2型细胞因子生物标志物高表达和低表达的重度哮喘患者气道转录组
2026/07/31
摘要
重度哮喘是一种异质性疾病。当2型（T2）细胞因子活性受到抑制时，驱动气道病理变化的机制仍不甚清楚。本研究旨在通过识别T2生物标志物高和低的重度哮喘患者的气道分子通路来提供新的见解。我们分析了英国难治性哮喘分层项目多中心重度哮喘队列（18 例皮质类固醇抵抗的T2生物标志物高[T2-高]患者、23 例T2生物标志物中等[T2－中等]患者、11 例 T2 生物标志物低[T2－低]患者）以及20例健康对照者在高剂量吸入皮质类固醇（ICS）治疗前后的支气管活检和刷检的临床和转录组学数据。与健康人相比，哮喘患者中许多失调的基因在接受ICS治疗的健康受试者中也发生了类似的失调。总体而言，重度哮喘的特征是黏蛋白、癌胚抗原相关细胞黏附分子5（CEACAM5）、典型的T2基因（POSTN、CLCA1、CCL26）、上皮肥大细胞基因和 CPA4上调，且不受ICS的影响。T2-高型重度哮喘表现为T2依赖性基因、上皮屏障和角蛋白基因上调，适应性免疫反应增强，纤毛功能受损。T2-低型哮喘表现为Th1和IL-17相关基因（IDO1、CXCL10、GBP1、LAG3）上调，γ-干扰素信号通路、神经免疫通路、气道平滑肌相关基因激活，以及中性粒细胞富集。T2-中型哮喘呈现出一种混合分子特征，兼具T2-高型和T2-低型的特点，且选择性表达病原体防御和抗病毒反应基因。研究结果通过U-BIOPRED 联盟的支气管镜检查数据得到了验证。本研究确定了与T2生物标志物高和低表型相关的重度哮喘气道分子内型，且不受皮质类固醇效应的影响。这些发现为重度哮喘的管理和靶向生物治疗的开发提供了新的见解。
The Airway Transcriptome in Type 2 Cytokine Biomarker-High and -Low Severe Asthma
Jiashu Shen, Rekha Chaudhuri, Stephen Bicknell, Adel H Mansur, Rahul Shrimanker, Ian D Pavord, Stephen J Fowler, Vanessa Brown, Lorcan P McGarvey, Peter H Howarth, Sven-Erik Dahlén, Ian M Adcock, Nazanin Zounemat-Kermani, Joseph R Arron, Liam G Heaney, David F Choy, Timothy S C Hinks, Emanuele Marchi, Peter Bradding; UK Medical Research Council Refractory Asthma Stratification programme (RASP‐UK)
Abstract
Severe asthma is a heterogeneous disease. The mechanisms driving airway pathology when type 2 (T2) cytokine activity is suppressed remain poorly understood. This study aimed to provide insight by identifying the airway molecular pathways of T2 biomarker-high and -low severe asthma. We analysed clinical and transcriptomic data from bronchial biopsies and brushes in the UK Refractory Asthma Stratification Programme multi-centre severe asthma cohort (18 corticosteroid-resistant T2 biomarker-high [T2-high], 23 T2 biomarker-intermediate [T2-intermediate], 11 T2 biomarker-low [T2-low]) plus 20 healthy controls pre- and post-treatment with high-dose inhaled corticosteroids (ICS). Many genes dysregulated in asthma vs. health were concordantly dysregulated in healthy subjects receiving ICS. Severe asthma as a whole, independent of confounding by ICS, was characterised by upregulation of mucins, CEACAM5, typical T2-genes (POSTN, CLCA1, CCL26), epithelial mast cell genes, and CPA4. T2-high severe asthma demonstrated upregulated T2-dependent genes, epithelial barrier and keratin genes, adaptive immune responses, and impaired ciliary function. T2-low asthma showed upregulated Th1- and IL-17-associated genes (IDO1, CXCL10, GBP1, LAG3), interferon-γ signalling, neuroimmune pathways, airway smooth muscle-related genes, and neutrophil enrichment. T2-intermediate asthma exhibited a mixed molecular profile sharing features of T2-high and T2-low endotypes, with selective expression of the pathogen defence and antiviral response genes. The results were validated using bronchoscopy data from the U-BIOPRED Consortium. This study defines airway molecular endotypes of severe asthma associated with T2 biomarker high and low phenotypes, independent of corticosteroid effects. These findings offer insights for severe asthma management and the development of targeted biologic therapies.
重度哮喘是一种异质性疾病。当2型（T2）细胞因子活性受到抑制时，驱动气道病理变化的机制仍不甚清楚。本研究旨在通过识别T2生物标志物高和低的重度哮喘患者的气道分子通路来提供新的见解。我们分析了英国难治性哮喘分层项目多中心重度哮喘队列（18 例皮质类固醇抵抗的T2生物标志物高[T2-高]患者、23 例T2生物标志物中等[T2－中等]患者、11 例 T2 生物标志物低[T2－低]患者）以及20例健康对照者在高剂量吸入皮质类固醇（ICS）治疗前后的支气管活检和刷检的临床和转录组学数据。与健康人相比，哮喘患者中许多失调的基因在接受ICS治疗的健康受试者中也发生了类似的失调。总体而言，重度哮喘的特征是黏蛋白、癌胚抗原相关细胞黏附分子5（CEACAM5）、典型的T2基因（POSTN、CLCA1、CCL26）、上皮肥大细胞基因和 CPA4上调，且不受ICS的影响。T2-高型重度哮喘表现为T2依赖性基因、上皮屏障和角蛋白基因上调，适应性免疫反应增强，纤毛功能受损。T2-低型哮喘表现为Th1和IL-17相关基因（IDO1、CXCL10、GBP1、LAG3）上调，γ-干扰素信号通路、神经免疫通路、气道平滑肌相关基因激活，以及中性粒细胞富集。T2-中型哮喘呈现出一种混合分子特征，兼具T2-高型和T2-低型的特点，且选择性表达病原体防御和抗病毒反应基因。研究结果通过U-BIOPRED 联盟的支气管镜检查数据得到了验证。本研究确定了与T2生物标志物高和低表型相关的重度哮喘气道分子内型，且不受皮质类固醇效应的影响。这些发现为重度哮喘的管理和靶向生物治疗的开发提供了新的见解。
（中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校）
（Allergy. 2026 Jul 20. doi: 10.1111/all.70441.）
（Allergy. 2026 Jul 20. doi: 10.1111/all.70441.）
The Airway Transcriptome in Type 2 Cytokine Biomarker-High and -Low Severe Asthma
Jiashu Shen, Rekha Chaudhuri, Stephen Bicknell, Adel H Mansur, Rahul Shrimanker, Ian D Pavord, Stephen J Fowler, Vanessa Brown, Lorcan P McGarvey, Peter H Howarth, Sven-Erik Dahlén, Ian M Adcock, Nazanin Zounemat-Kermani, Joseph R Arron, Liam G Heaney, David F Choy, Timothy S C Hinks, Emanuele Marchi, Peter Bradding; UK Medical Research Council Refractory Asthma Stratification programme (RASP‐UK)
Abstract
Severe asthma is a heterogeneous disease. The mechanisms driving airway pathology when type 2 (T2) cytokine activity is suppressed remain poorly understood. This study aimed to provide insight by identifying the airway molecular pathways of T2 biomarker-high and -low severe asthma. We analysed clinical and transcriptomic data from bronchial biopsies and brushes in the UK Refractory Asthma Stratification Programme multi-centre severe asthma cohort (18 corticosteroid-resistant T2 biomarker-high [T2-high], 23 T2 biomarker-intermediate [T2-intermediate], 11 T2 biomarker-low [T2-low]) plus 20 healthy controls pre- and post-treatment with high-dose inhaled corticosteroids (ICS). Many genes dysregulated in asthma vs. health were concordantly dysregulated in healthy subjects receiving ICS. Severe asthma as a whole, independent of confounding by ICS, was characterised by upregulation of mucins, CEACAM5, typical T2-genes (POSTN, CLCA1, CCL26), epithelial mast cell genes, and CPA4. T2-high severe asthma demonstrated upregulated T2-dependent genes, epithelial barrier and keratin genes, adaptive immune responses, and impaired ciliary function. T2-low asthma showed upregulated Th1- and IL-17-associated genes (IDO1, CXCL10, GBP1, LAG3), interferon-γ signalling, neuroimmune pathways, airway smooth muscle-related genes, and neutrophil enrichment. T2-intermediate asthma exhibited a mixed molecular profile sharing features of T2-high and T2-low endotypes, with selective expression of the pathogen defence and antiviral response genes. The results were validated using bronchoscopy data from the U-BIOPRED Consortium. This study defines airway molecular endotypes of severe asthma associated with T2 biomarker high and low phenotypes, independent of corticosteroid effects. These findings offer insights for severe asthma management and the development of targeted biologic therapies.
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线粒体脂肪酸氧化酶CPT1A缺陷导致重度哮喘气道上皮屏障功能障碍
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IL-33在雌性肥大细胞和中性粒细胞中诱导更强的反应：JNK信号通路的作用
