Immune network dysregulation precedes clinical diagnosis of asthma

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.