This suggests that improving 25(OH)D3 status in pregnancy or early infancy may reduce the development of allergic disease in high-risk infants by inhibiting cytokine profiles associated with allergy. Results of clinical trials are awaited to determine the efficacy of vitamin D supplementation in allergy prevention.

Non-pathogenic environmental microbial exposures during pregnancy can be transplacentally transcribed into beneficial immune training signals for the developing fetus.These signals equip offspring for more rapid adaptation to the microbe-rich postnatal environment by optimising immunoregulatory innate cell function. We have previously identified that maternal treatment with a microbial-derived therapeutic (OM-85) can protect offspring against allergic airways inflammation. Here, we show that oral treatment of pregnant mice with OM-85 induces transplacental signals that manifest in fetal bone marrow as an enriched population of conventional dendric cells (cDC) displaying enhanced functional maturation. Moreover, the myeloid progenitor populations directly upstream of this cDC pool were significantly boosted in response to maternal treatment. Transcriptomic analysis of fetal bone marrow identified maternal OM-85-induced activation of X-box binding protein 1 (XBP1), with upregulation of active XBP1 restricted to cDC precursors. These data provide direct evidence that transplacental immune training with a microbial-derived therapeutic can accelerate functional immune competence of the fetal bone marrow myeloid compartment. KTM, PGH and DHS designed the study. KTM, MB , NMS and JFLJ performed the experiments. KTM, ACJ, MB and DHS analysed the data. PAS and AB contributed to the project design and discussions on data interpretation. KTM, PAS, PGH and DHS wrote the manuscript. All authors reviewed the final version of the manuscript.

RationaleAtopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced Th2-associated airways inflammation. However, the vast majority of atopics do not develop asthma-related wheeze, despite ongoing exposure to aeroallergens to which they are strongly sensitized, indicating that additional pathogenic mechanism(s) operate in conjunction with Th2 immunity to drive asthma pathogenesis.ObjectivesEmploy systems level analyses to identify inflammation-associated gene networks operative at baseline in sputum-derived RNA from house dust mite-sensitized (HDMs) subjects with/without wheezing history; identify networks characteristic of the ongoing asthmatic state. All subjects resided in the constitutively-HDMhigh Perth environment.MethodsGenome wide expression profiling by RNASeq followed by gene coexpression network analysis.Measurements/ResultsHDMs-nonwheezers displayed baseline gene expression in sputum including IL-5, IL-13 and CCL17. HDMs-wheezers showed equivalent expression of these classical Th2-effector genes but their overall baseline sputum signatures were more complex, comprising hundreds of Th2-associated and epithelial-associated genes, networked into two separate coexpression modules. The first module was connected by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3, and contained genes that control mucociliary clearance.ConclusionsOur findings provide new insight into the inflammatory mechanisms operative at baseline in the airway mucosal microenvironment in atopic asthmatics undergoing natural perennial aeroallergen exposure. The molecular mechanism(s) that determine susceptibility to asthma amongst these subjects involve interactions between Th2-and epithelial function-associated genes within a complex co-expression network, which is not operative in equivalently sensitized/exposed atopic non-asthmatics.FundingThis study was funded by the Asthma Foundation WA, the Department of Health WA, and the NHMRC. AB is funded by a BrightSpark Foundation McCusker Fellowship. GLH is a NHMRC Fellow. AG is supported by the McCusker Charitable Foundation Bioinformatics Centre. ACJ is a recipient of an Australian Postgraduate Award and a Top-Up Award from the University of Western Australia.