Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD.
Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD.
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严重哮喘和慢性阻塞性肺疾病（COPD）有共同的病理生理特征，如相对皮质类固醇不敏感。我们最近发表了三个转录组相关簇（TAC），使用来自无偏生物标志物预测呼吸系统疾病结局（U-BIOPRED）队列的哮喘患者痰液转录组的分层分析，包括一个Th 2-高炎症特征（TAC 1）和两个Th 2-低特征（TAC 2和TAC 3）。我们研究了在哮喘中获得的基因表达特征是否可以用于识别具有类固醇敏感性的COPD患者亚组。使用基因集变异分析，我们检查了46例参与格罗宁根莱顿大学阻塞性肺病皮质类固醇COPD研究的患者的支气管活检组织转录组中3种TAC的分布和富集评分（ES），这些患者接受了30个月的吸入性皮质类固醇（ICS）治疗，伴或不伴长效β激动剂（LABA）。然后将识别的签名与治疗后的纵向临床变量相关联。差异基因表达和细胞卷积用于定义关键调控基因和细胞类型。COPD患者基线时的支气管活检显示3种TAC特征的广泛表达。ICS±LABA治疗后，30个月时TAC 1的ES显著降低，但TAC 2和TAC 3的ES未受影响。皮质类固醇敏感的TAC 1签名是从TAC 1 ICS响应基因开发的。该特征由通过单细胞RNA测序鉴定的肥大细胞特异性基因组成，并与ICS±LABA后的支气管活检肥大细胞数量呈正相关。基因转录的基线水平与30个月ICS±LABA后预测的RV/TLC %变化相关。来自哮喘组群的痰液来源的转录组特征可以在COPD患者的支气管活检中重现，并将气道肥大细胞的特征鉴定为皮质类固醇反应性的预测因子。
Severe asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3). We examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity. Using gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types. Bronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA. Sputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.
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