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Environmental exposures in early life appear to play an important role in the pathogenesis of childhood asthma, but the potentially modifiable exposures that lead to asthma remain uncertain.We sought to identify early-life environmental risk factors for childhood asthma in a birth cohort of high-risk inner-city children.We examined the relationship of prenatal and early-life environmental factors to the occurrence of asthma at 7 years of age among 442 children.Higher house dust concentrations of cockroach, mouse, and cat allergens in the first 3 years of life were associated with lower risk of asthma (for cockroach allergen: odds ratio per interquartile range increase in concentration, 0.55; 95% CI, 0.36-0.86; P .01). House dust microbiome analysis using 16S ribosomal RNA sequencing identified 202 and 171 bacterial taxa that were significantly (false discovery rate 0.05) more or less abundant, respectively, in the homes of children with asthma. A majority of these bacteria were significantly correlated with 1 of more allergen concentrations. Other factors associated significantly positively with asthma included umbilical cord plasma cotinine concentration (odds ratio per geometric SD increase in concentration, 1.76; 95% CI, 1.00-3.09; P = .048) and maternal stress and depression scores.Among high-risk inner-city children, higher indoor levels of pet or pest allergens in infancy were associated with lower risk of asthma. The abundance of a number of bacterial taxa in house dust was associated with increased or decreased asthma risk. Prenatal tobacco smoke exposure and higher maternal stress and depression scores in early life were associated with increased asthma risk.

Humans have populations of innate-like T lymphocytes with an invariant TCR α-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-γ by activated CD4+ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma.

Maternal depression and prenatal and early life stress may influence childhood wheezing illnesses, potentially through effects on immune development.To test the hypothesis that maternal stress and/or depression during pregnancy and early life are associated with recurrent wheezing and aeroallergen sensitivity and altered cytokine responses (enhanced type 2 or reduced virus-induced cytokine responses) from stimulated peripheral blood mononuclear cells at age 3 years.URECA (Urban Environment and Childhood Asthma) is a birth cohort at high risk for asthma (n = 560) in four inner cities. Maternal stress, depression, and childhood wheezing episodes were assessed by quarterly questionnaires beginning at birth. Logistic and linear regression techniques were used to examine the relation of maternal stress/depression to recurrent wheezing and peripheral blood mononuclear cell cytokine responses at age 3 years.Overall, 166 (36%) children had recurrent wheeze at age 3 years. Measures of maternal perceived stress at Years 2 and 3 were positively associated with recurrent wheeze (P 0.05). Maternal depression (any year) was significantly associated with recurrent wheezing (P ≤ 0.01). These associations were also significant when considered in a longitudinal analysis of cumulative stress and depression (P ≤ 0.02). Neither stress nor depression was significantly related to aeroallergen sensitization or antiviral responses. Contrary to our original hypothesis, prenatal and Year 1 stress and depression had significant inverse associations with several type 2 cytokine responses.In urban children at high risk for asthma, maternal perceived stress and depression were significantly associated with recurrent wheezing but not increased atopy or reduced antiviral responses.

Asthma in the inner‐city population is usually atopic in nature, and is associated with significant morbidity and mortality. However, the underlying immune abnormalities that underlie asthma in urban adults have not been well defined. We investigated the influence of atopy and asthma on cytokine responses of inner‐city adult women to define immune abnormalities associated with asthma and atopy. Blood samples were collected from 509 of 606 inner‐city women enrolled in the Urban Environment and Childhood Asthma (URECA) study. We tested for associations between atopy and asthma status and cytokine responses in peripheral blood mononuclear cells incubated ex vivo with a panel of innate and adaptive immune stimulants. Atopic subjects had heightened Th2 cytokine responses (IL‐4, IL‐5, IL‐13) to cockroach and dust mite antigens, tetanus toxoid, and phytohemagglutinin (P

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 T H 2-type inflammation; however, the early-life immune events that lead to T H 2 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 T H 2-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 T H 2 polarization, leading to the development of allergic asthma.

BACKGROUND: Comparisons of the technical acceptability of spirometry and impulse oscillometry (IOS) and clinical correlations of the measurements have not been well studied in young children. There are no large studies focused on African American and Hispanic children. OBJECTIVES: We sought to (1) compare the acceptability of spirometry and IOS in 3–5 year old children and (2) examine the relationship of maternal smoking during pregnancy to later lung function. METHODS: Spirometry and IOS were attempted at 4 sites from the URECA birth cohort at ages 3, 4 and 5 years (472, 471 and 479 children respectively). We measured forced expiratory flow in 0.5 sec (FEV(0.5)) with spirometry and area of reactance (A(X)), resistance and reactance at 5 Hz (R5 and X5 respectively) using IOS. RESULTS: Children were more likely to achieve acceptable maneuvers with spirometry than with IOS at age 3 (60% vs 46%, p< 0.001) and 5 years (89% vs 84%, p=0.02). Performance was consistent among the 4 study sites. In children without recurrent wheeze, there were strong trends for higher FEV(0.5) and lower R5 and A(X) over time. Maternal smoking during pregnancy was associated with higher A(X)at ages 4 and 5 years (p

Background Disadvantaged urban children have high rates of allergic diseases and wheezing, which are diseases associated with type 2–biased immunity. Objective We sought to determine whether environmental exposures in early life influence cytokine responses that affect the development of recurrent wheezing illnesses and allergic sensitization. Methods A birth cohort of 560 urban families was recruited from neighborhoods with high rates of poverty, and 467 (83%) children were followed until 3 years of age. Cytokine responses were measured in blood cell samples obtained at birth (cord blood) and ages 1 and 3 years. Cytokine responses were examined in relation to personal characteristics and environmental exposures to allergens and endotoxin and to the development of allergic sensitization and recurrent wheeze assessed at age 3 years. Results Cytokine responses generally increased with age, but responses at birth were poorly predictive for those at ages 1 and 3 years. Exposure to certain allergens (cockroach, mouse, dust mite) was significantly associated with enhanced cytokine responses at age 3 years, including IFN-α and IL-10 responses to certain stimulants and responses to phytohemagglutinin. Regarding the clinical outcomes, reduced LPS-induced IL-10 responses at birth were associated with recurrent wheeze. In contrast, reduced respiratory syncytial virus–induced IL-8 responses and increased 5′—cytosine—phosphate—guanine—3′ (CpG)-induced IL-12p40 and allergen-induced IL-4 responses were associated with atopy. Conclusions These findings suggest that diverse biologic exposures, including allergens and endotoxin, in urban homes stimulate the development of cytokine responses in early life, and that cytokine responses to specific microbial and viral stimuli are associated with the development of allergic sensitization and recurrent wheeze.

SummaryBackground 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

Background. The risk of developing childhood asthma has been linked to the severity and etiology of viral respiratory illnesses in early childhood. Since inner-city infants have unique environmental exposures, we hypothesized that patterns of respiratory viral infections would also be distinct. Methods. We compared the viral etiology of respiratory illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285 infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens by multiplex polymerase chain reaction. Results. Overall, inner-city infants had lower rates of viral detection. Considering specific viruses, sick urban infants had lower rates of detectable rhinovirus or respiratory syncytial virus infection and higher rates of adenovirus infection. Every urban site had a higher proportion of adenovirus-positive samples associated with illnesses (10%–21%), compared with Madison (6%). Conclusions. These findings provide evidence that inner-city babies have different patterns of viral respiratory illnesses than babies who grow up in a more suburban location. These findings raise important questions about the etiology of virus-negative illnesses in urban infants and the possibility of long-term consequences of early life infections with adenovirus in this population. Children who grow up in large, low-income urban areas are especially prone to develop asthma, and this has prompted efforts to identify urban environmental or lifestyle factors that promote this disease. Factors under investigation include exposure to allergens, such as those of cockroaches and mice; stress; diet; lack of exercise; genetics; and exposure to indoor and outdoor pollutants [1, 2]. Another factor that is strongly related to asthma is the development of virus-induced wheezing illnesses in infancy. Recently, it has been reported that wheezing illnesses caused by human rhinoviruses (HRVs) are associated with a particularly high risk of recurrent wheezing and asthma [3, 4], as is airway colonization in the first few months with specific

Background Women in poor urban neighborhoods have high rates of stress and allergic diseases, but whether stress or stress correlates such as depression promote inflammatory and type 2 cytokine responses is unknown. Objective To examine associations among external stressors, perceived stress, depression, and peripheral blood mononuclear cell cytokine responses of mothers enrolled in the Urban Environment and Childhood Asthma Study and test the hypothesis that stress would be positively associated with type 2 and selected proinflammatory (tumor necrosis factor-α and interleukin-8) responses. Methods Questionnaire data from mothers living in 4 inner cities included information about external stress, stress perception, and depression. The external stress domains (interpersonal problems, housing, and neighborhood stress) were combined into a Composite Stressor score. Peripheral blood mononuclear cells were stimulated ex vivo and cytokine responses to innate, adaptive, and polyclonal immune stimuli were compared with stress and depression scores for 469 of the 606 study participants. Results There were no significant positive associations between Composite Stressor scores, perceived stress, or depression scores and proinflammatory or type 2 cytokine responses, and these findings were not modified by allergy or asthma status. There were some modest associations with individual stressors and cytokine responses, but no consistent relations were noted. Depression was associated with decreased responses to some stimuli, particularly dust mite. Conclusion Composite measurements of stressors, perceived stress, or depression were not positively related to proinflammatory or type 2 cytokine responses in these young urban women. These data do not support the hypothesis that these factors promote cytokine responses associated with allergy. Trial Registration ClinicalTrials.gov, identifier NCT00114881.

Objective Previous data suggest that food allergy (FA) might be more common in inner-city children; however, these studies have not collected data on both sensitization and clinical reactivity or early-life exposures. Methods Children in the Urban Environment and Childhood Asthma birth cohort were followed through age 5 years. Household exposures, diet, clinical history, and physical examinations were assessed yearly; levels of specific IgE to milk, egg, and peanut were measured at 1, 2, 3, and 5 years of age. On the basis of sensitization (IgE ≥0.35 kU/L) and clinical history over the 5-year period, children were classified as having FA or being possibly allergic, sensitized but tolerant, or not allergic/not sensitized. Results Five hundred sixteen children were included. Overall, 55.4% were sensitized (milk, 46.7%; egg, 31.0%; and peanut, 20.9%), whereas 9.9% were categorized as having FA (peanut, 6.0%; egg, 4.3%; and milk, 2.7%; 2.5% to >1 food). The remaining children were categorized as possibly allergic (17.0%), sensitized but tolerant (28.5%), and not sensitized (44.6%). Eighteen (3.5%) reported reactions to foods for which IgE levels were not measured. Food-specific IgE levels were similar in children with FA versus sensitized but tolerant children, except for egg, levels of which were higher in patients with FA at ages 1 and 2 years. FA was associated with recurrent wheeze, eczema, aeroallergen sensitization, male sex, breast-feeding, and lower endotoxin exposure in year 1 but not with race/ethnicity, income, tobacco exposure, maternal stress, or early introduction of solid foods. Conclusions Even given that this was designed to be a high-risk cohort, the cumulative incidence of FA is extremely high, especially considering the strict definition of FA that was applied and that only 3 common allergens were included.

Viral respiratory tract infections are the leading cause of acute illness during infancy and are closely linked to chronic inflammatory airway diseases later in life. However, the determinants of susceptibility to acute respiratory tract infections still need to be defined.We investigated whether the individual variation in antiviral response at birth determines the risk for acute respiratory tract illness in the first year of life.We studied 82 children who were enrolled in a birth cohort study of inner-city children with at least 1 parent with allergy or asthma. We cultured cord blood monocytes and assessed IFNG and CCL5 mRNA production at 24 hours after inoculation with respiratory syncytial virus. We also monitored the frequency of acute respiratory tract illness at 3-month intervals and analyzed nasal lavage samples for respiratory tract viruses at the time of illness during the first year.Respiratory tract infection was reported for 88% of subjects, and respiratory tract viruses were recovered in 74% of symptomatic children. We observed a wide range of antiviral responses in cord blood monocytes across the population. Furthermore, a decrease in production of IFNG (but not CCL5) mRNA in response to respiratory syncytial virus infection of monocytes was associated with a significant increase in the frequency of upper respiratory tract infections (r = -0.42, P.001) and the prevalence of ear and sinus infections, pneumonias, and respiratory-related hospitalizations.Individual variations in the innate immune response to respiratory tract viruses are detectable even at birth, and these differences predict the susceptibility to acute respiratory tract illness during the first year of life.

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 5 560) 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. (J Allergy Clin Immunol 2014;nnn:nnn-nnn.)

M O N D A Y 750 Cysteine Proteases Induce Production and Extracellular Release of IL-33 in Airway Epithelial Cells S. Seno, K. Iijima, S. M. O’Grady, H. Kita; Mayo Clinic, Rochester, MN, Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, JAPAN, Departments of Integrated Biology and Physiology and Animal Science, University of Minnesota, St. Paul, MN. RATIONALE: Interleukin (IL)-33 plays a pivotal role in T helper (Th) 2-type immune responses. IL-33 is constitutively expressed and stored in the nucleus of airway epithelial cells and is considered an ‘‘alarmin’’, which is released extracellularly when cells are damaged. Little is known regarding the mechanisms involved in production and secretion of IL-33. METHODS: Normal human bronchial epithelial (NHBE) cells were cultured with cysteine proteases (bromelain, papain) or extracts of house dust mite (HDM) in vitro. Na€ive non-sensitized mice were exposed to cysteine proteases in vivo. The mechanisms were studied by pharmacologic inhibitors and small interfering RNA (siRNA). RESULTS: NHBE cells constitutively expressed mRNA and produced protein for IL-33; IL-33 was localized mainly in the nucleus of resting cells. Cysteine proteases at low concentrations (e.g. 0.1 mg/ml) did not affect production but induced extracellular release of IL-33 within 2 h. In contrast, these cysteine proteases at high concentrations (e.g. 50 mg/ ml) enhanced IL-33 production. Similarly, HDM extracts induced IL-33 release, which is dependent on extracts’ cysteine protease activities. Pharmacologic inhibitors and siRNAs for a protease receptor (PAR2) and a purinergic receptor (P2Y2) attenuated both IL-33 production and release induced by cysteine proteases. Airway exposure of mice to cysteine proteases enhanced production of IL-33 in vivo. CONCLUSIONS: Production and extracellular release of IL-33 by airway epithelial cells is upregulated by exposure to cysteine proteases through receptors sensing protease activities and cellular stress. Cysteine protease activities in allergens may play important roles in promoting Th2-type immune responses in the airway.