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

Abstract

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.

Dynamically upregulated mast cell CPA3 patterns in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

“…Taken together, our study agrees with previous data on increased sputum CPA3 in COPD ( 29 , 43 , 45 ) and elevated CPA3 in IPF ( 39 ). It is likely that the strikingly increased and strategically localized MC CPA3 mRNA expression revealed in this study will impact pathophysiological and immunopathological processes in COPD and IPF lungs.…”

“…It is, however, noteworthy that, as for asthma ( 34 , 44 ), CPA3 levels in COPD and IPF may be particularly elevated in the subcategory of patients that have a type 2 immunity and eosinophil signature ( 29 , 45 ). Indeed, the present correlation between pooled patient mast cell CPA3 mRNA and eosinophils supports this possibility.…”

Carboxypeptidase A3—A Key Component of the Protease Phenotype of Mast Cells

“…CPA3 is involved in the pathogenesis of cancer, inflammatory diseases of the gastrointestinal tract, respiratory and cardiovascular systems, disorders of the musculoskeletal system, as well as in immunogenesis. In particular, CPA3 can also be considered as a diagnostic marker and pharmacological target in the treatment of a number of pathological conditions [8,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. In addition, CPA3 in serum appeared as a good biomarker for identifying severe COVID-19 patients [31].…”

Prospects of DNA microarray application in management of chronic obstructive pulmonary disease: A systematic review

“…The focus is on GATA binding protein 2 (GATA2), a receptor tyrosine kinase type Ⅲ (KIT), and histidine decarboxylase (HDC), which are strongly associated with decreased lung function, while GATA2 plays an important role in macrophages/basophils development and proliferation, which in turn leads to the acute inflammation. There is also a study by Yu et al [25] , that constructs 7 gene signature based on difference analysis and trait module analysis. Over-expression of genes constituting these signatures could indicate onset of pathological processes contributing to COPD; therefore, patients that show high levels of gene signature expression should be under observation.…”

“…Winter et al [25] 2021 Affymetrix Sputum, peripheral blood TPSB2, CPA3, KIT, GATA2, SOCS2, ENO2, GPR56, HDC COPD, chronic obstructive pulmonary disease.…”