Background The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. Objective To assess whether the trajectory to asthma begins already at birth and epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We used Methylated CpG Island Recovery Assay (MIRA)-chip to survey DNA methylation in cord blood mononuclear cells (CBMC) from 36 children (18 non-asthmatic, 18 asthmatic by age 9) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n=60) and in two replication cohorts (The Manchester Asthma and Allergy Study, n=30, and the Childhood Origins of ASThma Study, n=28) was analyzed by bisulfite sequencing or Illumina 450K arrays. CBMC-derived IL-1β was measured by ELISA. Results Neonatal immune cells harbored 589 differentially methylated regions (DMRs) that distinguished IIS children who did and did not develop asthma by age 9. In all three cohorts, methylation in SMAD3, the most connected node within the network of asthma-associated DMRs, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. Conclusions The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and pro-inflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.

Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs, and define contextually relevant novel therapeutic targets.

Our findings suggest that the mononuclear phagocyte population is directly involved in the production of proinflammatory chemokines that attract other immune cells. Rapid recruitment of CD14(+) monocytes to the challenged site indicates that these proinflammatory mononuclear phagocytes have a central role in orchestrating local allergic inflammation.