Bogdan Jakieła1, Grazyna Bochenek, Marek Sanak. 1. 2nd Department of Internal Medicine, Jagiellonian University School of Medicine, Kraków, Poland. bogumil.j@poczta.fm
Abstract
INTRODUCTION: Ineffective response to glucocorticoids (GCs) in severe asthma may result from enhanced T-cell activation, immune dysregulation, or altered expression of glucocorticoid receptor (GR). OBJECTIVES: The aim of the study was to analyze the expression of GR isoforms and in vitro sensitivity of lymphocytes to GCs in severe, steroid-dependent asthma. PATIENTS AND METHODS: We analyzed the immunophenotype of peripheral blood lymphocytes, the effect of dexamethasone (DEX) on lymphocyte activation and proliferation, and the levels of GRalpha and GRbeta mRNA in peripheral blood lymphocytes of 11 healthy subjects, 15 moderate asthmatics, 11 severe asthmatics on low-dose oral GCs, and 14 severe asthmatics with suboptimal symptom control on high-dose oral GCs. RESULTS: The average level of GRbeta mRNA in lymphocytes was more than 300-fold lower than GRalpha, and this ratio was comparable in all groups. Lymphocytes from steroid-dependent asthmatics were sensitive to steroids in in-vitro activation assays, as evidenced by a significant decrease in activation antigen (CD25, CD69) expression, and inhibition of mitogen-induced proliferation upon incubation with DEX. The results of in vitro functional assays were similar in all groups and did not correlate with the GRalpha/GRbeta ratio. CONCLUSIONS: Steroid dependency in severe asthma is not associated with GRbeta upregulation in lymphocytes or abnormal T-cell reactivity in the presence of GCs. These data suggest that testing for the expression of GRalpha and GRbeta isoforms in blood lymphocytes will not be useful in predicting sensitivity to GCs in severe asthma.
INTRODUCTION: Ineffective response to glucocorticoids (GCs) in severe asthma may result from enhanced T-cell activation, immune dysregulation, or altered expression of glucocorticoid receptor (GR). OBJECTIVES: The aim of the study was to analyze the expression of GR isoforms and in vitro sensitivity of lymphocytes to GCs in severe, steroid-dependent asthma. PATIENTS AND METHODS: We analyzed the immunophenotype of peripheral blood lymphocytes, the effect of dexamethasone (DEX) on lymphocyte activation and proliferation, and the levels of GRalpha and GRbeta mRNA in peripheral blood lymphocytes of 11 healthy subjects, 15 moderate asthmatics, 11 severe asthmatics on low-dose oral GCs, and 14 severe asthmatics with suboptimal symptom control on high-dose oral GCs. RESULTS: The average level of GRbeta mRNA in lymphocytes was more than 300-fold lower than GRalpha, and this ratio was comparable in all groups. Lymphocytes from steroid-dependent asthmatics were sensitive to steroids in in-vitro activation assays, as evidenced by a significant decrease in activation antigen (CD25, CD69) expression, and inhibition of mitogen-induced proliferation upon incubation with DEX. The results of in vitro functional assays were similar in all groups and did not correlate with the GRalpha/GRbeta ratio. CONCLUSIONS:Steroid dependency in severe asthma is not associated with GRbeta upregulation in lymphocytes or abnormal T-cell reactivity in the presence of GCs. These data suggest that testing for the expression of GRalpha and GRbeta isoforms in blood lymphocytes will not be useful in predicting sensitivity to GCs in severe asthma.
Authors: Po-Jui Chang; Charalambos Michaeloudes; Jie Zhu; Nooreen Shaikh; Josephine Baker; Kian Fan Chung; Pankaj K Bhavsar Journal: Am J Respir Crit Care Med Date: 2015-01-01 Impact factor: 30.528