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 with asthma demonstrate a high prevalence of aeroallergen sensitization and 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 PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma. METHODS In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years. RESULTS PBMCs from the cases showed higher levels of expression of natural killer (NK) cell-related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects 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 the key TH2-type cytokines IL9, IL13, and CCL17, as well as a dendritic cell-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 with both aeroallergen sensitization and asthma. CONCLUSION These findings provide important mechanistic insight into an early-life immune pathway involved in TH2 polarization, leading to the development of allergic asthma.

中文翻译：

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变应原诱导的自然杀伤细胞激活代表变应性哮喘发展过程中的早期免疫应答。

背景技术城市人口中的儿童哮喘是主要的公共卫生负担，而了解促进哮喘发作的早期免疫机制是预防疾病的关键。哮喘儿童表现出较高的空气过敏原致敏率和TH2型炎症。然而，导致TH2倾斜和疾病发展的早期免疫事件尚不清楚。目的我们试图对2岁时收集的PBMC进行RNA测序，以确定在过敏和哮喘患儿中发生的免疫反应网络。方法在一个具有高哮喘风险的市区出生队列中，我们使用RNA测序技术比较了2岁或2岁以上气敏性过敏儿童（包括尘螨，蟑螂或两者兼有）在PBMC中的基因表达，（3岁）的哮喘患者（7岁）（哮喘）和7岁（年龄）没有气敏原致敏或哮喘的对照受试者。结果病例中的PBMC表现出较高水平的自然杀伤（NK）细胞相关基因表达。蟑螂或尘螨变应原刺激破伤风抗原后，破伤风的PBMC与对照组相比显示出244个基因的差异表达。该基因组包括紧密连接的NK细胞样基因网络的上调，反映了细胞激活和炎症信号分子（包括关键的TH2型细胞因子IL9，IL13和CCL17）以及树突状细胞样的诱导模式基因网络，包括CD1脂质抗原呈递分子的上调。在独立组的迟发性过敏致敏和哮喘患儿中，NK细胞样反应是可重现的，并且被发现仅对同时具有气敏性过敏和哮喘的患儿具有特异性。结论这些发现为涉及TH2极化的早期生命免疫途径提供了重要的机制见解，从而导致了过敏性哮喘的发展。