Abstract
Allergic asthma is a chronic disease beginning in childhood that is characterized by dominant T-helper 2 cell activation without adequate counter-regulation by T-helper 1 cell and regulatory T cell activity. Prior transcriptomic studies of childhood asthma have primarily investigated subjects who already have a disease diagnosis, and have generally taken an approach of differential gene expression as opposed to differential gene interactions. The immune states that predispose towards allergic sensitization and disease development remain ill defined. We thus characterize immune networks of asthmatic predisposition in children at the age of 2, prior to the diagnosis of allergic asthma, who are subsequently diagnosed with asthma at the age of 7. We show extensive differences of gene expression networks and gene regulatory networks in children who develop asthma versus those who do not using transcriptomic data from stimulated peripheral blood mononuclear cells. Moreover, transcription factors that bind proximally to one another share patterns of dysregulation, suggesting that network differences prior to asthma diagnosis result from altered accessibility of gene targets. In summary, we demonstrate non-allergen-specific immune network dysregulation in individuals long before clinical asthma diagnosis.
Highlights
Allergic asthma is a chronic disease beginning in childhood that is characterized by dominant T-helper 2 cell activation without adequate counter-regulation by T-helper 1 cell and regulatory T cell activity
We identify significantly altered interactions in our gene expression networks. We demonstrate that these altered expression networks can be explained by regulatory differences, and provide evidence that broad epigenetic alterations cause the downstream disruption of these networks
Gene network investigation powered by associations of stimulated gene expression across subjects allows us to uncover immune imbalances that precede clinical diagnosis of asthma
Summary
Allergic asthma is a chronic disease beginning in childhood that is characterized by dominant T-helper 2 cell activation without adequate counter-regulation by T-helper 1 cell and regulatory T cell activity. It is important to characterize early immune states that predispose toward clinical diagnosis of asthma in order to facilitate identification of individuals that are poised to develop disease. Less is known regarding the differential basal immune states that predispose towards allergic sensitization and disease development, “asthmatic poise.”. Our laboratory has previously reported altered Th2 cytokine elaboration in response to common aeroallergens in the cord blood mononuclear cells of neonates with differing in utero microbial exposures[7]. These differential immune signatures can be probed as early as birth. Genome-wide methylation changes have been demonstrated in response to environmental a gents[15], and were identified in a meta-analysis of children who develop a sthma[16]
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