Allergen-induced activation of natural killer cells represents an early-life immune response in the development of allergic asthma.
ABSTRACT: BACKGROUND:Childhood asthma in inner-city populations is a major public health burden, and understanding early-life immune mechanisms that promote asthma onset is key to disease prevention. Children with asthma demonstrate a high prevalence of aeroallergen sensitization and TH2-type inflammation; however, the early-life immune events that lead to TH2 skewing and disease development are unknown. OBJECTIVE:We sought to use RNA sequencing of PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma. METHODS:In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years. RESULTS:PBMCs from the cases showed higher levels of expression of natural killer (NK) cell-related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell-like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules, including the key TH2-type cytokines IL9, IL13, and CCL17, as well as a dendritic cell-like gene network, including upregulation of CD1 lipid antigen presentation molecules. The NK cell-like response was reproducible in an independent group of children with later-onset allergic sensitization and asthma and was found to be specific to only those children with both aeroallergen sensitization and asthma. CONCLUSION:These findings provide important mechanistic insight into an early-life immune pathway involved in TH2 polarization, leading to the development of allergic asthma.
Project description:BACKGROUND:Wheezing illnesses cause major morbidity in infants and are frequent precursors to asthma. OBJECTIVE:We sought to examine environmental factors associated with recurrent wheezing in inner-city environments. METHODS:The Urban Environment and Childhood Asthma study examined a birth cohort at high risk for asthma (n = 560) in Baltimore, Boston, New York, and St Louis. Environmental assessments included allergen exposure and, in a nested case-control study of 104 children, the bacterial content of house dust collected in the first year of life. Associations were determined among environmental factors, aeroallergen sensitization, and recurrent wheezing at age 3 years. RESULTS:Cumulative allergen exposure over the first 3 years was associated with allergic sensitization, and sensitization at age 3 years was related to recurrent wheeze. In contrast, first-year exposure to cockroach, mouse, and cat allergens was negatively associated with recurrent wheeze (odds ratio, 0.60, 0.65, and 0.75, respectively; P ? .01). Differences in house dust bacterial content in the first year, especially reduced exposure to specific Firmicutes and Bacteriodetes, was associated with atopy and atopic wheeze. Exposure to high levels of both allergens and this subset of bacteria in the first year of life was most common among children without atopy or wheeze. CONCLUSIONS:In inner-city environments children with the highest exposure to specific allergens and bacteria during their first year were least likely to have recurrent wheeze and allergic sensitization. These findings suggest that concomitant exposure to high levels of certain allergens and bacteria in early life might be beneficial and suggest new preventive strategies for wheezing and allergic diseases.
Project description:Peripheral blood samples from children enrolled in the URECA cohort were collected at age 2. In short, at each URECA research center, within 16 hours of blood collection, mononuclear cells were separated and incubated (48 hours, 37C, 5% CO2) in the presence of German cockroach extract (10mg/mL; CR), dust mite extract (Dermatophagoides pteronyssinus, 10mg/mL; DM), tetanus toxoid (5mg/mL; TT), or medium alone (NS). Overall design: For the initial case-control cohort (cohort 1), cases (n=21) were URECA participants who met the following inclusion criteria: a) ≥2 aeroallergen sensitizations at age 3, 5, and 7 including sensitization to DM and/or CR at each age, b) a diagnosis of asthma at age 7, and c) had PBMC RNA samples collected at age 2. Controls (n=30) were URECA participants with: a) no aeroallergen sensitization through age 7, b) did not have asthma at age 7, and c) had PBMC RNA samples collected at age 2. Controls were selected to match to cases on at least a bivariate level according to the following variables: gender, race, URECA site, birth season, and levels of Bla g 1, Der f 1, and Def p 1 measured in the home 3 months after birth. All available NS, CR, DM, and TT stimulation PBMC samples from these 51 individuals were selected for RNA-sequencing. For cohort 2, seven additional URECA participants were selected who met the following inclusion criteria: a) ≥1 aeroallergen sensitization by age 7 including CR sensitization, b) a diagnosis of asthma at age 7, and c) PBMC RNA samples collected at age 2. Fourteen additional controls were selected to match these cases by the same criteria as the controls of cohort 1. Furthermore, all URECA participants with PBMC RNA samples collected at age 2 and who had sufficient year 7 outcome data for group classification were added to the sequencing run to allow a 4 group comparison based on CR sensitization (age 3, yes/no) and asthma (age 7, yes/no). For the latter analyses, only NS and CR stimulation PBMC samples were used for RNA-sequencing.
Project description:Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood.To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing.A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model.Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50-1.1).Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.
Project description:Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood.To define the relationship between specific viral illnesses and early childhood asthma development.A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed.Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR , 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age.Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.
Project description:BACKGROUND:Mouse models of atopic march suggest that systemic, skin-derived thymic stromal lymphopoietin (TSLP) mediates progression from eczema to asthma. OBJECTIVE:We investigated whether circulating TSLP is associated with eczema, allergic sensitization, or recurrent wheezing in young children. METHODS:A prospective analysis of the relationship between plasma levels of TSLP to allergic sensitization and recurrent wheezing was conducted in the birth cohort from the Urban Environment and Childhood Asthma (URECA) study. Plasma TSLP levels were measured at 1, 2, and 3 years of age and analysed for correlation with clinical parameters in each of the three years. Only those children with consecutive samples for all three years were included in this analysis. RESULTS:We detected TSLP in 33% of 236 children for whom plasma samples were available for all three years. Overall, a consistently significant association was not found between TSLP and eczema or allergic sensitization. With regard to recurrent wheezing, children with detectable TSLP at one year of age were significantly less likely to experience recurrent wheezing by 3 years compared with those children without detectable TSLP, but this was only seen in children without aeroallergen sensitization at 3 years (P < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE:Contrary to our expectations, circulating TSLP was not significantly associated with eczema, allergen sensitization, or recurrent wheezing during the first three years of life. Early presence of circulating TSLP was significantly associated with reduced incidence of recurrent wheeze in those children not sensitized to aeroallergen. These findings suggest a possible underlying distinction between pathogenesis of developing atopic vs. non-atopic recurrent wheeze.
Project description:Asthma prevalence varies widely among neighborhoods within New York City. Exposure to mouse and cockroach allergens has been suggested as a cause.To test the hypotheses that children living in high asthma prevalence neighborhoods (HAPNs) would have higher concentrations of cockroach and mouse allergens in their homes than children in low asthma prevalence neighborhoods (LAPNs), and that these exposures would be related to sensitization and asthma.In the New York City Neighborhood Asthma and Allergy Study, a case-control study of asthma, children 7 to 8 years old from HAPNs (n = 120) and LAPNs (n = 119) were recruited through the same middle-income health insurance plan. Children were classified as asthma cases (n = 128) or controls without asthma (n = 111) on the basis of reported symptoms or medication use. Allergens were measured in bed dust.HAPN homes had higher Bla g 2 (P = .001), Mus m 1 (P = .003), and Fel d 1 (P = .003) and lower Der f 1 (P = .001) than LAPN homes. Sensitization to indoor allergens was associated with asthma, but relevant allergens differed between LAPNs and HAPNs. Sensitization to cockroach was more common among HAPN than LAPN children (23.7% vs 10.8%; P = .011). Increasing allergen exposure was associated with increased probability of sensitization (IgE) to cockroach (P < .001), dust mite (P = .009), and cat (P = .001), but not mouse (P = .58) or dog (P = .85).These findings further demonstrate the relevance of exposure and sensitization to cockroach and mouse in an urban community and suggest that cockroach allergen exposure could contribute to the higher asthma prevalence observed in some compared with other New York City neighborhoods.
Project description:The aim of this study was to examine if food and/or aeroallergen sensitization was associated with worse asthma, pulmonary function tests (PFT), and laboratory markers.At our institution, 386 children with asthma were divided into allergic and nonallergic groups based on allergen-specific immunoglobulin E (IgE) testing classes 1-6 versus 0. Asthma severity and/or control, IgE level, eosinophil counts and/or percentages, forced vital capacity (FVC), forced expiratory volume in the first second of expiration (FEV1), and FEV1/FVC, were compared by using bivariate, regression, and subgroup analyses for children who were highly allergic (?4 allergens).A total of 291 subjects with asthma were allergic, significantly older, and had higher mean IgE levels and eosinophil counts and percentages (all p < 0.001). A total of 203 subjects who were highly allergic had worse obstruction on PFTs. Increasing age predicted allergen sensitization after confounder adjustment, odds ratio (OR) 1.54 (95% confidence interval [CI], 1.18-2.02). Similarly, PFT obstruction was associated with multiple allergen sensitization (OR 0.97 [95% CI, 0.93-1.02]).Increasing age predicted allergic sensitization and multiple allergen sensitization. Worse obstruction on PFT also predicted multiple allergen sensitization. Continued surveillance of aeroallergen sensitization and PFT results may be beneficial in asthma management, particularly in older urban children.
Project description:Cockroach and mouse allergens have both been implicated as causes in inner-city asthma morbidity in multicenter studies, but whether both allergens are clinically relevant within specific inner-city communities is unclear.Our study aimed to identify relevant allergens in Baltimore City.One hundred forty-four children (5-17 years old) with asthma underwent skin prick tests at baseline and had clinical data collected at baseline and 3, 6, 9, and 12 months. Home settled dust samples were collected at the same time points for quantification of indoor allergens. Participants were grouped based on their sensitization and exposure status to each allergen. All analyses were adjusted for age, sex, and serum total IgE level.Forty-one percent were mouse sensitized/exposed, and 41% were cockroach sensitized/exposed based on bedroom floor exposure data. Mouse sensitization/exposure was associated with acute care visits, decreased FEV1/forced vital capacity percentage values, fraction of exhaled nitric oxide levels, and bronchodilator reversibility. Cockroach sensitization/exposure was only associated with acute care visits and bronchodilator reversibility when exposure was defined by using bedroom floor allergen levels. Mouse-specific IgE levels were associated with poor asthma health across a range of outcomes, whereas cockroach-specific IgE levels were not. The relationships between asthma outcomes and mouse allergen were independent of cockroach allergen. Although sensitization/exposure to both mouse and cockroach was generally associated with worse asthma, mouse sensitization/exposure was the primary contributor to these relationships.In a community with high levels of both mouse and cockroach allergens, mouse allergen appears to be more strongly and consistently associated with poor asthma outcomes than cockroach allergen. Community-level asthma interventions in Baltimore should prioritize reducing mouse allergen exposure.
Project description:Although mouse and cockroach allergy is known to be important in urban children with asthma, the independent association of mouse and cockroach sensitization with rhinitis in these children is unknown.To determine the association of mouse and cockroach sensitization with rhinitis in urban children with asthma.As part of the Mouse Allergen and Asthma Intervention Trial, 499 urban children (5-17 years) with persistent asthma underwent spirometry, skin prick testing to 14 common environmental allergens, and serology for mouse-specific IgE. In 269 subjects, cockroach-specific IgE serology was also obtained. Patient/parent-reported rhinitis in the last 2 weeks and the last 1 year was the primary outcome measure. Mouse/cockroach exposure was measured by reported frequency of sightings. Mouse allergen-settled bedroom dust samples were also measured in mouse-sensitized children.Rhinitis was reported in 49.9% and 70.2% of the participants within the last 2 weeks and the last 1 year, respectively. Serum mouse IgE level of 0.35 IU/mL or more was associated with rhinitis in the past 2 weeks (adjusted odds ratio, 2.15; 95% CI, 1.02-4.54; P = .04) and the past 1 year (adjusted odds ratio, 2.40; 95% CI, 1.12-5.1; P = .02) after controlling for age, race, sex, the presence of any smokers at home, primary caregiver education level, number of allergen sensitivities, cockroach IgE level of 0.35 IU/mL or more, and study site (Boston or Baltimore). Measures of home mouse exposure were not associated with rhinitis, regardless of mouse sensitivity. Cockroach sensitivity was not associated with rhinitis regardless of sensitization to other allergens.In urban children with asthma, increased mouse IgE, but not cockroach IgE, in the sera (mouse IgE ? 0.35 IU/mL) may be associated independently with rhinitis.
Project description:Triclosan and parabens are chemicals used in personal care and medical products as microbicides and preservatives. Triclosan and paraben exposure may be associated with allergy (atopy), but these associations have not been evaluated with respect to other atopic states such as eczema (atopic dermatitis). This study examines the associations of urinary triclosan and paraben concentrations with allergic sensitization and asthma in children according to eczema history. We performed a cross-sectional analysis of U.S. children aged 6-18 years who participated in the National Health and Nutrition Examination Survey (2005-2006). Triclosan and paraben concentrations were measured in urine. We assessed associations of triclosan and parabens with allergic sensitization and asthma using multivariable logistic regression in 837 children with complete data and stratified our results by eczema status. After covariate adjustment, triclosan and methyl and propyl paraben concentrations were positively associated with the odds of aeroallergen sensitization. Eczema did not significantly modify the association between triclosan or paraben levels and aeroallergen sensitization, asthma, or wheeze. The odds of parent-reported atopic asthma increased 34% (95% CI, 0, 81) across triclosan concentration quartiles. Increasing triclosan concentrations (quartiles) were associated with 2.3 times the odds of food sensitization (95% CI, 1.14, 4.44) among children with eczema, but not among children without eczema (OR, 1.25; 95% CI 0.93, 1.68; effect measure modification, p = 0.04). Triclosan and paraben exposures may increase the risk of atopic asthma and aeroallergen sensitization. Prospective studies are necessary to confirm these findings and determine if these chemicals pose a risk to children's health.