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 FcεR1, 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-α 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.

Although transient, suboptimal neonatal T-cell activation pathways that signal through the NF-κB complex may affect the developmental transition of T-cell phenotypes in the periphery shortly after birth and may increase the risk of food allergy.

Background: Exposure to arsenic via drinking water is a global environmental health problem. In utero exposure to arsenic via drinking water increases the risk of lower respiratory tract infections during infancy and mortality from bronchiectasis in early adulthood.Objectives: We aimed to investigate how arsenic exposure in early life alters lung development and pathways involved in innate immunity.Methods: Pregnant BALB/c, C57BL/6, and C3H/HeARC mice were exposed to 0 (control) or 100 μg/L arsenic via drinking water from gestation day 8 until the birth of their offspring. We measured somatic growth, lung volume, and lung mechanics of mice at 2 weeks of age. We used fixed lungs for structural analysis and collected lung tissue for gene expression analysis by microarray.Results: The response to arsenic was genetically determined, and C57BL/6 mice were the most susceptible. Arsenic-exposed C57BL/6 mice were smaller in size, had smaller lungs, and had impaired lung mechanics compared with controls. Exposure to arsenic in utero up-regulated the expression of genes in the lung involved in mucus production (Clca3, Muc5b, Scgb3a1), innate immunity (Reg3γ, Tff2, Dynlrb2, Lplunc1), and lung morphogenesis (Sox2). Arsenic exposure also induced mucous cell metaplasia and increased expression of CLCA3 protein in the large airways.Conclusions: Alterations in somatic growth, lung development, and the expression of genes involved in mucociliary clearance and innate immunity in the lung are potential mechanisms through which early life arsenic exposure impacts respiratory health.

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