Subrata Lily S, Bizzintino Joelene, Mamessier Emilie, Bosco Anthony, McKenna Katherine L, Wikström Matthew E, Goldblatt Jack, Sly Peter D, Hales Belinda J, Thomas Wayne R, Laing Ingrid A, LeSouëf Peter N, Holt Patrick G
Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, The University of Western Australia, Perth, Western Australia, Australia.
J Immunol. 2009 Aug 15;183(4):2793-800. doi: 10.4049/jimmunol.0900695. Epub 2009 Jul 20.
Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated "exhausted" phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcepsilonR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R(+) alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-alpha can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.
需要住院治疗的儿童重度哮喘急性发作通常与病毒感染有关，且几乎仅发生于特应性个体中，但这些合并症的意义尚不清楚。我们推测，与气传变应原和病毒反应相关的免疫炎症途径之间存在潜在相互作用，且在急性发作期间可在循环细胞中检测到这些相互作用的证据。为验证这一推测，我们采用了基于基因组学的方法，通过微阵列和流式细胞术对急性发作期与恢复期采集的外周血单个核细胞亚群进行分析。我们发现，急性发作期间循环T细胞呈现出激活后“耗竭”的表型，而单核细胞/树突状细胞群体则表现出CCR2表达上调，并伴有表型变化，这些变化极有可能在它们募集到特应性肺组织后增强局部炎症。值得注意的是，FcepsilonR1上调，已知其可通过IgE介导的变应原捕获显著增强变应原摄取/呈递给Th2效应细胞的能力，其次是对IL-4/IL-13依赖的IL-13R(+)交替激活巨噬细胞进行编程，在实验环境中已证明这些巨噬细胞是自分泌IL-13产生的强大来源。我们还表明，这种与疾病相关的激活谱可通过特应性单核细胞的细胞因子暴露在体外重现，此外，IFN-α在这一过程中可发挥正向和负向作用。我们的研究结果表明，特应性儿童的呼吸道病毒感染可能引发一个依赖特应性的级联反应，该反应通过利用潜在的特应性相关机制，放大并维持由先天性抗病毒免疫引发的气道炎症。这些相互作用可能解释了特应性个体对严重病毒诱导的哮喘急性发作的独特易感性。
