独特蛋白酶表型的上皮内肥大细胞积聚在高Th2细胞型哮喘中的作用
2010/08/11
背景：前期研究已经显示，肥大细胞类胰蛋白酶和羧肽酶A3（CPA3）在哮喘患者气道上皮存在差异性表达。基于上皮细胞针对Th2细胞因子活性的基因标志，我们将哮喘分为2种亚型：高Th2型和低Th2型。
目的：本文旨在描述哮喘患者上皮内肥大细胞（IEMCs）的特征。
方法：对健康对照者和哮喘患者，糖皮质激素吸入治疗（ICSs）前后，检测上皮细胞基因表达及对支气管活检样本采用立体测量法检测肥大细胞数量。此外，对培养的气道上皮细胞和肥大细胞进行基因表达检测和蛋白定量检测。
结果：非监督聚类法分析显示，气道上皮细胞中的肥大细胞基因表达与IL-13标记基因表达密切相关。肥大细胞基因表达水平与ICSs肺功能改善正相关。与低Th2哮喘和健康对照相比，高Th2哮喘患者的IEMC 密度是正常的2倍（P = .015），这些细胞以表达类胰蛋白酶和CPA3（而不是糜蛋白酶）为特征。在培养的气道上皮细胞中，IL-13能诱导干细胞因子表达；将肥大细胞暴露于IL-13活化的上皮细胞的条件培养液，糜蛋白酶表达下调，但类胰蛋白酶和CPA3表达无显著变化。
结论：高Th2哮喘患者IEMC的数量增加，具有独特的蛋白酶表型（类胰蛋白酶和CPA3高表达，糜蛋白酶低表达），IEMC的数量能预测患者对ICSs的反应。IL-13刺激上皮细胞产生干细胞因子可以解释高Th2哮喘患者上皮细胞中肥大细胞积聚的原因。
（林江涛 审校）
J Allergy Clin Immunol. 2010 May;125(5):1046-1053.e8.
Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma.
Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV.
Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA, USA.
Abstract
BACKGROUND: Previously, we found that mast cell tryptases and carboxypeptidase A3 (CPA3) are differentially expressed in the airway epithelium in asthmatic subjects. We also found that asthmatic subjects can be divided into 2 subgroups ("T(H)2 high" and "T(H)2 low" asthma) based on epithelial cell gene signatures for the activity of T(H)2 cytokines.
OBJECTIVES: We sought to characterize intraepithelial mast cells (IEMCs) in asthma.
METHODS: We performed gene expression profiling in epithelial brushings and stereology-based quantification of mast cell numbers in endobronchial biopsy specimens from healthy control and asthmatic subjects before and after treatment with inhaled corticosteroids (ICSs). We also performed gene expression and protein quantification studies in cultured airway epithelial cells and mast cells.
RESULTS: By means of unsupervised clustering, mast cell gene expression in the airway epithelium related closely to the expression of IL-13 signature genes. The levels of expression of mast cell genes correlate positively with lung function improvements with ICSs. IEMC density was 2-fold higher than normal in subjects with T(H)2-high asthma compared with that seen in subjects with T(H)2-low asthma or healthy control subjects (P = .015 for both comparisons), and these cells were characterized by expression of tryptases and CPA3 but not chymase. IL-13 induced expression of stem cell factor in cultured airway epithelial cells, and mast cells exposed to conditioned media from IL-13-activated epithelial cells showed downregulation of chymase but no change in tryptase or CPA3 expression.
CONCLUSION: IEMC numbers are increased in subjects with T(H)2-high asthma, have an unusual protease phenotype (tryptase and CPA3 high and chymase low), and predict responsiveness to ICSs. IL-13-stimulated production of stem cell factor by epithelial cells potentially explains mast cell accumulation in T(H)2-high asthmatic epithelium
J Allergy Clin Immunol. 2010 May;125(5):1046-1053.
目的：本文旨在描述哮喘患者上皮内肥大细胞（IEMCs）的特征。
方法：对健康对照者和哮喘患者，糖皮质激素吸入治疗（ICSs）前后，检测上皮细胞基因表达及对支气管活检样本采用立体测量法检测肥大细胞数量。此外，对培养的气道上皮细胞和肥大细胞进行基因表达检测和蛋白定量检测。
结果：非监督聚类法分析显示，气道上皮细胞中的肥大细胞基因表达与IL-13标记基因表达密切相关。肥大细胞基因表达水平与ICSs肺功能改善正相关。与低Th2哮喘和健康对照相比，高Th2哮喘患者的IEMC 密度是正常的2倍（P = .015），这些细胞以表达类胰蛋白酶和CPA3（而不是糜蛋白酶）为特征。在培养的气道上皮细胞中，IL-13能诱导干细胞因子表达；将肥大细胞暴露于IL-13活化的上皮细胞的条件培养液，糜蛋白酶表达下调，但类胰蛋白酶和CPA3表达无显著变化。
结论：高Th2哮喘患者IEMC的数量增加，具有独特的蛋白酶表型（类胰蛋白酶和CPA3高表达，糜蛋白酶低表达），IEMC的数量能预测患者对ICSs的反应。IL-13刺激上皮细胞产生干细胞因子可以解释高Th2哮喘患者上皮细胞中肥大细胞积聚的原因。
（林江涛 审校）
J Allergy Clin Immunol. 2010 May;125(5):1046-1053.e8.
Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma.
Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV.
Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA, USA.
Abstract
BACKGROUND: Previously, we found that mast cell tryptases and carboxypeptidase A3 (CPA3) are differentially expressed in the airway epithelium in asthmatic subjects. We also found that asthmatic subjects can be divided into 2 subgroups ("T(H)2 high" and "T(H)2 low" asthma) based on epithelial cell gene signatures for the activity of T(H)2 cytokines.
OBJECTIVES: We sought to characterize intraepithelial mast cells (IEMCs) in asthma.
METHODS: We performed gene expression profiling in epithelial brushings and stereology-based quantification of mast cell numbers in endobronchial biopsy specimens from healthy control and asthmatic subjects before and after treatment with inhaled corticosteroids (ICSs). We also performed gene expression and protein quantification studies in cultured airway epithelial cells and mast cells.
RESULTS: By means of unsupervised clustering, mast cell gene expression in the airway epithelium related closely to the expression of IL-13 signature genes. The levels of expression of mast cell genes correlate positively with lung function improvements with ICSs. IEMC density was 2-fold higher than normal in subjects with T(H)2-high asthma compared with that seen in subjects with T(H)2-low asthma or healthy control subjects (P = .015 for both comparisons), and these cells were characterized by expression of tryptases and CPA3 but not chymase. IL-13 induced expression of stem cell factor in cultured airway epithelial cells, and mast cells exposed to conditioned media from IL-13-activated epithelial cells showed downregulation of chymase but no change in tryptase or CPA3 expression.
CONCLUSION: IEMC numbers are increased in subjects with T(H)2-high asthma, have an unusual protease phenotype (tryptase and CPA3 high and chymase low), and predict responsiveness to ICSs. IL-13-stimulated production of stem cell factor by epithelial cells potentially explains mast cell accumulation in T(H)2-high asthmatic epithelium
J Allergy Clin Immunol. 2010 May;125(5):1046-1053.
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病毒在急性哮喘加重中的作用
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