Maternal prenatal immunity, neonatal trained immunity, and early airway microbiota shape childhood asthma development.
Maternal prenatal immunity, neonatal trained immunity, and early airway microbiota shape childhood asthma development.
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母亲的产前免疫力、新生儿训练有素的免疫力和早期气道微生物群影响儿童哮喘的发展。
DOI：
10.1111/all.15442
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发表时间：
2022-12
期刊：
影响因子：
12.4
通讯作者：
Vercelli, Donata
中科院分区：
文献类型：
--
作者：
DeVries, Avery;McCauley, Kathryn;Fadrosh, Douglas;Fujimura, Kei E.;Stern, Debra A.;Lynch, Susan, V;Vercelli, Donata
关键词：
人们认为，儿童哮喘的发生是在子宫内开始的，并通过产后接触进一步促进。然而，潜在的机制仍未得到充分探索。我们假设，产前母体免疫功能障碍与儿童哮喘风险增加相关（由妊娠晚期 IFN-γ:IL-13 分泌量低所揭示）通过表观遗传机制改变新生儿免疫训练，并促进哮喘微生物群在生命早期气道定植。我们在产前、围产期和产后采样的母婴二人出生队列中检查了与母亲产前免疫力（IFN-γ：IL-13 比率）和儿童哮喘可能相关的表观遗传、免疫学和微生物特征（N = 155）。分别通过阵列分析和 ELISA 评估脐带血单核细胞 (CBMC) 中的表观基因组 DNA 甲基化和细胞因子产生。通过 16S rRNA 测序对 2-36 个月龄的鼻咽微生物组组成进行了表征。非哮喘母亲所生新生儿的母亲产前免疫状态与甲基化谱相关。富含微生物反应元素的差异甲基化 CpG 位点模块与儿童哮喘相关。 IFN-γ:IL-13 比率最低的母亲所生的新生儿 CBMC 对微生物产物的体外反应性受损，这表明儿童期患哮喘的新生儿先天免疫有缺陷。这些婴儿表现出独特的上呼吸道微生物群发育模式，其特征是生命早期嗜血杆菌定植，并在 36 个月大时转变为以莫拉氏菌为主的微生物群。母亲的产前免疫状态通过改变表观基因组和出生时训练的先天免疫来影响孩子的哮喘发展，并且与生命早期的病理性上呼吸道微生物定植有关。通过综合的、代际的方法，我们描述了影响儿童期哮喘发展的母亲和早期生命的表观遗传、免疫学和微生物特征。我们证明，在非哮喘母亲的孩子中，母亲的产前免疫状态 (IFN-γ:IL-13) 通过改变新生儿的表观基因组和经过训练的先天免疫，并促进生命早期病理性上呼吸道微生物定植，从而塑造孩子患哮喘的途径。这些结果为将母亲产前健康与儿童哮喘发病机制联系起来的机制研究提供了一个新的框架。缩写：CBMC，脐带血单核细胞； IFN，干扰素； IL，白细胞介素； LPS，脂多糖； PBMC，外周血单个核细胞； rRNA，核糖体RNA
The path to childhood asthma is thought to initiate in utero and be further promoted by postnatal exposures. However, the underlying mechanisms remain underexplored. We hypothesized that prenatal maternal immune dysfunction associated with increased childhood asthma risk (revealed by low IFN‐γ:IL‐13 secretion during the third trimester of pregnancy) alters neonatal immune training through epigenetic mechanisms and promotes early‐life airway colonization by asthmagenic microbiota. We examined epigenetic, immunologic, and microbial features potentially related to maternal prenatal immunity (IFN‐γ:IL‐13 ratio) and childhood asthma in a birth cohort of mother–child dyads sampled pre‐, peri‐, and postnatally (N = 155). Epigenome‐wide DNA methylation and cytokine production were assessed in cord blood mononuclear cells (CBMC) by array profiling and ELISA, respectively. Nasopharyngeal microbiome composition was characterized at age 2–36 months by 16S rRNA sequencing. Maternal prenatal immune status related to methylome profiles in neonates born to non‐asthmatic mothers. A module of differentially methylated CpG sites enriched for microbe‐responsive elements was associated with childhood asthma. In vitro responsiveness to microbial products was impaired in CBMCs from neonates born to mothers with the lowest IFN‐γ:IL‐13 ratio, suggesting defective neonatal innate immunity in those who developed asthma during childhood. These infants exhibited a distinct pattern of upper airway microbiota development characterized by early‐life colonization by Haemophilus that transitioned to a Moraxella‐dominated microbiota by age 36 months. Maternal prenatal immune status shapes asthma development in her child by altering the epigenome and trained innate immunity at birth, and is associated with pathologic upper airway microbial colonization in early life. Through an integrated, inter‐generational approach, we characterized maternal and early‐life epigenetic, immunologic and microbial features that influence asthma development during childhood. We demonstrate that, in children of non‐asthmatic mothers, maternal prenatal immune status (IFN‐γ:IL‐13) shapes the child's path to asthma by altering the epigenome and trained innate immunity in the neonate, and promoting pathologic upper airway microbial colonization in early life. These results provide a novel framework for mechanistic research linking maternal prenatal health to childhood asthma pathogenesis. Abbreviations: CBMC, cord blood mononuclear cells; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cells; rRNA, ribosomal RNA
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影响因子：
16.6
作者：
Durack J;Kimes NE;Lin DL;Rauch M;McKean M;McCauley K;Panzer AR;Mar JS;Cabana MD;Lynch SV
通讯作者：
Lynch SV
影响因子：
3.6
作者：
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通讯作者：
Rastogi D
影响因子：
17.1
作者：
Arrieta, Marie-Claire;Stiemsma, Leah T.;Finlay, B. Brett
通讯作者：
Finlay, B. Brett
影响因子：
14.2
作者：
Ege, MJ;Bieli, C;Braun-Fahrländer, C
通讯作者：
Braun-Fahrländer, C
影响因子：
12.4
作者：
Calvani, M;Alessandri, C;Volterrani, A
通讯作者：
Volterrani, A