T-helper Type 2-driven Inflammation Defines Major Subphenotypes of Asthma
T-helper Type 2-driven Inflammation Defines Major Subphenotypes of Asthma
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DOI：
10.1164/rccm.200903-0392oc
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发表时间：
2009-09-01
影响因子：
24.7
通讯作者：
Fahy, John V.
中科院分区：
文献类型：
--
作者：
Woodruff, Prescott G.;Modrek, Barmak;Fahy, John V.
基本原理-T 辅助细胞 2 型 (Th2) 炎症由 IL-4、IL-5 和 IL-13 介导，被认为是哮喘的核心分子机制，而 Th2 细胞因子是新兴的治疗靶点。然而，临床研究越来越多地表明哮喘具有异质性。 目的：确定这种临床异质性是否反映了与 Th2 炎症相关的潜在分子机制的异质性。方法：使用微阵列和聚合酶链反应分析 42 名轻至中度哮喘患者和 28 名健康对照受试者的气道上皮刷检结果，我们根据 IL-13 诱导基因的高或低表达对哮喘受试者进行分类。然后，我们验证了这种分类，并通过分析支气管活检中的细胞因子表达、炎症和重塑标志物、对吸入皮质类固醇的反应性以及重复检查的可重复性来研究其临床意义。测量和主要结果：基因表达分析确定了两个大小均匀且不同的亚组，“Th2-高”和“Th2-低”哮喘（后者与对照受试者无法区分）。这些亚组在支气管活检中IL-5和IL-13的表达以及气道高反应性、血清IgE、血液和气道嗜酸性粒细胞增多、上皮下纤维化和气道粘蛋白基因表达方面存在显着差异（均P < 0.03）。吸入皮质类固醇预期的肺功能改善仅限于 Th2 高哮喘，并且 Th2 标志物在重复评估中是可重复的。结论：哮喘可根据 Th2 炎症程度分为至少两种不同的分子表型。 Th2 细胞因子可能只是一部分哮喘患者的相关治疗靶点。此外，当前的模型不能充分解释非 Th2 驱动的哮喘，这种哮喘占患者的很大一部分，并且对当前的治疗反应不佳。
Rationale-T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous.Objectives: To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation.Methods: Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination.Measurements and Main Results: Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation.Conclusions: Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.