Fitzpatrick Anne M, Huang Min, Mohammad Ahmad F, Stephenson Susan T, Kamaleswaran Rishikesan, Grunwell Jocelyn R
Department of Pediatrics, Emory University, Atlanta, Ga.
Division of Pulmonary Medicine, Children's Healthcare of Atlanta, Atlanta, Ga.
J Allergy Clin Immunol Glob. 2024 Feb 13;3(2):100229. doi: 10.1016/j.jacig.2024.100229. eCollection 2024 May.
The innate mechanisms associated with viral exacerbations in preschool children with recurrent wheezing are not understood.
We sought to assess differential gene expression in blood neutrophils from preschool children with recurrent wheezing, stratified by aeroallergen sensitization, at baseline and after exposure to polyinosinic:polycytidylic acid (poly(I:C)) and also to examine whether poly(I:C)-stimulated blood neutrophils influenced airway epithelial gene expression.
Blood neutrophils were purified and cultured overnight with poly(I:C) and underwent next-generation sequencing with Reactome pathway analysis. Primary human small airway epithelial cells were treated with poly(I:C)-treated neutrophil culture supernatants and were analyzed for type 1 interferon gene expression with a targeted array. Symptoms and exacerbations were assessed in participants over 12 months.
A total of 436 genes were differently expressed in neutrophils from children with versus without aeroallergen sensitization at baseline, with significant downregulation of type 1 interferons. These type 1 interferons were significantly upregulated in sensitized children after poly(I:C) stimulation. Confirmatory experiments demonstrated similar upregulation of type 1 interferons in IL-4-treated neutrophils stimulated with poly(I:C). Poly(I:C)-treated neutrophil supernatants from children with aeroallergen sensitization also induced a type 1 interferon response in epithelial cells. Children with aeroallergen sensitization also had higher symptom scores during exacerbations, and these symptom differences persisted for 3 days after prednisolone treatment.
Type 1 interferon responses are dysregulated in preschool children with aeroallergen sensitization, which is in turn associated with exacerbation severity. Given the importance of type 1 interferon signaling in viral resolution, additional studies of neutrophil type 1 interferon responses are needed in this population.
复发性喘息学龄前儿童中与病毒加重相关的固有机制尚不清楚。
我们试图评估复发性喘息学龄前儿童血液中性粒细胞中的差异基因表达，根据气传变应原致敏情况在基线时以及暴露于聚肌苷酸:聚胞苷酸（聚肌胞苷酸）后进行分层，并且检查聚肌胞苷酸刺激的血液中性粒细胞是否影响气道上皮基因表达。
纯化血液中性粒细胞，用聚肌胞苷酸培养过夜，然后进行带有Reactome通路分析的下一代测序。用聚肌胞苷酸处理的中性粒细胞培养上清液处理原代人小气道上皮细胞，并用靶向阵列分析1型干扰素基因表达。在12个月内对参与者的症状和病情加重情况进行评估。
在基线时，有气传变应原致敏的儿童与无气传变应原致敏的儿童相比，中性粒细胞中有436个基因表达不同，1型干扰素显著下调。在聚肌胞苷酸刺激后，致敏儿童中这些1型干扰素显著上调。确证实验表明，在聚肌胞苷酸刺激的白细胞介素-4处理的中性粒细胞中，1型干扰素也有类似的上调。来自有气传变应原致敏儿童的聚肌胞苷酸处理的中性粒细胞上清液也在上皮细胞中诱导了1型干扰素反应。有气传变应原致敏的儿童在病情加重期间也有更高的症状评分，并且这些症状差异在泼尼松龙治疗后持续3天。
在有气传变应原致敏的学龄前儿童中，1型干扰素反应失调，这反过来又与病情加重的严重程度相关。鉴于1型干扰素信号在病毒清除中的重要性，需要对该人群中性粒细胞的1型干扰素反应进行更多研究。
