严重哮喘患者肥大细胞活化差异与粒细胞炎症的关系
2021/12/24
摘要
背景：肥大细胞（MC）在炎症以及先天性和适应性免疫中发挥作用，但它们与重症哮喘（SA）的关系尚未明确。
目的：我们通过将已发表的MC激活信号应用于痰细胞转录组，研究U-BIOPRED哮喘队列的表型特征。
方法：研究84例SA，20例轻度/中度（MMA）哮喘和16例非哮喘健康参与者。我们使用基因组变异分析，通过哮喘严重程度，痰粒细胞表型和三个先前定义的痰分子表型或转录组相关簇（TAC1,2,3）计算了九个MC激活特征的富集评分（ES）。
结果：除了未激活的，重复的FcεR1激活的和IFN-γ激活的MC特征在SA中富集。来自哮喘支气管活检的FcεR1IgE激活和单细胞特征在嗜酸性粒细胞性哮喘和TAC1分子表型中高度富集。对于这些特征具有高ES的受试者具有升高的相似基因和途径的痰水平。IL-33和LPS激活的MC特征在嗜中性粒细胞和混合粒细胞性哮喘以及TAC2分子表型中具有更大的ES。这些受试者表现出嗜中性粒细胞，NF-κB和IL-1β/TNFα途径活化。IFN-γ刺激的特征在TAC2和TAC3中具有最大的ES，其与对病毒感染的应答相关。在独立的ADEPT哮喘队列中获得了类似的结果。
结论：MC激活的基因特征允许检测SA表型，并表明可以诱导MC呈现与特定临床表型相关的不同转录表型。IL-33激活的MCs特征与严重的嗜中性粒细胞性哮喘相关，而IgE激活具有嗜酸性粒细胞表型的MC。
Association of Differential Mast Cell Activation to Granulocytic Inflammation in Severe Asthma
Angelica Tiotiu, Yusef Badi, Nazanin Zounemat Kermani, Marek Sanak, Johan Kolmert, Craig E Wheelock, Philip M Hansbro, Sven-Erik Dahlén, Peter J Sterk, Ratko Djukanovic, Yike Guo, Sharon Mumby, Ian M Adcock, Kian Fan Chung, U-BIOPRED consortium project team
Abstract
Background: Mast cells (MC) play a role in inflammation and both innate and adaptive immunity but their involvement in severe asthma (SA) remains undefined.
Objective: We investigated the phenotypic characteristics of the U-BIOPRED asthma cohort by applying published MC activation signatures to the sputum cell transcriptome.
Methods: 84 SA, 20 mild/moderate (MMA) asthma, and 16 non-asthmatic healthy participants were studied. We calculated enrichment scores (ES) for nine MC activation signatures by asthma severity, sputum granulocyte status and three previously-defined sputum molecular phenotypes or transcriptome-associated clusters (TAC1, 2, 3) using gene-set variation analysis.
Results: MC signatures except unstimulated, repeated FcεR1-stimulated and IFNγ-stimulated were enriched in SA. A FcεR1-IgE-stimulated and a single cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum levels of similar genes and pathways. IL-33- and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-κB, and IL-1β/TNFα pathway activation. The IFNγ-stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT asthma cohort.
Conclusions: Gene signatures of MC activation allow the detection of SA phenotypes and indicate that MC can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33-stimulated MCs signature was associated with severe neutrophilic asthma while IgE-activated MC with an eosinophilic phenotype.
背景：肥大细胞（MC）在炎症以及先天性和适应性免疫中发挥作用，但它们与重症哮喘（SA）的关系尚未明确。
目的：我们通过将已发表的MC激活信号应用于痰细胞转录组，研究U-BIOPRED哮喘队列的表型特征。
方法：研究84例SA，20例轻度/中度（MMA）哮喘和16例非哮喘健康参与者。我们使用基因组变异分析，通过哮喘严重程度，痰粒细胞表型和三个先前定义的痰分子表型或转录组相关簇（TAC1,2,3）计算了九个MC激活特征的富集评分（ES）。
结果：除了未激活的，重复的FcεR1激活的和IFN-γ激活的MC特征在SA中富集。来自哮喘支气管活检的FcεR1IgE激活和单细胞特征在嗜酸性粒细胞性哮喘和TAC1分子表型中高度富集。对于这些特征具有高ES的受试者具有升高的相似基因和途径的痰水平。IL-33和LPS激活的MC特征在嗜中性粒细胞和混合粒细胞性哮喘以及TAC2分子表型中具有更大的ES。这些受试者表现出嗜中性粒细胞，NF-κB和IL-1β/TNFα途径活化。IFN-γ刺激的特征在TAC2和TAC3中具有最大的ES，其与对病毒感染的应答相关。在独立的ADEPT哮喘队列中获得了类似的结果。
结论：MC激活的基因特征允许检测SA表型，并表明可以诱导MC呈现与特定临床表型相关的不同转录表型。IL-33激活的MCs特征与严重的嗜中性粒细胞性哮喘相关，而IgE激活具有嗜酸性粒细胞表型的MC。
(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)
(Am J Respir Crit Care Med. 2021 Nov 23. doi: 10.1164/rccm.202102-0355OC.)
(Am J Respir Crit Care Med. 2021 Nov 23. doi: 10.1164/rccm.202102-0355OC.)
Association of Differential Mast Cell Activation to Granulocytic Inflammation in Severe Asthma
Angelica Tiotiu, Yusef Badi, Nazanin Zounemat Kermani, Marek Sanak, Johan Kolmert, Craig E Wheelock, Philip M Hansbro, Sven-Erik Dahlén, Peter J Sterk, Ratko Djukanovic, Yike Guo, Sharon Mumby, Ian M Adcock, Kian Fan Chung, U-BIOPRED consortium project team
Abstract
Background: Mast cells (MC) play a role in inflammation and both innate and adaptive immunity but their involvement in severe asthma (SA) remains undefined.
Objective: We investigated the phenotypic characteristics of the U-BIOPRED asthma cohort by applying published MC activation signatures to the sputum cell transcriptome.
Methods: 84 SA, 20 mild/moderate (MMA) asthma, and 16 non-asthmatic healthy participants were studied. We calculated enrichment scores (ES) for nine MC activation signatures by asthma severity, sputum granulocyte status and three previously-defined sputum molecular phenotypes or transcriptome-associated clusters (TAC1, 2, 3) using gene-set variation analysis.
Results: MC signatures except unstimulated, repeated FcεR1-stimulated and IFNγ-stimulated were enriched in SA. A FcεR1-IgE-stimulated and a single cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum levels of similar genes and pathways. IL-33- and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-κB, and IL-1β/TNFα pathway activation. The IFNγ-stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT asthma cohort.
Conclusions: Gene signatures of MC activation allow the detection of SA phenotypes and indicate that MC can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33-stimulated MCs signature was associated with severe neutrophilic asthma while IgE-activated MC with an eosinophilic phenotype.
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靶向P2Y13受体抑制IL-33和HMGB1的释放并改善实验性哮喘
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血清吸入皮质类固醇检测用于监测重度哮喘患者的依从性
