Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Sean N Parker Center for Allergy Research and Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, CA, USA.
Cell Rep. 2021 Apr 13;35(2):108974. doi: 10.1016/j.celrep.2021.108974.
Clinical definitions of asthma fail to capture the heterogeneity of immune dysfunction in severe, treatment-refractory disease. Applying mass cytometry and machine learning to bronchoalveolar lavage (BAL) cells, we find that corticosteroid-resistant asthma patients cluster largely into two groups: one enriched in interleukin (IL)-4 innate immune cells and another dominated by interferon (IFN)-γ T cells, including tissue-resident memory cells. In contrast, BAL cells of a healthier population are enriched in IL-10 macrophages. To better understand cellular mediators of severe asthma, we developed the Immune Cell Linkage through Exploratory Matrices (ICLite) algorithm to perform deconvolution of bulk RNA sequencing of mixed-cell populations. Signatures of mitosis and IL-7 signaling in CD206FcεRICD127IL-4 innate cells in one patient group, contrasting with adaptive immune response in T cells in the other, are preserved across technologies. Transcriptional signatures uncovered by ICLite identify T-cell-high and T-cell-poor severe asthma patients in an independent cohort, suggesting broad applicability of our findings.
临床哮喘定义未能捕捉到严重、治疗抵抗疾病中免疫功能障碍的异质性。我们应用液质联用和机器学习分析支气管肺泡灌洗液（BAL）细胞，发现皮质激素抵抗性哮喘患者主要分为两类：一类富含白细胞介素（IL）-4 固有免疫细胞，另一类以干扰素（IFN）-γ T 细胞为主，包括组织驻留记忆细胞。相比之下，更健康人群的 BAL 细胞富含 IL-10 巨噬细胞。为了更好地了解严重哮喘的细胞介质，我们开发了免疫细胞连接通过探索矩阵（ICLite）算法来对混合细胞群体的批量 RNA 测序进行去卷积。在一个患者群体中，CD206FcεRICD127IL-4 固有细胞中细胞有丝分裂和 IL-7 信号的特征，与另一个群体中 T 细胞的适应性免疫反应形成对比，在不同技术中得以保留。ICLite 揭示的转录特征在一个独立队列中鉴定出 T 细胞高和 T 细胞低的严重哮喘患者，提示我们的发现具有广泛的适用性。
