Gender differences in the T-cell profiles of the airways in COPD patients associated with clinical phenotypes

Abstract

Helena Forsslund,1 Mingxing Yang,1 Mikael Mikko,1 Reza Karimi,1 Sven Nyrén,2 Benita Engvall,1 Johan Grunewald,1 Heta Merikallio,1,3 Riitta Kaarteenaho,3–5 Jan Wahlström,1 Åsa M Wheelock,1 C Magnus Sköld1 1Department of Medicine Solna and Centre for Molecular Medicine, Respiratory Medicine Unit, 2Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; 3Respiratory Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland; 4Unit of Medicine and Clinical Research, Pulmonary Division, University of Eastern Finland, 5Center for Medicine and Clinical Research, Division of Respiratory Medicine, Kuopio University Hospital, Kuopio, Finland Abstract: T lymphocytes are believed to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). How T cells are recruited to the lungs and contribute to the inflammatory process is largely unknown. COPD is a heterogeneous disease, and discriminating disease phenotypes based on distinct molecular and cellular pathways may provide new approaches for individualized diagnosis and therapies. Bronchoalveolar lavage (BAL) and blood samples were obtained from 40 never-smokers, 40 smokers with normal lung function, and 38 COPD patients. T-cell chemokine receptor expression was analyzed with flow cytometry, and soluble BAL cytokines and chemokines were measured using a cytokine multiplex assay. Correlations with gender and clinical characteristics including lung imaging were investigated using multivariate modeling. Th1/Tc1- and Th2/Tc2-associated soluble analytes and T-cell chemokine receptors were analyzed as cumulative Th1/Tc1 and Th2/Tc2 immune responses. A higher expression of chemokine receptor CCR5 on CD8+ T cells in BAL and higher percentage of CXCR3+CD8+ T cells in blood was found in female smokers with COPD compared to those without COPD. CCR5 expression on CD4+ and CD8+ T cells was lower in BAL from male smokers with COPD compared to those without COPD. Among female smokers with COPD, Th1/Tc1 immune response was linked to BAL macrophage numbers and goblet cell density, and Th2/Tc2 response was associated with the measures of emphysema on high-resolution computed tomography. The highly gender-dependent T-cell profile in COPD indicates different links between cellular events and clinical manifestations in females compared to males. Our findings may reveal mechanisms of importance for the difference in clinical course in female COPD patients compared to males. Keywords: bronchoalveolar lavage, chemokines, cytokines, Th1/Th2

Keywords

• COPD
• T-cells
• Gender differences
• Chemokines