Pathways Activated during Human Asthma Exacerbation as Revealed by Gene Expression Patterns in Blood
Pathways Activated during Human Asthma Exacerbation as Revealed by Gene Expression Patterns in Blood
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DOI：
10.1371/journal.pone.0021902
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发表时间：
2011-07-14
期刊：
影响因子：
3.7
通讯作者：
O'Toole, Margot
中科院分区：
文献类型：
--
作者：
Bjornsdottir, Unnur S.;Holgate, Stephen T.;O'Toole, Margot
背景：哮喘急性发作仍然是一个主要的未满足的临床需求。在急性加重期间获得气道组织和支气管肺泡灌洗样本的困难极大地阻碍了对自然发生的急性加重的研究。进行这项研究，以确定是否外周血单核细胞（PBMC）的mRNA表达谱可以提供信息的系统性分子通路参与哮喘acquisitions.Methodology/主要调查结果：在一年的过程中，基因表达水平在稳定的哮喘，急性发作，两周后的急性发作进行了比较，使用寡核苷酸阵列。对于118名至少经历过一次哮喘急性发作的受试者，将急性发作期间收集的外周血单核细胞样本中的基因表达模式与静止期哮喘期间收集的同一受试者的多个样本中观察到的模式进行比较。协方差分析确定的基因，其表达水平在急性加重期间发生变化，并在两周后恢复到静止水平。使用K-均值聚类检查表达谱中访问之间的异质性。三个不同的加重相关的基因表达的签名进行了鉴定。一个特征表明，即使在没有呼吸道感染症状的患者中，先天免疫基因也被激活。由IL 15介导的抗原非依赖性T细胞活化也由该标记指示。第二个特征揭示了通过抗原受体和随后的适应性免疫下游事件的淋巴细胞活化的强有力证据。在第三个签名中确定的基因的数量太少，无法得出结论的机制驱动这些accelations.Conclusions/意义：这项研究表明，分析PBMC揭示了全身的变化，伴随着哮喘加重，并奠定了基础，为今后的比较研究使用PBMC。
Background: Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations.Methodology/Principal Findings: Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations.Conclusions/Significance: This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.