对气道炎症的分析揭示了哮喘中 T2 类生物反应失效的机制
2025/08/01
摘要
背景：靶向T2生物制剂革新了哮喘治疗，但患者对生物制剂的临床反应存在个体差异。
目的：评估接受抗IL5生物制剂治疗的T2高型哮喘患者气道炎症，探讨不同气道炎症机制是否解释生物制剂疗效差异。
方法：对英国多中心美泊利单抗急性加重（MEX）研究中T2高型重症哮喘患者的诱导痰进行蛋白质组学分析（Olink，1463蛋白面板）和高灵敏度细胞因子检测（ELISAs）。样本包括：美泊利单抗治疗前（n=28）、治疗稳定期（n=43）及首次急性加重时（n=26）。
结果：美泊利单抗稳定期的痰液蛋白聚类分析鉴定出两个群组。群组1在美泊利单抗治疗前、稳定期及急性加重期均显示出差异表达痰蛋白水平升高。群组1患者确诊年龄更小、哮喘病程更长、FEV1%预测值更低且美泊利单抗治疗期间ACQ5评分更高。群组1表现出促炎细胞因子（IL-1β、IL-6、sIL6R）、上皮警报蛋白（TSLP、IL-33）及中性粒细胞活化标志物（髓过氧化物酶[MPO]、中性粒细胞弹性蛋白酶[NE]、中性粒细胞胞外陷阱[NET]）的表达增加。所有患者均保持T2高型特征，两个群组间的呼出气一氧化氮（FeNO）水平、嗜酸性粒细胞数量及其活性（嗜酸性粒细胞衍生的神经毒素[EDN]）无差异。
结论：在T2高型重症哮喘患者队列中，病程较长的群组即使处于美泊利单抗稳定期，仍表现出更差的临床参数、痰蛋白水平升高以及中性粒细胞活性、促炎因子和上皮警报蛋白标志物增加。这表明存在未被靶向T2生物制剂干预的生物学特征，可能导致生物制剂疗效欠佳，并为重症哮喘提供了潜在的可治疗性气道特征。
Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma
P. J. McDowell, A. Azim, J. Busby, S. Diver, F. Yang, C. Borg, et al.
Abstract
BACKGROUND:
Targeted T2 biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients.
OBJECTIVE:
Assess airways inflammation in T2-high asthma patients treated with anti-IL5 biologics to investigate if differential mechanisms of airway inflammation explains varied response to biologics.
METHODS:
Proteomic analysis (Olink, 1463 protein panel) & high sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high, severe asthma patients in the UK multicentre Mepolizumab EXacerbation (MEX) study. Samples included were pre-mepolizumab (n=28), stable on mepolizumab (n=43) & at first exacerbation (n=26).
RESULTS:
Clustering of sputum proteins while stable on mepolizumab identified two clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab & at exacerbation. Cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1% & higher ACQ5 on mepolizumab. Cluster 1 had increased expression of pro-inflammatory cytokines (IL1beta, IL6, sIL6R), epithelial alarmins (TSLP, IL 33) and neutrophil activation (MPO, NE & Neutrophil extracellular trap (NET). All patients were T2-high with no difference in FeNO, eosinophil number or activity (EDN) across the two clusters.
CONCLUSION:
In a cohort of T2-high severe asthma patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2-biologics which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.
背景：靶向T2生物制剂革新了哮喘治疗，但患者对生物制剂的临床反应存在个体差异。
目的：评估接受抗IL5生物制剂治疗的T2高型哮喘患者气道炎症，探讨不同气道炎症机制是否解释生物制剂疗效差异。
方法：对英国多中心美泊利单抗急性加重（MEX）研究中T2高型重症哮喘患者的诱导痰进行蛋白质组学分析（Olink，1463蛋白面板）和高灵敏度细胞因子检测（ELISAs）。样本包括：美泊利单抗治疗前（n=28）、治疗稳定期（n=43）及首次急性加重时（n=26）。
结果：美泊利单抗稳定期的痰液蛋白聚类分析鉴定出两个群组。群组1在美泊利单抗治疗前、稳定期及急性加重期均显示出差异表达痰蛋白水平升高。群组1患者确诊年龄更小、哮喘病程更长、FEV1%预测值更低且美泊利单抗治疗期间ACQ5评分更高。群组1表现出促炎细胞因子（IL-1β、IL-6、sIL6R）、上皮警报蛋白（TSLP、IL-33）及中性粒细胞活化标志物（髓过氧化物酶[MPO]、中性粒细胞弹性蛋白酶[NE]、中性粒细胞胞外陷阱[NET]）的表达增加。所有患者均保持T2高型特征，两个群组间的呼出气一氧化氮（FeNO）水平、嗜酸性粒细胞数量及其活性（嗜酸性粒细胞衍生的神经毒素[EDN]）无差异。
结论：在T2高型重症哮喘患者队列中，病程较长的群组即使处于美泊利单抗稳定期，仍表现出更差的临床参数、痰蛋白水平升高以及中性粒细胞活性、促炎因子和上皮警报蛋白标志物增加。这表明存在未被靶向T2生物制剂干预的生物学特征，可能导致生物制剂疗效欠佳，并为重症哮喘提供了潜在的可治疗性气道特征。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（The Journal of allergy and clinical immunology 2025 DOI: 10.1016/j.jaci.2025.05.031）
Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma
P. J. McDowell, A. Azim, J. Busby, S. Diver, F. Yang, C. Borg, et al.
Abstract
BACKGROUND:
Targeted T2 biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients.
OBJECTIVE:
Assess airways inflammation in T2-high asthma patients treated with anti-IL5 biologics to investigate if differential mechanisms of airway inflammation explains varied response to biologics.
METHODS:
Proteomic analysis (Olink, 1463 protein panel) & high sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high, severe asthma patients in the UK multicentre Mepolizumab EXacerbation (MEX) study. Samples included were pre-mepolizumab (n=28), stable on mepolizumab (n=43) & at first exacerbation (n=26).
RESULTS:
Clustering of sputum proteins while stable on mepolizumab identified two clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab & at exacerbation. Cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1% & higher ACQ5 on mepolizumab. Cluster 1 had increased expression of pro-inflammatory cytokines (IL1beta, IL6, sIL6R), epithelial alarmins (TSLP, IL 33) and neutrophil activation (MPO, NE & Neutrophil extracellular trap (NET). All patients were T2-high with no difference in FeNO, eosinophil number or activity (EDN) across the two clusters.
CONCLUSION:
In a cohort of T2-high severe asthma patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2-biologics which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.
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美泊利单抗对伴或不伴慢性鼻-鼻窦炎伴鼻息肉的重症哮喘患者的疗效：真实世界汇总分析
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黏液栓评分可预测重度哮喘患者对生物制剂的临床及肺功能反应
