Background-The genetic etiology of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of

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Rationale and ObjectiveAutophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.MethodsUsing genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP.Measurements and Main ResultsWe demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls.ConclusionGenetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.

Objective-To present methodology to identify atopic parents and determine the prevalence of sensitization to 15 aeroallergens in their infant offspring.Study design-A birth cohort of infants was identified from birth records; an infant was enrolled if 1 of the parents reported allergy respiratory symptoms and had a positive skin prick test (SPT) to a common aeroallergen. At age 1 year, these infants were tested to the same aeroallergens.Results-Of the 680 enrolled infants, 28.4% were SPT+ to 1 or more aeroallergens and/or food, and 18.0% were positive to 1 or more aeroallergens. By category of allergens, 9.7% were sensitized to pollens, 7.5% to molds, 4.3% to house dust mite and/or cockroach, and 3.4% to dog and/or cat. Of the infants who were positive to an aeroallergen, 65.7% remained positive at age 2 years.Conclusions-Infants born to atopic parents with percutaneous sensitization to aeroallergens are at increased risk for aeroallergen sensitization during infancy, which persists to age 2 years. These findings suggest that current clinical practices, which generally avoid skin testing before age 2 years, be reassessed in this population of high-risk children.In the Third National Health and Nutrition Examination Survey, (NHANES III), conducted in 1988-1994, 50% of children age 4 to 17 years exhibited a positive skin prick test (SPT) to at least 1 of 4 aeroallergens. 1 Over the last 2 decades, these high rates of aeroallergen sensitization have been accompanied by an estimated doubling in the incidence of allergic respiratory diseases, with an 11% gap for asthma attacks (26% vs 15%) between black and white children. 2,3 Aside from food allergies and atopic dermatitis, the potential for development of atopic respiratory disorders in infancy is often deemphasized, even though sensitization to allergens at younger ages has been shown to be more important than sensitization later in childhood for the development of wheezing symptoms and asthma. 4,5 Thus, early recognition of aeroallergen sensitization during the first and second years of life may facilitate surveillance of infants at highest risk for later expression of allergic respiratory disease. 6Although parental history of asthma and allergic rhinitis 7-9 are important risk factors for childhood asthma, 10-12 little is known about percutaneous sensitization profiles of infants born to parents with confirmed aeroallergen sensitization. This is due in part to the difficulties NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript inherent in performing the SPT in infants as well as parents, despite the fact that this procedure can be safely performed in patients of all ages and is more sensitive than in vitro measurements of serum-specific IgE. 13 Moreover, in all but 1 birth cohort study of infants in which SPT has been performed, the number of aeroallergens evaluated was 7 or less. 14-17Here we report methods used to precisely identify atopic parents and successfully recruit their high-risk infants for the Cincinnati Childhood All...

Background Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEP), increases risk for asthma and asthma exacerbation, however the underlying mechanisms remain poorly understood. Objective To examine the impact of DEP exposure on the generation and persistence of allergen-specific memory T-cells in asthma and translate these findings by determining the impact of early DEP exposure on the prevalence of allergic asthma in children. Methods The impact of DEP on HDM-specific memory responses was determined using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort were analyzed to determine the impact of the DEP exposure on asthma outcomes. Results DEP co-exposure with HDM resulted in persistent Th2/Th17 CD127+ effector/memory cells in the lungs, spleen and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased levels of Th2 cytokines in only mice that had been previously exposed to both HDM and DEP versus HDM alone. Based on these data, we examined whether DEP exposure was similarly associated increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the CCAAPS birth cohort. Early life exposure to high DEP was associated with significantly increased asthma prevalence among allergic children, but not among non-allergic children. Conclusion These findings suggest that DEP exposure results in accumulation of allergen specific Th2/Th17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma.

Background Asthma is a complex disorder influenced by genetics and the environment. Recent findings have linked abnormal DNA methylation in T cells with asthma; however, the potential dysregulation of methylation in airway epithelial cells is unknown. Studies of mouse models of asthma have observed greater levels of 5-hydoxymethylcytosine (5-hmC) and TET1 expression in lungs. TET proteins are known to catalyze methylation through modification of 5-mC to 5-hydroxymethylcytosine (5-hmC). Objective Associations between TET1 methylation and asthma and traffic-related air pollution were examined. Methods TET1 methylation levels from DNA derived from nasal airway epithelial cells collected from 12 African-American children with physician-diagnosed asthma and their non-asthmatic siblings were measured using Illumina 450K arrays. Regions of interest were verified by locus-specific pyrosequencing in 35 additional sibling pairs and replicated in an independent population (N=186). Exposure to traffic-related air pollution (TRAP) at participants’ early life and current home addresses was estimated using a land-use regression model. Methylation studies in saliva, PBMCs, and human bronchial epithelial cells (HBEC) were done to support our findings. Results Loss of methylation at a single CpG site in the TET1 promoter (cg23602092) and increased global 5hmC was significantly associated with asthma. In contrast, TRAP exposure at participants’ current homes significantly increased methylation at the same site. Patterns were consistent across tissue sample types. 5-aza-2'-deoxycytidine and diesel exhaust particle exposure in HBEC was associated with altered TET1 methylation, expression and global 5-hmC. Conclusions Our findings suggest a possible role of TET1 methylation in asthma and response to TRAP. Capsule summary TET1 DNA methylation might serve as a biomarker for asthma and higher risk of exposure-related asthma exacerbations.

Background Allergic sensitization to fungi have been associated with asthma severity. As a result, it has been largely assumed that the contribution of fungi to allergic disease is mediated through their potent antigenicity. Objective We sought to determine the mechanism by which fungi impact asthma development and severity. Methods We integrated epidemiologic and experimental asthma models to explore the impact of fungal exposure on asthma development and severity. Results We report that fungal exposure enhances allergen-driven TH2 responses promoting severe allergic asthma. This effect is independent of fungal sensitization, and can be reconstituted with β-glucan and abrogated by neutralization of IL-17A. Further, this severe asthma is resistant to steroids and characterized by mixed TH2 and TH17 responses, including IL-13+IL17+CD4+ double-producing T-effector cells. Steroid resistance is dependent on fungal-induced TH17 responses as steroid sensitivity was restored in IL-17RC−/− mice. Similarly, in children with asthma, fungal exposure was associated with increased serum IL-17A and asthma severity. Conclusion Our data demonstrate that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. Further, our results provide strong rationale for combination treatment strategies targeting IL-17A for this subgroup of fungal-exposed difficult-to-treat asthmatics.

Previous studies of allergic rhinitis in children have not documented the environmental risk factors for infants at age one. We examined the relationship of environmental tobacco smoke (ETS) and visible mold exposures on the development of allergic rhinitis, rhinitis and upper respiratory infection (URI) in a birth cohort where at least one parent was skin prick test (SPT) positive. ETS exposure and upper respiratory symptoms were obtained by questionnaires. Visible mold was classified as none, low or high during home visit. Infants had a SPT at age one. After adjustment for potential confounders, exposure to >20 cigarettes per day was associated with an increased risk of developing allergic rhinitis at age one [odds ratio (OR) = 2.7; 95% CI 1.04–6.8] and rhinitis symptoms during the first year (OR = 1.9; 95% CI 1.1–3.2). Infants with low (OR = 1.5; 95% CI 1.1–2.3) or high (OR = 5.1; 95% CI 2.2–12.1) levels of visible mold in their homes were more likely to have more frequent URI during the first year. Older siblings were protective for development of both rhinitis symptoms and allergic rhinitis. This study suggests that ETS exposure, rather than visible mold, is associated with rhinitis and allergic rhinitis in infants. The analysis also suggests that mold may be a stronger risk factor for URI that ETS.