Multinational study on rural environmental protection for childhood asthma – a central role for dendritic and regulatory B-cells during immune maturation

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This multinational study aims to identify central mechanisms of environmental protection for childhood asthma in both Europe and China. By assessing dendritic cells (DC) and regulatory B-cells (Breg) during immune maturation, this project aims to disentangle novel central regulatory hubs which contribute to asthma protection via two strong asthma-protective environments. The unique chance of having consecutive blood samples of children at several ages of an European birth cohort from the strongest asthma-protective environment, namely farming, available and in parallel recruiting Chinese children from urban HongKong (and Guangzhou) with high asthma prevalence and rural Conghua with low prevalence at age 6 years allows the comparison of asthma-protective mechanisms across Europe and China. Different dusts from both strong “asthma-protective” areas will be analysed for microbiome components by 16srRNA and metagenomics to identify lead components for future studies. Two central cell populations, namely DC and Bregs will be examined to disentangle their functional contribution for this environmental protection. For functional assessment of DC and Bregs, kinetic and dose-dependent experiments following dust stimulation will be performed in peripheral blood of children, complemented by co-culture models of farm-dust primed DCs and their interaction with B/T-cells. In parallel, murine models aim to identify novel regulators using genetically modified mice. Finally, a potential specific window of maintaining healthy immune balance will be examined in the birth cohort by asssessing age-dependent differences for protective environmental exposure. Immune regulation of children at birth, age 6 and 10 yrs will be screened by RNA-seq and age-dependent cellular regulation of DCs/Bregs will be examined by flow cytometry. As a proof-of-principle experiment functional stimulation of Breg-depleted PBMCs will be performed in children with onset of wheeze, children with manifest asthma and healthy controls in order to identify regulation during early onset of disease and during manifest asthma.This project will not only disentangle a central role of DCs and Bregs, but also represents a unique opportunity to dissect mechanisms how environment-mediated protection against childhood asthma may be implemented in future prevention studies. Furthermore, these experiments have the potential to identify the most critical time windows in humans and mice, where healthy immune regulation can be maintained or even restored by environmental exposure. This is crucial for future protective strategies against childhood asthma.