Asthma Is Associated with Multiple Alterations in Anti-Viral Innate Signalling Pathways
Asthma Is Associated with Multiple Alterations in Anti-Viral Innate Signalling Pathways
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DOI：
10.1371/journal.pone.0106501
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发表时间：
2014-09-09
期刊：
影响因子：
3.7
通讯作者：
Upham, John W.
中科院分区：
文献类型：
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作者：
Pritchard, Antonia L.;White, Olivia J.;Upham, John W.
背景：人鼻病毒（HRV）感染是哮喘急性发作的主要诱因。抗病毒免疫在哮喘中似乎是异常的，气道结构细胞和迁移的骨髓来源的细胞都报告了免疫功能障碍。虽然有报道称哮喘患者产生抗病毒干扰素（IFN）的能力下降，但尚未对其相关分子事件进行详细分析。目的：比较哮喘患者和健康人外周血单个核细胞（PBMC）经HRV刺激后I型IFN合成的分子途径。22例过敏性哮喘患者和20例健康献血员的PBMC与HRV共同培养24小时。Toll样受体（TLR），IFN调节和NF κ β途径的多个组件进行了比较，在mRNA和蛋白质水平。结果：在先天免疫反应HRV的多个缺陷被确定在哮喘，IFN α，IFN β和干扰素刺激基因的表达显着低于健康受试者。这伴随着细胞内信号分子的表达减少，包括干扰素调节因子（IRF 1，IRF 7），NF-κ B家族成员（p50，p52，p65和I κ K α）和STAT 1，以及对TLR 7/TLR 8激活的反应性降低。这些观察结果不能归因于哮喘中树突状细胞（DC）亚群数量的改变或病毒RNA敏感受体TLR 7/TLR 8的基线表达。在健康受试者中，阻断I型IFN或耗尽浆细胞样DC的活性重演了许多在asthma.Conclusions中观察到的异常：在哮喘中确定了先天性抗病毒信号传导途径的多种异常，在IFN依赖性和IFN独立性分子中发现了缺陷。
Background: Human rhinovirus (HRV) infection is a major trigger for asthma exacerbations. Anti-viral immunity appears to be abnormal in asthma, with immune dysfunction reported in both airway structural cells and migratory, bone marrow derived cells. Though decreased capacity to produce anti-viral interferons (IFNs) has been reported in asthma, a detailed analysis of the molecular events involved has not been undertaken.Objective: To compare the molecular pathway controlling type I IFN synthesis in HRV-stimulated peripheral blood mononuclear cells (PBMC) from asthmatic and healthy subjects.Methods: PBMC from 22 allergic asthmatics and 20 healthy donors were cultured with HRV for 24 hours. Multiple components of the Toll-like receptor (TLR), IFN regulatory and NF kappa beta pathways were compared at the mRNA and protein level.Results: Multiple deficiencies in the innate immune response to HRV were identified in asthma, with significantly lower expression of IFN alpha, IFN beta and interferon stimulated genes than in healthy subjects. This was accompanied by reduced expression of intra-cellular signalling molecules including interferon regulatory factors (IRF1, IRF7), NF-kappa B family members (p50, p52, p65 and I kappa K alpha) and STAT1, and by reduced responsiveness to TLR7/TLR8 activation. These observations could not be attributed to alterations in the numbers of dendritic cell (DC) subsets in asthma or baseline expression of the viral RNA sensing receptors TLR7/TLR8. In healthy subjects, blocking the activity of type-I IFN or depleting plasmacytoid DC recapitulated many of the abnormalities observed in asthma.Conclusions: Multiple abnormalities in innate anti-viral signalling pathways were identified in asthma, with deficiencies in both IFN-dependent and IFN-independent molecules identified.