过敏原诱导的NK细胞活化代表过敏性哮喘发展过程中的早期免疫应答
2018/06/04
摘要
背景：儿童哮喘是城市人群中一项重大的公共卫生负担，了解促进哮喘发作的早期免疫机制是疾病预防的关键。空气过敏原致敏和2型T辅助细胞（Th2）性炎症在哮喘儿童中具有较高的患病率，然而，引起Th2细胞异常和相关疾病发生的早期免疫事件尚属未知。
目的：我们尝试采集2岁过敏或哮喘儿童的外周血单核细胞（PBMCs）并应用RNA测序来确定其发生的免疫反应网络。
方法：在高哮喘风险的城市出生队列中，将3岁时发生≥2个空气过敏原致敏（包括尘螨（DM）和/或蟑螂（CR））和7岁时发生哮喘的患者（即病例组）与7岁时未发生任何空气过敏原致敏或哮喘的患者（即匹配对照组）进行比较，比较在其2岁时收集的PBMCs中RNA序列的基因表达情况。
结果：病例组的PBMCs具有更高水平的自然杀伤细胞（NK细胞）相关基因表达。在CR或DM变应原而非破伤风抗原刺激后，病例组PBMCs与对照组相比存在244个基因的差异表达。该基因组包括上调密集连接的NK细胞样基因网络（反映细胞活化的模式和诱导Th2型细胞因子包括IL9，IL13和CCL17等炎症信号分子）以及树突细胞（DC）样基因网络（包括上调CD1脂质抗原呈递分子）。NK细胞样反应在一组独立的发生迟发性变态反应和哮喘的儿童中是可反复出现的，并且这种情况仅出现于那些同时发生空气过敏原致敏和哮喘的儿童。
结论：这些研究结果为过敏性哮喘的发生提供了重要机制，即Th2极化相关的早期免疫通路。
Allergen induced activation of NK cells represents an early life immune response in development of allergic asthma
Salman Siddiqui,et al. JACI 2018 Mar 3 Abstract
Abstract
BACKGROUND：Childhood asthma in inner city populations is a major public health burden and understanding early life immune mechanisms that promote asthma onset is key to disease prevention. Children who develop asthma demonstrate a high prevalence of aeroallergen sensitization and T helper 2 (Th2)-type inflammation, however the early life immune events that lead to Th2 skewing and disease development are unknown.
OBJECTIVE：We sought to use RNA sequencing of peripheral blood mononuclear cells (PBMCs) collected at age 2 to determine networks of immune responses that occur in children who develop allergy and asthma.
METHODS：In a high asthma risk inner city birth cohort, we compared gene expression by RNA sequencing in PBMCs collected at age 2 between children who developed ≥2 aeroallergen sensitizations including dust mite (DM) and/or cockroach (CR) by age 3 and asthma by age 7(cases) and matched controls who did not develop any aeroallergen sensitization or asthma by age 7.
RESULTS：PBMCs from the cases showed higher levels of expression of natural killer (NK) cell related genes. After CR or DM allergen but not tetanus antigen stimulation, PBMCs from the cases compared to the control group, showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell-like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules including key Th2-type cytokines IL9, IL13, and CCL17 as well as a dendritic cell (DC)- like gene network including upregulation of CD1 lipid antigen presentation molecules. The NK cell-like response was reproducible in an independent group of children with later onset allergic sensitization and asthma, and was found to be specific to only those children that develop both aeroallergen sensitization and asthma.
CONCLUSION：These findings provide important mechanistic insight into an early life immune pathway involved in Th2 polarization leading to development of allergic asthma.
背景：儿童哮喘是城市人群中一项重大的公共卫生负担，了解促进哮喘发作的早期免疫机制是疾病预防的关键。空气过敏原致敏和2型T辅助细胞（Th2）性炎症在哮喘儿童中具有较高的患病率，然而，引起Th2细胞异常和相关疾病发生的早期免疫事件尚属未知。
目的：我们尝试采集2岁过敏或哮喘儿童的外周血单核细胞（PBMCs）并应用RNA测序来确定其发生的免疫反应网络。
方法：在高哮喘风险的城市出生队列中，将3岁时发生≥2个空气过敏原致敏（包括尘螨（DM）和/或蟑螂（CR））和7岁时发生哮喘的患者（即病例组）与7岁时未发生任何空气过敏原致敏或哮喘的患者（即匹配对照组）进行比较，比较在其2岁时收集的PBMCs中RNA序列的基因表达情况。
结果：病例组的PBMCs具有更高水平的自然杀伤细胞（NK细胞）相关基因表达。在CR或DM变应原而非破伤风抗原刺激后，病例组PBMCs与对照组相比存在244个基因的差异表达。该基因组包括上调密集连接的NK细胞样基因网络（反映细胞活化的模式和诱导Th2型细胞因子包括IL9，IL13和CCL17等炎症信号分子）以及树突细胞（DC）样基因网络（包括上调CD1脂质抗原呈递分子）。NK细胞样反应在一组独立的发生迟发性变态反应和哮喘的儿童中是可反复出现的，并且这种情况仅出现于那些同时发生空气过敏原致敏和哮喘的儿童。
结论：这些研究结果为过敏性哮喘的发生提供了重要机制，即Th2极化相关的早期免疫通路。
(中国医科大学附属第一医院呼吸与危重症医学科 李文扬 摘译 杨冬审校)
(Salman Siddiqui,et al. JACI 2018 Mar 3 Abstract)
(Salman Siddiqui,et al. JACI 2018 Mar 3 Abstract)
Allergen induced activation of NK cells represents an early life immune response in development of allergic asthma
Salman Siddiqui,et al. JACI 2018 Mar 3 Abstract
Abstract
BACKGROUND：Childhood asthma in inner city populations is a major public health burden and understanding early life immune mechanisms that promote asthma onset is key to disease prevention. Children who develop asthma demonstrate a high prevalence of aeroallergen sensitization and T helper 2 (Th2)-type inflammation, however the early life immune events that lead to Th2 skewing and disease development are unknown.
OBJECTIVE：We sought to use RNA sequencing of peripheral blood mononuclear cells (PBMCs) collected at age 2 to determine networks of immune responses that occur in children who develop allergy and asthma.
METHODS：In a high asthma risk inner city birth cohort, we compared gene expression by RNA sequencing in PBMCs collected at age 2 between children who developed ≥2 aeroallergen sensitizations including dust mite (DM) and/or cockroach (CR) by age 3 and asthma by age 7(cases) and matched controls who did not develop any aeroallergen sensitization or asthma by age 7.
RESULTS：PBMCs from the cases showed higher levels of expression of natural killer (NK) cell related genes. After CR or DM allergen but not tetanus antigen stimulation, PBMCs from the cases compared to the control group, showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell-like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules including key Th2-type cytokines IL9, IL13, and CCL17 as well as a dendritic cell (DC)- like gene network including upregulation of CD1 lipid antigen presentation molecules. The NK cell-like response was reproducible in an independent group of children with later onset allergic sensitization and asthma, and was found to be specific to only those children that develop both aeroallergen sensitization and asthma.
CONCLUSION：These findings provide important mechanistic insight into an early life immune pathway involved in Th2 polarization leading to development of allergic asthma.
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