BACKGROUND Type 2 (T2) inflammation drives airway dysfunction in many patients with asthma; yet, we lack a comprehensive understanding of the airway immune cell types and networks that sustain this inflammation. Moreover, defects in the airway immune system in patients with asthma without T2 inflammation are not established. OBJECTIVES To determine the gene networks that sustain T2 airway inflammation in T2-high asthma and to explore the gene networks that characterize T2-low asthma. METHODS Network analysis of sputum cell transcriptome expression data from 84 subjects with asthma and 27 healthy control subjects was used to identify immune cell type-enriched networks that underlie asthma subgroups. RESULTS Sputum T2 gene expression was characterized by an immune cell network derived from multiple innate immune cells, including eosinophils, mast cells/basophils, and inflammatory dendritic cells. Clustering of subjects within this network stratified subjects into T2-high and T2-low groups, but it also revealed a subgroup of T2-high subjects with uniformly higher expression of the T2 network. These "T2-ultrahigh subjects" were characterized clinically by older age and more severe airflow obstruction and pathologically by a second T2 network derived from T2-skewed, CD11b+/CD103-/IRF4+ classical dendritic cells. Subjects with T2-low asthma were differentiated from healthy control subjects by lower expression of a cytotoxic CD8+ T-cell network, which was negatively correlated with body mass index and plasma IL-6 concentrations. CONCLUSIONS Persistent airway T2 inflammation is a complex construct of innate and adaptive immunity gene expression networks that are variable across individuals with asthma and persist despite steroid treatment. Individuals with T2-low asthma exhibit an airway deficiency in cytotoxic T cells associated with obesity-driven inflammation.

中文翻译：

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确定 T2 高和 T2 低哮喘气道免疫功能障碍的转录组学方法。

背景 2 型 (T2) 炎症导致许多哮喘患者气道功能障碍；然而，我们对维持这种炎症的气道免疫细胞类型和网络缺乏全面的了解。此外，尚未确定无 T2 炎症的哮喘患者存在气道免疫系统缺陷。目的 确定维持 T2 高哮喘中 T2 气道炎症的基因网络，并探索表征 T2 低哮喘的基因网络。方法 对 84 名哮喘受试者和 27 名健康对照受试者的痰细胞转录组表达数据进行网络分析，以确定哮喘亚组背后的免疫细胞类型丰富网络。结果 痰 T2 基因表达的特征是源自多种先天免疫细胞的免疫细胞网络，包括嗜酸性粒细胞、肥大细胞/嗜碱性粒细胞和炎症树突细胞。该网络内的受试者聚类将受试者分为 T2 高组和 T2 低组，但它也揭示了 T2 高受试者的亚组，其 T2 网络的表达一致较高。这些“T2超高受试者”的临床特征是年龄较大和更严重的气流阻塞，病理学特征是源自T2倾斜的CD11b+/CD103-/IRF4+经典树突状细胞的第二个T2网络。患有 T2 低哮喘的受试者与健康对照受试者的区别在于细胞毒性 CD8+ T 细胞网络的表达较低，这与体重指数和血浆 IL-6 浓度呈负相关。结论 持续性气道 T2 炎症是先天性和适应性免疫基因表达网络的复杂结构，在哮喘患者中存在差异，并且尽管接受类固醇治疗仍持续存在。患有 T2 低哮喘的个体表现出与肥胖引起的炎症相关的细胞毒性 T 细胞气道缺陷。