Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.

The characteristic pathologic features of asthma in adults and school-aged children develop in preschool children with confirmed wheeze between the ages of 1 and 3 years, a time when intervention may modify the natural history of asthma.

Rationale-Little is known about vitamin D status and its effect on asthma pathophysiology in children with severe, therapy-resistant asthma (STRA).Objectives-Relationships between serum vitamin D, lung function, and pathology were investigated in pediatric STRA. Methods-Serum 25-hydroxyvitamin D [25(OH)D3 ] was measured in 86 children (mean age, 11.7 yr): 36 with STRA, 26 with moderate asthma (MA), and 24 without asthma (control subjects). Relationships between 25(OH)D 3 , the asthma control test (ACT), spirometry, corticosteroid use, and exacerbations were assessed. Twenty-two of 36 children with STRA underwent fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy with assessment of airway inflammation and remodeling. Measurements and Main Results-25(OH)D 3 levels (median [IQR]) were significantly lower in nmol/L) than in nmol/L) and control subjects (56.5 [45-67] nmol/L) (P < 0.001). There was a positive relationship between 25(OH)D 3 levels and percent predicted FEV 1 (r = 0.4, P < 0.001) and FVC (r = 0.3, P = 0.002) in all subjects. 25(OH)D 3 levels were positively associated with ACT (r = 0.6, P < 0.001), and inversely associated with exacerbations (r=−0.6, P < 0.001) and inhaled steroid dose (r=−0.39, P = 0.001) in MA and and STRA. Airway smooth muscle (ASM) mass, but not epithelial shedding or reticular basement membrane thickness, was inversely related to 25(OH)D 3 levels (r=−0.6, P = 0.008). Copyright © 2011 by the American Thoracic SocietyCorrespondence and requests for reprints should be addressed to Atul Gupta, M.D., Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. atulgupta@doctors.org.uk. Author Contributions: A.G. recruited the majority of the patients, collected patient samples, conducted the majority of the experiments, analyzed the data, and took the lead on writing the manuscript. A.S. performed some of the experimental work. A.G., A.B., C.H., and S.S. conceptualized, delineated the hypotheses, and designed the experiments A.B., C.H., D.R., and S.S. contributed to the interpretation of the analyses, supervised the project, and helped with revising the manuscript. A.B. and S.S. also performed bronchoscopies and obtained samples. W.B. performed some of the statistical analyses. There was a positive correlation between ASM mass and bronchodilator reversibility (r = 0.6, P = 0.009) and an inverse correlation between ASM mass and ACT (r = −0.7, P < 0.001). Author DisclosuresConclusions-Lower vitamin D levels in children with STRA were associated with increased ASM mass and worse asthma control and lung function. The link between vitamin D, airway structure, and function suggests vitamin D supplementation may be useful in pediatric STRA. Keywordsvitamin D; asthma; remodeling; airway smooth muscle; pediatrics For most children with ready access to healthcare, asthma can be controlled with low doses of inhaled steroids. There remains, however, a significant number of individuals with asthma who, despite apparentl...

Background-The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood.