Centre for Healthy Lungs, The University of Newcastle, Lot 1 Kookaburra Circuit, New Lambton Heights, NSW, 2305, AustraliaTel +64 2 4042 0207Email Michael.Fricker@newcastle.edu.auPurpose: The clinical and inflammatory associations of mast cells (MCs) and basophils in chronic obstructive pulmonary disease (COPD) are poorly understood. We previously developed and validated a qPCR-based MC/basophil gene signature in asthma to measure these cells in sputum samples. Here, we measured this gene signature in a COPD and control population to explore the relationship of sputum MCs/basophils to inflammatory and COPD clinical characteristics.Patients and Methods: MC/basophil signature genes (TPSAB1/TPSB2, CPA3, ENO2, GATA2, KIT, GPR56, HDC, SOCS2) were measured by qPCR in sputum from a COPD (n=96) and a non-respiratory control (n=17) population. Comparative analyses of gene expression between the COPD and the control population, and between eosinophilic COPD and non-eosinophilic COPD were tested. Logistic regression analysis and Spearman correlation were used to determine relationships of sputum MC/basophil genes to inflammatory (sputum eosinophil proportions, blood eosinophils) and clinical (age, body mass index, quality of life, lung function, past year exacerbations) characteristics of COPD.Results: MC/basophil genes were increased in COPD versus control participants (CPA3, KIT, GATA2, HDC) and between eosinophilic-COPD and non-eosinophilic COPD (TPSB2, CPA3, HDC, SOCS2). We found all MC/basophil genes were positively intercorrelated. In COPD, MC/basophil genes were associated with eosinophilic airway inflammation (GATA2, TPSB2, CPA3, GPR56, HDC, SOCS2), blood eosinophilia (all genes) and decreased lung function (KIT, GATA2, GPR56, HDC).Conclusion: We demonstrate associations of MCs and basophils with eosinophilic inflammation and lower lung function in COPD. These findings are consistent with prior results in asthma and may represent a new tool for endotyping eosinophilic-COPD.Keywords: basophils, mast cells, COPD, gene expression, inflammatio