LPS结合蛋白和激活信号在儿童哮喘发作期上调
2023/07/21
摘要
儿童哮喘发作与呼吸道病毒感染和特应性有关，导致全身免疫激活和免疫细胞浸润气道。驱动免疫激活和随后免疫细胞迁移到气道的基因网络仍不完全清楚。PBMC的细胞和分子图谱用于从特应性哮喘儿童（n=19）获得的配对样本，这些儿童在急性病毒相关发作期间和随后的恢复期。采用系统级分析来识别共表达网络并推断这些网络的驱动因素，随后通过哮喘儿童的独立样本进行验证。在及西贡发作期间，PBMC在免疫细胞丰度和共表达基因的复杂互连网络的上调方面表现出显著变化。这些与先天免疫、炎症和重塑功能的启动有关。我们鉴定了细菌LPS、糖皮质激素和TGFB1下游的激活特征。我们还证实LPS结合蛋白在血浆中的蛋白水平上调。已知在哮喘发病机制中积极或消极参与的多种基因网络在急性加重期间在循环PBMC中上调，支持了循环免疫细胞的潜在致病性和保护性功能的系统预编程促进迁移到气道的假设。对LPS的敏感性增强可能通过暴露于环境LPS来调节急性哮喘发作的严重程度。
LPS binding protein and activation signatures are upregulated during asthma exacerbations in children
Anya C Jones, Jonatan Leffler, Ingrid A Laing, Joelene Bizzintino, Siew-Kim Khoo, Peter N LeSouef, Peter D Sly, Patrick G Holt, Deborah H Strickland, Anthony Bosco
Abstract
Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS.
儿童哮喘发作与呼吸道病毒感染和特应性有关，导致全身免疫激活和免疫细胞浸润气道。驱动免疫激活和随后免疫细胞迁移到气道的基因网络仍不完全清楚。PBMC的细胞和分子图谱用于从特应性哮喘儿童（n=19）获得的配对样本，这些儿童在急性病毒相关发作期间和随后的恢复期。采用系统级分析来识别共表达网络并推断这些网络的驱动因素，随后通过哮喘儿童的独立样本进行验证。在及西贡发作期间，PBMC在免疫细胞丰度和共表达基因的复杂互连网络的上调方面表现出显著变化。这些与先天免疫、炎症和重塑功能的启动有关。我们鉴定了细菌LPS、糖皮质激素和TGFB1下游的激活特征。我们还证实LPS结合蛋白在血浆中的蛋白水平上调。已知在哮喘发病机制中积极或消极参与的多种基因网络在急性加重期间在循环PBMC中上调，支持了循环免疫细胞的潜在致病性和保护性功能的系统预编程促进迁移到气道的假设。对LPS的敏感性增强可能通过暴露于环境LPS来调节急性哮喘发作的严重程度。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Respir Res. 2023 Jul 12;24(1):184. doi: 10.1186/s12931-023-02478-3.)
(Respir Res. 2023 Jul 12;24(1):184. doi: 10.1186/s12931-023-02478-3.)
LPS binding protein and activation signatures are upregulated during asthma exacerbations in children
Anya C Jones, Jonatan Leffler, Ingrid A Laing, Joelene Bizzintino, Siew-Kim Khoo, Peter N LeSouef, Peter D Sly, Patrick G Holt, Deborah H Strickland, Anthony Bosco
Abstract
Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS.
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肺中的自然杀伤细胞：在哮喘和病毒诱导的发作中的潜在作用？
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顺式和反式eQTM分析揭示气道上皮中特应性哮喘的新表观遗传学和转录组免疫标志物
