上皮内肥大细胞在 T(H)2 高哮喘中的积累与独特的蛋白酶表型有关。
Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma.
机构信息
Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA, USA.
出版信息
J Allergy Clin Immunol. 2010 May;125(5):1046-1053.e8. doi: 10.1016/j.jaci.2010.03.003.
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.
背景
此前，我们发现肥大细胞胰蛋白酶和羧肽酶 A3（CPA3）在哮喘患者的气道上皮中差异表达。我们还发现，根据上皮细胞 T(H)2 细胞因子活性的基因特征，哮喘患者可以分为 2 个亚组（“T(H)2 高”和“T(H)2 低”哮喘）。
目的
我们旨在描述哮喘中的气道上皮内肥大细胞（IEMC）。
方法
我们对健康对照者和哮喘患者经吸入性皮质类固醇（ICS）治疗前后的上皮刷检物进行基因表达谱分析，并对支气管活检标本进行基于体视学的肥大细胞计数。我们还对培养的气道上皮细胞和肥大细胞进行基因表达和蛋白定量研究。
结果
通过无监督聚类，气道上皮中的肥大细胞基因表达与 IL-13 特征基因的表达密切相关。肥大细胞基因的表达水平与 ICS 治疗时的肺功能改善呈正相关。与 T(H)2 低哮喘或健康对照组相比，T(H)2 高哮喘患者的 IEMC 密度高 2 倍（两者比较 P 值均为.015），这些细胞的特征是表达胰蛋白酶和 CPA3，但不表达糜蛋白酶。IL-13 在培养的气道上皮细胞中诱导干细胞因子的表达，暴露于 IL-13 激活的上皮细胞条件培养基中的肥大细胞表现出糜蛋白酶的下调，但胰蛋白酶或 CPA3 的表达没有变化。
结论
T(H)2 高哮喘患者的 IEMC 数量增加，具有异常的蛋白酶表型（胰蛋白酶和 CPA3 高，糜蛋白酶低），并预测对 ICS 的反应性。上皮细胞中 IL-13 刺激的干细胞因子的产生可能解释了 T(H)2 高哮喘上皮中肥大细胞的积累。
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