National Heart & Lung Institute, Imperial College London, London, United Kingdom.
J Allergy Clin Immunol. 2012 Jun;129(6):1506-1514.e6. doi: 10.1016/j.jaci.2012.03.044.
Asthmatic patients have defective rhinovirus-induced IFN-β and IFN-λ production from bronchial epithelial cells and IFN-λ from bronchoalveolar lavage (BAL) cells. Whether bronchoalveolar lavage cells have defective type I interferon responses to rhinovirus is unknown, as are mechanisms explaining defective rhinovirus interferon induction in asthmatic patients.
We sought to investigate rhinovirus induction of type I interferons in BAL and blood mononuclear cells from asthmatic patients and healthy subjects and to investigate mechanisms of any deficiency observed.
BAL and blood mononuclear cells from atopic asthmatic patients and healthy subjects were infected with rhinovirus ex vivo. Interferon proteins were analyzed by using ELISA. mRNA expression of key components of interferon induction pathways were analyzed by using quantitative PCR.
Rhinovirus induction of type I interferon protein was delayed and deficient in BAL cells from asthmatic patients, and lower interferon levels were associated with greater airway hyperresponsiveness and skin prick test response positivity. Expression of Toll-like receptor (TLR) 3, TLR7, TLR8, retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA-5), TIR domain-containing adapter-inducing IFN-β (TRIF), myeloid differentiation primary response gene 88 (MyD88), caspase recruitment domain adaptor inducing IFN-β (CARDIF), IL-1 receptor-associated kinase 4 (IRAK4), IκB kinase β (IKKB), IκB kinase ι (IKKI), interferon regulatory factors 3 and 7, and rhinovirus induction of expression of the virus-inducible molecules TLR3, TLR7, RIG-I, and MDA-5 were not impaired in these interferon-deficient BAL cells in asthmatic patients. Defective rhinovirus interferon induction was not observed in blood mononuclear cells.
Rhinovirus induction of type I interferons in BAL cells is delayed and deficient and might be a marker of more severe asthma. Defective rhinovirus interferon induction in asthmatic patients was not accompanied by differences in the expression or induction of key molecules implicated in viral induction of interferons.
哮喘患者的支气管上皮细胞产生的鼻病毒诱导的 IFN-β 和 IFN-λ 以及支气管肺泡灌洗液 (BAL) 细胞产生的 IFN-λ 存在缺陷。目前尚不清楚 BAL 细胞对鼻病毒是否存在Ⅰ型干扰素反应缺陷，以及哮喘患者中鼻病毒诱导干扰素产生缺陷的机制。
我们旨在研究哮喘患者和健康受试者的 BAL 细胞和血液单核细胞对鼻病毒的Ⅰ型干扰素诱导作用，并研究观察到的任何缺陷的机制。
采用 ex vivo 方法，用鼻病毒感染特应性哮喘患者和健康受试者的 BAL 细胞和血液单核细胞。采用 ELISA 分析干扰素蛋白。采用定量 PCR 分析干扰素诱导途径关键成分的 mRNA 表达。
哮喘患者的 BAL 细胞对鼻病毒诱导的Ⅰ型干扰素蛋白的诱导延迟且存在缺陷，较低的干扰素水平与气道高反应性和皮肤点刺试验阳性反应的相关性更强。哮喘患者 IFN 缺陷的 BAL 细胞中，Toll 样受体 (TLR) 3、TLR7、TLR8、维甲酸诱导基因 I (RIG-I)、黑色素瘤分化相关基因 5 (MDA-5)、TIR 结构域包含衔接子诱导 IFN-β (TRIF)、髓样分化初级反应基因 88 (MyD88)、CARDIF、IL-1 受体相关激酶 4 (IRAK4)、IKKβ (IKKB)、IKKι (IKKI)、干扰素调节因子 3 和 7 以及病毒诱导分子 TLR3、TLR7、RIG-I 和 MDA-5 的表达均未受损。这些 IFN 缺陷的 BAL 细胞中并未观察到血液单核细胞中鼻病毒诱导的Ⅰ型干扰素诱导缺陷。
哮喘患者 BAL 细胞中鼻病毒诱导的Ⅰ型干扰素的诱导延迟且存在缺陷，这可能是更严重哮喘的一个标志物。哮喘患者鼻病毒诱导的 IFN 缺陷并不伴有病毒诱导 IFN 表达的关键分子的差异。
