Impaired type I interferon regulation in the blood transcriptome of recurrent asthma exacerbations.
Impaired type I interferon regulation in the blood transcriptome of recurrent asthma exacerbations.
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DOI：
10.1186/s12920-018-0340-3
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发表时间：
2018-02-27
影响因子：
2.7
通讯作者：
Britto CJ
中科院分区：
文献类型：
--
作者：
Gomez JL;Diaz MP;Nino G;Britto CJ
哮喘加重是哮喘发病的重要原因。呼吸道感染通常与儿童和成人的哮喘恶化有关。一些哮喘患者对病毒感染的易感性增加，因此哮喘加重的比率增加。我们试图确定血液中与呼吸道感染(AETRI)引发的哮喘恶化(AETRI)相关的转录特征，并确定其与哮喘加重风险增加的相关性。我们进行了一项分两步进行的研究，使用可公开获得的、先前在哮喘患者外周血单个核细胞(PBMC)中生成的转录转录信号来识别哮喘加重风险增加的新标记物。在第一步中，我们鉴定了一种对鼻病毒有反应的体外PBMC标志。在第二步中，我们使用体外签名来筛选独立的体内队列中哮喘恶化的PBMC转录本。在活体队列中识别和研究了三个不同的亚组：1.单一的AETRI；2.多个AETRI；以及3.单一的非感染性哮喘加重。在所有的独立比较中，我们都进行了路径和网络分析。我们还进行了免疫学基因集浓缩分析(GSEA)，比较了单一AETRI和非感染性哮喘恶化之间的差异。体外标记鉴定出4354个差异表达基因(DEG)，其折叠变化(Fc)≥为1.2，假发现率(Fdr)为 <； 。根据这一体外签名对独立的成人哮喘队列进行筛选后的后续分析发现，在单一≥的受试者中，有238个DEGS(FC AETRI1.1，FDR<； 0.1)，而在单一的非感染性哮喘恶化中没有DEGS。对单一和多个AETRI受试者的反应进行比较，发现了两个不一致的基因亚组。在最大的不一致子集(n= 63基因)中，我们在急性加重期间的多个AETRI中发现了I型干扰素和STAT1受损的反应，并在基线时上调了STAT1的反应。在多个AETRI患者中，STAT1在基线水平上调伴随着促炎分子的上调，包括IL-15、干扰素刺激基因(ISGs)、几种Toll样受体2、− 4、− 5和− 8以及髓系细胞1(TREM1)网络上表达的触发受体。患有哮喘和多个AETRI的受试者在基线时表现出促炎信号，与STAT、IL-15和ISGs升高相关，在急性哮喘加重期间STAT1反应受损。本文的在线版本(10.1186/s12920-0180340-3)包含补充材料，可供授权用户使用。
Asthma exacerbations are an important cause of morbidity in asthma. Respiratory infections are often involved in asthma exacerbations in both children and adults. Some individuals with asthma have increased susceptibility to viral infections and as a result increased rates of asthma exacerbations. We sought to identify a transcriptomic signature in the blood associated with asthma exacerbations triggered by respiratory infections (AETRI) and determine its association with increased risk for asthma exacerbations. We conducted a two-step study using publicly available, previously generated transcriptomic signatures in peripheral blood mononuclear cells (PBMCs) from asthmatics to identify novel markers of increased risk for asthma exacerbations. In the 1st step, we identified an in vitro PBMC signature in response to rhinovirus. In the 2nd step, we used the in vitro signature to filter PBMC transcripts in response to asthma exacerbations in an independent in vivo cohort. Three different subgroups were identified and studied in the in vivo cohort: 1. Single AETRI; 2. Multiple AETRIs; and 3. Single non-infectious asthma exacerbations. We performed pathway and network analyses in all independent comparisons. We also performed an immunologic gene set enrichment analysis (GSEA) of the comparison between single AETRI and non-infectious asthma exacerbations. The in vitro signature identified 4354 differentially expressed genes (DEGs) with a fold change (FC) ≥ 1.2, false discovery rate (FDR) < 0.05. Subsequent analyses filtered by this in vitro signature on an independent cohort of adult asthma identified 238 DEGs (FC≥1.1, FDR < 0.1) in subjects with a single AETRI and no DEGs in single non-infectious asthma exacerbations. A comparison between the response in subjects with single and multiple AETRIs identified two discordant gene subsets. In the largest discordant subset (n = 63 genes) we identified an impaired type I interferon and STAT1 response in multiple AETRIs during the acute phase of the exacerbation and an upregulated STAT1 response at baseline. The STAT1 upregulation at baseline in subjects with multiple AETRIs was accompanied by upregulation of pro-inflammatory molecules including IL-15, interferon-stimulated genes (ISGs), several toll-like receptors 2, − 4, − 5 and − 8 and a triggering receptor expressed on myeloid cells 1 (TREM1) network. Subjects with asthma and multiple AETRIs display a pro-inflammatory signature at baseline, associated with elevated STAT, IL-15 and ISGs, and an impaired STAT1 response during acute asthma exacerbations. The online version of this article (10.1186/s12920-018-0340-3) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/j.jaci.2013.06.035
发表时间：
2013-10
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Chen Z;Wang S;Erekosima N;Li Y;Hong J;Qi X;Merkel P;Nagabhushanam V;Choo E;Katial R;Alam R;Trikha A;Chu HW;Zhuang Y;Jin M;Bai C;Huang H
通讯作者：
Huang H
影响因子：
4.3
作者：
Miller, Mary K.;Lee, June H.;Wenzel, Sally E.
通讯作者：
Wenzel, Sally E.
影响因子：
3.7
作者：
Pritchard, Antonia L.;White, Olivia J.;Upham, John W.
通讯作者：
Upham, John W.
影响因子：
3.7
作者：
Bjornsdottir, Unnur S.;Holgate, Stephen T.;O'Toole, Margot
通讯作者：
O'Toole, Margot
影响因子：
1.2
作者：
Figueroa, Gloria;Parira, Tiyash;Agudelo, Marisela
通讯作者：
Agudelo, Marisela