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Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS. [ABSTRACT FROM AUTHOR]

High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups. [ABSTRACT FROM AUTHOR]

Background: Antigen‐specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non‐atopic/non‐asthmatic age‐matched healthy controls. Methods: We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. Results: We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non‐atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non‐asthmatic children also after adjusting for serum IgE levels. Conclusion: Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non‐asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children. [ABSTRACT FROM AUTHOR]

Asthma is a chronic disease of the airways, most commonly driven by immuno-inflammatory responses to ubiquitous airborne antigens. Epidemiological studies have shown that disease is initiated early in life when the immune and respiratory systems are functionally immature and less able to maintain homeostasis in the face of continuous antigen challenge. Here, we examine the cellular and molecular mechanisms that underlie initial aeroallergen sensitization and the ensuing regulation of secondary responses to inhaled allergens in the airway mucosa. In particular, we focus on how T-regulatory (Treg) cells influence early asthma initiation and the potential of Treg cells as therapeutic targets for drug development in asthma. [ABSTRACT FROM AUTHOR]