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ABSTRACT: Rationale. Innate immune responses marked by increases in TNF-α have been associated with asthma but whether such alterations are evident prior to symptoms is not yet clear. Objectives: To determine if prevalence of childhood asthma or asthma-related traits are predicted by perinatal innate immune status and if maternal factors related to pregnancy influence asthma prevalence and innate immune status. Measurements and Main Results: In the Tucson Infant Immune Study (a nonselected birth cohort), presence of eczema and wheezing in the child's first year and physician-diagnosed asthma through age 9 and asthma in the parents was obtained from parent-completed questionnaires. TNF-α, IL-6, IL-10, and IL-12 were measured in supernatants of LPS-stimulated PBMCs at birth and 3 months as was TNF-α in plasma. TNF-α SNPs were genotyped by Sequenom. Percent predicted FEV1/FVC was measured at age 9. Maternal weight gain during pregnancy and prepregnancy weight were ascertained from medical records. Infants with persistently elevated LPS-induced TNF-α at birth and 3 months were at increased risk for childhood asthma (OR =4.1; CI =1.9-8.8; n=233; p=0.0003) and had decreased FEV1/FVC ratios at age 9. Children with mothers in the top tertile for pregnancy weight gain had increased risk for asthma (OR=3.4; CI =1.7-6.9; n=225; p=0.001) and persistently elevated TNF-α in early life (OR=2.9 ; CI=1.4-8.2; n=195; p=.013). These relations were independent of maternal asthma/rhinitis. Conclusions Persistently elevated LPS-induced TNF-α production early in life acts as a predictive biomarker for childhood asthma, and excess pregnancy weight gain in the mother appears to contribute to both.
American Journal of Respiratory and Critical Care Medicine 04/2013; · 11.08 Impact Factor
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ABSTRACT: Familial aggregation of specific response to allergens and asthma adjusted for age and sensitization to multiple allergens was assessed in two large population cohorts.
Allergen skin prick tests (SPTs) were administered to 1151 families in the Tucson Children's Respiratory Study (CRS) and 435 families in the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD). Sensitization was defined by wheal size ≥3 mm; physician-diagnosed asthma at age ≥8 yr was based on questionnaires. Using S.A.G.E. 6.1 software ASSOC and FCOR, familial correlations of crude and adjusted phenotypes were evaluated.
Crude estimates of parent-offspring (P-O) and sibling correlations were statistically significant for most allergens, ranging from 0.03 to 0.29. After adjusting for age of assessment and 'other atopy' (SPT-positive response to additional allergens), correlations were reduced by 14-71%. Sibling correlations for specific response to allergens were consistently higher than P-O correlations, but this difference was significant only for dust mite and weed mix in the TESAOD population. Familial correlation for atopic status (any positive SPTs vs. none) tended to be higher than for specific allergens. Asthma, with and without adjustment, showed greater familial correlation than either specific or general SPT response and significantly higher sibling correlation in TESAOD than in CRS, probably due to the older age of the siblings and the longer period of ascertainment.
Significant familial aggregation of specific response to allergen after adjustment for other atopy appears to reflect a genetic propensity toward atopy, dependent on shared familial exposures. Results also suggest that inheritance of asthma is independent of atopic sensitization.
Pediatric Allergy and Immunology 02/2012; 23(1):21-7. · 2.46 Impact Factor
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Justin Mostecki,
Suzanne L Cassel,
Walter T Klimecki,
Debra A Stern,
Judit Knisz,
Sachiyo Iwashita,
Penelope Graves,
Rachel L Miller,
Maartje van Peer, Marilyn Halonen,
Fernando D Martinez,
Donata Vercelli,
Paul B Rothman
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ABSTRACT: SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate Ig H chain class switching to IgE. Analysis of mice with mutations in the SOCS-1 gene demonstrated that IgE levels increase with loss of SOCS-1 alleles. This suggested that overall SOCS-1 acts as an inhibitor of IgE expression in vivo. A genetic association study was performed in 474 children enrolled in the Tucson Children's Respiratory Study to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of the C-allele for a novel, 3' genomic single nucleotide polymorphism (SNP) in the SOCS-1 gene (SOCS1+1125G > C; rs33932899) were found to have significantly lower levels of serum IgE compared with those of homozygotes for the G-allele. Analysis demonstrated that the SOCS1+1125G > C SNP was in complete linkage disequilibrium with an SNP at position SOCS1-820G > T (rs33977706) of the SOCS-1 promoter. Carriers of the T-allele at the SOCS1-820G > T were also found to be associated with the decreased IgE. The promoter SNP increased transcriptional activity of the SOCS-1 promoter in reporter assays and human B cells. Consistent with this observation, the presence of this polymorphism within the promoter abolished binding of yin yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the SOCS-1 promoter may affect IgE production.
The Journal of Immunology 09/2011; 187(5):2794-802. · 5.79 Impact Factor
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ABSTRACT: The association between vitamin D status at birth and childhood allergic outcomes is uncertain. The desert climate of Tucson offers a unique setting for studying the health effects of higher exposure to vitamin D.
To assess the relationship between cord blood 25-hydroxyvitamin D (25[OH]D) levels and allergic outcomes through age 5 years.
Cord blood 25(OH)D levels were measured in 219 participants in the Tucson Infant Immune Study, a population-based birth cohort. Plasma total IgE and specific IgE levels to 6 aeroallergens were measured at 1, 2, 3, and 5 years. Skin prick test (SPT) positivity (wheal diameter ≥ 3 mm) and physician-diagnosed active allergic rhinitis and asthma were assessed at age 5 years. Longitudinal models were used to assess the relationship between 25(OH)D and IgE levels. Logistic regression models were used to assess the relationship of 25(OH)D level with SPT positivity, allergic rhinitis, and asthma.
The median cord blood 25(OH)D level was 64 nmol/L (interquartile range, 49-81 nmol/L). Relative to the reference group (50-74.9 nmol/L), both low (<50 nmol/L) and high (≥ 100 nmol/L) levels were associated with increased total IgE (coefficient = 0.27, P = .006 and coefficient = 0.27, P = .04, respectively) and detectable inhalant allergen-specific IgE (odds ratio = 2.4, P = .03 and odds ratio = 4.0, P = .01, respectively) through age 5 years. High 25(OH)D levels were also associated with increased SPT positivity (odds ratio = 4.0, P = .02). By contrast, the 25(OH)D level was not significantly associated with allergic rhinitis or asthma.
Both low and high levels of cord blood 25(OH)D were associated with increased aeroallergen sensitization. The association between vitamin D status and actual allergic diseases merits further study.
The Journal of allergy and clinical immunology 08/2011; 128(5):1093-9.e1-5. · 9.17 Impact Factor
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ABSTRACT: Although it has been postulated that allergic disease is associated with a predominance of T(H)2 cells, whether IgE levels and asthma might differ in their relation to early-life cytokine production is not known.
We sought to assess the relationship between first-year adaptive immune cytokine production with asthma and total IgE levels through age 5 years in a nonselected birth cohort.
Mitogen (concanavalin A/phorbol 12-myristate 13-acetate)-stimulated IL-4, IL-5, IL-13, and IFN-γ levels were measured in supernatants from cord blood mononuclear cells and PBMCs at birth, 3 months, and 12 months. Total serum IgE levels and physician-diagnosed active asthma were assessed at 1, 2, 3, and 5 years. Longitudinal models that adjust for both T(H)1 and T(H)2 cytokine production were used to determine relations of outcomes.
Relations of cytokines to total IgE levels and asthma were strikingly different. Total IgE levels through age 5 years were positively associated with 12-month IL-4 (P < .001), IL-5 (P < .001), and IL-13 (P = .02) levels when adjusted for IFN-γ levels and inversely associated with 12-month IFN-γ levels after IL-4 adjustment (P = .01). Active asthma through age 5 years was positively associated with 3-month IL-13 levels adjusted for IFN-γ (odds ratio, 2.6; P < .001) and inversely associated with 3-month IFN-γ levels adjusted for IL-13 (odds ratio, 0.5; P = .001). These relations were strongest for nonatopic asthma.
Total IgE levels and active asthma through age 5 years are associated with adaptive cytokine production in early life, although relations vary temporally and with regard to the relative importance of individual cytokines.
The Journal of allergy and clinical immunology 06/2011; 128(2):397-402.e2. · 9.17 Impact Factor
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ABSTRACT: Variation in the Toll-like receptor 2 gene (TLR2/-16934) is associated with allergic diseases among farmers' children but not among children not living on farms.
To test the hypothesis that the same genetic variant conferring protection in the farming environment is associated with reduced risk of developing allergic phenotypes among urban children attending day care in early life.
In 2 population-based birth cohorts (Manchester, United Kingdom, Manchester Asthma and Allergy Study [MAAS]; Tucson, Ariz, Tucson Infant Immune Study [IIS]), participants were recruited prenatally and followed prospectively (MAAS: 3, 5, 8 and 11 years; IIS: 1, 2, 3 and 5 years). We assessed allergic sensitization and atopic wheezing at each follow-up.
A total of 727 children participated in Manchester and 263 in Tucson. We found no significant associations between TLR2/-16934 and sensitization and atopic wheeze in either cohort. However, a different pattern emerged when we explored the interaction between TLR2/-16934 and day care attendance on these outcomes. We found a significant interaction between day care and TLR2/-16934 on the development of sensitization in the longitudinal model in MAAS in that children carrying the T allele who attended day care were less likely to be sensitized than those who did not attend day care, whereas among AA homozygotes, the association tended to be in the opposite direction. In a longitudinal model in IIS, we found a significant interaction between day care attendance and TLR2/-16934 on the development atopic wheezing. Significant interactions between TLR2/-16934 and day care were maintained when adjusting for socioeconomic status.
The effect of day care on sensitization and atopic wheezing may differ among children with different variants of the TLR2 gene.
The Journal of allergy and clinical immunology 02/2011; 127(2):390-397.e1-9. · 9.17 Impact Factor
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ABSTRACT: Recent studies have suggested that a restrictive pattern assessed with a single spirometric test is associated with increased morbidity and mortality. This study was undertaken to determine demographic, clinical and mortality profiles of subjects with either a recurrent or an inconsistent restrictive spirometric pattern assessed prospectively.
Data from 2048 adult participants in the population-based TESAOD study were analysed. Normal (forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) ratio >or=70% and FVC >or=80% predicted), restrictive (FEV(1)/FVC >or=70% and FVC <80% predicted) and obstructive (FEV(1)/FVC <70%) patterns were assessed at the enrollment survey in 1972 and in 11 subsequent follow-up surveys up to 1996. Demographic and clinical characteristics were measured at enrollment and vital status and cause of death were assessed at January 2005.
Overall, 12% of participants had a restrictive spirometric pattern at enrollment. They were less likely to be male, to smoke and to have asthma, and had lower IgE levels than subjects in the obstructive group. Among subjects with a restrictive pattern at enrollment, 38% developed an obstructive pattern during follow-up. The remaining 62% had either a recurrent (restrictive pattern >or=50% of follow-up surveys) or inconsistent (restrictive pattern <50% of follow-up surveys) longitudinal restrictive pattern. The recurrent and inconsistent restrictive groups had increased mortality risk for all-cause (adjusted HR 1.7 (95% CI 1.3 to 2.3) and 1.9 (95% CI 1.4 to 2.6), respectively), heart disease (2.0 (95% CI 1.3 to 3.1) and 2.7 (95% CI 1.7 to 4.3)), stroke (2.4 (95% CI 0.9 to 6.3) and 3.5 (95% CI 1.2 to 9.8)) and diabetes (8.0 (95% CI 2.9 to 21.8) and 6.0 (95% CI 1.9 to 19.2)).
The restrictive spirometric pattern identifies a pulmonary condition that is distinguishable from obstructive lung disease and is associated with an increased risk of life-threatening comorbidities.
Thorax 06/2010; 65(6):499-504. · 6.84 Impact Factor
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ABSTRACT: Previous studies on the relationship of chronic bronchitis to incident airflow limitation and all-cause mortality have provided conflicting results, with positive findings reported mainly by studies that included populations of young adults. This study sought to determine whether having chronic cough and sputum production in the absence of airflow limitation is associated with onset of airflow limitation, all-cause mortality and serum levels of C-reactive protein (CRP) and interleukin-8 (IL-8), and whether subjects' age influences these relationships.
1412 participants in the long-term Tucson Epidemiological Study of Airway Obstructive Disease who at enrolment (1972-1973) were 21-80 years old and had FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) > or = 70% and no asthma were identified. Chronic bronchitis was defined as cough and phlegm production on most days for > or = 3 months in two or more consecutive years. Incidence of airflow limitation was defined as the first follow-up survey with FEV(1)/FVC <70%. Serum IL-8 and CRP levels were measured in cryopreserved samples from the enrolment survey.
After adjusting for covariates, chronic bronchitis at enrolment significantly increased the risk for incident airflow limitation and all-cause mortality among subjects <50 years old (HR 2.2, 95% CI 1.3 to 3.8; and HR 2.2, 95% CI 1.3 to 3.8; respectively), but not among subjects > or = 50 years old (HR 0.9, 95% CI 0.6 to 1.4; and HR 1.0, 95% CI 0.7 to 1.3). Chronic bronchitis was associated with increased IL-8 and CRP serum levels only among subjects <50 years old.
Among adults <50 years old, chronic bronchitis unaccompanied by airflow limitation may represent an early marker of susceptibility to the effects of cigarette smoking on systemic inflammation and long-term risk for chronic obstructive pulmonary disease and all-cause mortality.
Thorax 08/2009; 64(10):894-900. · 6.84 Impact Factor
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ABSTRACT: Regulation of human immune cell cytokine production in vivo is not well understood due in part to limitations on imposing experimental conditions. We proposed that life-imposed conditions (pregnancy, birth, age, gender), combined with large sample size, repeat sampling, and family-based recruitment would serve to reveal peripheral blood cell-derived cytokine patterns reflective of in vivo regulation regarding Th1/Th2 balance and familial correlation. Mononuclear cells were obtained from 483 trios in the Tucson Infant Immune Study: from mothers pre- and postpartum, infants at birth and at 3 mo, and fathers. Con A/PMA-stimulated supernatants were assayed by ELISA for IFN-gamma, IL-4, IL-13, IL-5, and IL-10 and allergen-stimulated supernatants for IFN-gamma, IL-4, and IL-13. Mitogen-stimulated prepartum samples were not globally Th2 biased, differing from postpartum only by a modestly reduced IFN-gamma:IL-5 ratio. Prepartum samples actually produced less IL-10 and IL-13 although more IL-5 than paternal samples. Newborns were also not globally Th2 biased, with mitogen stimulation producing approximately 10-fold less IL-4, IL-5, and IFN-gamma than adults but only 2- to 3-fold less IL-13 and IL-10. Despite these group differences, all cytokines showed marked positive intraindividual correlations (all p < 0.001). Allergen stimulation gave results consistent with a lack of global Th2 bias. Mitogen stimulation revealed parent-child and parent-parent correlations. Thus, rather than a global Th2 bias, cytokine production in pregnant mothers and newborns appears regulated so as to maintain a relative balance among the cytokines, with the nature of the balance differing in mothers and infants and with production influenced by familial factors that include shared environment.
The Journal of Immunology 04/2009; 182(5):3285-93. · 5.79 Impact Factor
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ABSTRACT: Most patients who develop persistent airflow limitation do so either as a manifestation of chronic obstructive pulmonary disease that is largely related to smoking or as a consequence of persistent asthma. We sought to compare the natural course of lung function associated with persistent airflow limitation in subjects with and without asthma from early to late adult life.
We studied 2552 participants aged 25 or more who had multiple questionnaire and lung function data from the long-term prospective population-based Tucson Epidemiological Study of Airway Obstructive Disease. Persistent airflow limitation was defined as FEV(1)/FVC ratio consistently < 70% in all completed surveys subsequent to the first survey with airflow limitation. Participants were divided into nine groups based on the combination of their physician-confirmed asthma status (never, onset < or = 25 years, or onset > 25 years) and the presence of airflow limitation during the study follow-up (never, inconsistent, or persistent).
Among subjects with an asthma onset < or = 25 years, blood eosinophilia increased significantly the odds of developing persistent airflow limitation (adjusted ORs: 3.7, 1.4-9.5), whereas cigarette smoking was the strongest risk factor for persistent airflow limitation among non-asthmatics and among subjects with asthma onset after age 25 years. Among subjects with persistent airflow limitation, the natural course of lung function differed between subjects with asthma onset < or = 25 years and non-asthmatics, with the former having lower FEV(1) levels at age 25 (predicted value for a 175-cm tall male of 3400 versus 4090 ml, respectively; p<0.001) and the latter having greater FEV(1) loss between age 25 and 75 (1590 versus 2140 ml; p=0.003).
In subjects who have asthma onset before 25 years of age and persistent airflow limitation in adult life, the bulk of the FEV(1) deficit is already established before age 25 years.
Respiratory medicine 10/2008; 102(10):1473-82. · 2.33 Impact Factor
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ABSTRACT: Incidence of asthma increases during early adulthood. We aimed to estimate the contributions of sex and early life factors to asthma diagnosed in young adults.
1246 healthy newborn babies were enrolled in the Tucson Children's Respiratory Study. Parental characteristics, early-life wheezing phenotypes, airway function, and bronchial hyper-responsiveness to cold dry air and sensitisation to Alternaria alternata were determined before age 6 years. Physician-diagnosed asthma, both chronic and newly diagnosed, and airway function were recorded at age 22 years.
Of 1246 babies enrolled, 849 had follow-up data at 22 years. Average incidence of asthma at age 16-22 years was 12.6 per thousand person-years. 49 (27%) of all 181 cases of active asthma at 22 years were newly diagnosed, of which 35 (71%) were women. Asthma remittance by 22 years was higher in men than in women (multinomial odds ratio [M-OR] 2.0, 95% CI 1.2-3.2, p=0.008). Age at diagnosis was linearly associated with the ratio of forced expiratory volume at 1 s to forced vital capacity at age 22 years. Factors independently associated with chronic asthma at 22 years included onset at 6 years (7.4, 3.9-14.0) and persistent wheezing (14.0, 6.8-28.0) in early life, sensitisation to A alternata (3.6, 2.1-6.4), low airway function at age 6 years (2.1, 1.1-3.9), and bronchial hyper-responsiveness at 6 years (4.5, 1.9-10.0). Bronchial hyper-responsiveness (6.9, 2.3-21.0), low airway function at 6 years (2.8, 1.1-6.9), and late-onset (4.6, 1.7-12.0) and persistent wheezing (4.0, 1.2-14.0) predicted newly diagnosed asthma at age 22 years.
Asthma with onset in early adulthood has its origins in early childhood.
The Lancet 10/2008; 372(9643):1058-64. · 38.28 Impact Factor
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ABSTRACT: Environmental tobacco smoke is associated with several negative health outcomes in children, including an increased susceptibility to infections. One of the postulated mechanisms for these effects is the impairment of the immune system function and/or development. Yet, it remains unknown whether cumulative exposure to parental smoking is associated with altered immune responses in childhood and whether these effects are independent of in utero exposure to maternal smoking. In a population-based birth cohort, we sought to determine the relation of parental smoking, as assessed prospectively since pregnancy, to the child's interferon gamma and interleukin 4 production at 11 years of age.
We used data on 512 children and their parents from the Tucson Children's Respiratory Study cohort. Information on maternal and paternal smoking was collected prospectively by questionnaire, and pack-years for mother, father, and both parents combined were assessed prospectively between the prenatal period and year 11. At age 11 years, children's interferon gamma and interleukin 4 production from mitogen-stimulated peripheral blood mononuclear cells was measured.
Children of parents who smoked between the prenatal period and year 11 were more likely to be in lower quartiles of interferon gamma production than children of nonsmoking parents. In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with interferon gamma production in the child. These dose-response relationships with interferon gamma remained significant for both paternal and parental pack-years among children of mothers who did not smoke during pregnancy, suggesting the existence of specific postnatal effects of environmental tobacco smoke exposure. In contrast, no significant effects of parental smoking were found on interleukin 4 production.
Interferon gamma responses of school-aged children are impacted by parental smoking.
PEDIATRICS 06/2008; 121(6):e1563-9. · 4.47 Impact Factor
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ABSTRACT: Early day care is inversely associated with asthma and atopy in later childhood, but its association with early immunologic markers of asthma risk is not known.
We sought to assess the relation of day care by 3 months to total IgE levels through age 3 years.
Day care was assessed prospectively among 362 nonselected infants enrolled in the Infant Immune Study. Children were categorized based on day-care status by 3 months of age as follows: no day care, day care inside the home with other children, day care outside the home with no other children, or day care outside the home with other children. Total IgE levels were measured in blood obtained at 3, 12, 24, and 36 months. Relations between day care and IgE levels were assessed at each age and longitudinally, with stratification by maternal asthma and atopy.
Day care by 3 months was associated with decreased IgE levels through age 3 years (coefficient: -0.19 log IU/mL, P = .001). The greatest effect was evident for children cared for outside the home. Stratified analyses indicated that the relation existed primarily among children who had atopic or asthmatic mothers. Day-care entry after 3 months showed no relation with IgE levels.
Day-care attendance by 3 months is associated with decreased total IgE levels in the first 3 years of life in children of mothers who are atopic, asthmatic, or both.
Early day-care exposure can reduce IgE levels, which in turn might reflect a reduced risk of allergic disease in predisposed children.
The Journal of allergy and clinical immunology 12/2007; 120(5):1201-7. · 9.17 Impact Factor
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ABSTRACT: Diminished cytokine production in infancy has been associated with an increased risk for allergen sensitization and early-life wheeze.
We sought to assess the effect of low cytokine production in the first year of life on the development of wheeze through age 13 years.
Cytokine production (IFN-gamma and IL-2) by mitogen-stimulated mononuclear cells was determined from peripheral blood samples (9.4 months, n = 118) in a subset of healthy infants enrolled in the Tucson Children's Respiratory Study. The occurrence of wheeze during the previous year was ascertained at ages 2, 3, 6, 8, 11, and 13 years by means of questionnaire. Relative risk for wheeze was computed with generalized estimating equations.
The risk of wheezing between 2 and 13 years was significantly higher for subjects with low 9-month IFN-gamma production (relative risk, 2.29; 95% CI, 1.35-3.89) and borderline significant for those with intermediate IFN-gamma production (relative risk, 1.59; 95% CI, 0.95-2.68) compared with those who produced high levels of IFN-gamma (P value for linear association = .002). Nine-month IL-2 production was unrelated to wheeze. In relation to complex wheezing phenotypes, 9-month IFN-gamma production was inversely related to toddler wheeze (occurring only before age 6 years, P = .03) and chronic wheeze (occurring before and after age 6 years, P = .007) but not school-age wheeze (occurring only after age 6 years, P = .06).
The results suggest that characteristics of the immune system present during the first year of life can anticipate the likelihood of development of episodes of airway obstruction characterized by wheezing.
Immune susceptibility to asthma is established very early during postnatal life.
Journal of Allergy and Clinical Immunology 11/2007; 120(4):835-41. · 11.00 Impact Factor
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ABSTRACT: Total IgE in human subjects tracks strongly from birth onward through unknown mechanisms. Regulation of IgE might occur in relation to adaptive immune cytokine production. In vitro studies have assessed the role of individual cytokines in regulating IgE production in human subjects.
We sought to investigate the association between IgE levels in vivo and the capacity of the individuals to produce adaptive immune cytokines.
Blood samples from participants in the Tucson Infant Immune Study (children at birth and at 3 and 12 months of age, fathers, and mothers before and after delivery) were assessed for percentage of eosinophils and plasma total IgE levels. IFN-gamma, IL-4, IL-5, IL-13, and IL-10 levels were measured in supernatants of mitogen-stimulated PBMCs and examined cross-sectionally for relation to cytokine production by using simple regression, multiple regression with cytokines only and with other known predictors of IgE levels, and longitudinally by means of random effects modeling.
After adjusting for eosinophils and other predictors, IL-5 production (but not that of other cytokines) was associated directly with total IgE levels in children at 3 months (P = .009) and 12 months (P = .011) of age but not at birth. The IL-5/IgE association was present also in fathers (P = .040) and in mothers, both during pregnancy (P < .001) and after delivery (P = .030).
This study indicates that mitogen-stimulated IL-5 production is associated with in vivo total IgE levels, independent of the production of other cytokines and circulating eosinophils.
Understanding the regulation of IgE in vivo might help elucidate the development of allergic responses in individuals.
Journal of Allergy and Clinical Immunology 11/2007; 120(4):820-6. · 11.00 Impact Factor
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ABSTRACT: Respiratory syncytial virus (RSV) infections are extremely common in early childhood but are most severe in infants in the first few months of life. Unresponsive adaptive immunity and hyporesponsive innate immunity were previously found to be the typical responses of neonate mononuclear cells (MCs) to live RSV. Investigating the mechanism of innate immune hyporesponsiveness in neonate MCs to live RSV revealed that in contrast to the previously reported low expression of interferon (IFN)-gamma, IFN-alpha expression in response to live RSV was significantly greater than that observed in adult MCs. Inhibition of live RSV-induced IFN-alpha with anti-IFN-alpha antibodies in neonate MCs led to significant increases in innate cytokine [IFN-gamma, interleukin (IL)-12, IL-18 and tumor necrosis factor (TNF)-alpha] but not adaptive immune cytokine [IL-2] production. Although MCs from adults responded to live RSV with upregulation of interferon regulatory factor-1 (IRF-1) mRNA, IRF-1 mRNA in RSV-treated neonate MCs was not detectable. However, in the presence of anti-IFN-alpha antibodies, live RSV induced detectable IRF-1 mRNA expression in neonate MCs. These data support the possibility that the severity of early life RSV-induced illnesses may occur via a mechanism in which live RSV induces IFN-alpha that in turn leads to innate immune suppression in neonate MCs.
Immunological investigations 02/2007; 36(4):441-56. · 1.16 Impact Factor
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Lisa Cameron,
Robin B Webster,
Jannine M Strempel,
Patricia Kiesler,
Michael Kabesch,
Harikrishnan Ramachandran,
Lizhi Yu,
Debra A Stern,
Penelope E Graves,
I Carla Lohman,
Anne L Wright, Marilyn Halonen,
Walter T Klimecki,
Donata Vercelli
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ABSTRACT: IL-13 is a central mediator of allergic inflammation. The single nucleotide polymorphism IL13-1112C>T (rs1800925) is associated with allergic phenotypes in ethnically distinct populations, but the underlying mechanism(s) remain unknown. Using in vivo, in vitro, and in silico analysis, we show that the IL13-1112T allele enhanced IL13 promoter activity in primary human and murine CD4(+) Th2 lymphocytes. Increased expression of IL13-1112T in Th2 cells was associated with the creation of a Yin-Yang 1 binding site that overlapped a STAT motif involved in negative regulation of IL13 expression and attenuated STAT6-mediated transcriptional repression. Because IL-13 secretion was increased in IL13-1112TT homozygotes, we propose that increased expression of IL13-1112T in vivo may underlie its association with susceptibility to allergic inflammation. Interestingly, IL13-1112T had opposite transcriptional effects in nonpolarized CD4(+) T cells, paralleled by distinct patterns of DNA-protein interactions at the IL13 promoter. Our findings suggest the nuclear milieu dictates the functional outcome of genetic variation.
The Journal of Immunology 01/2007; 177(12):8633-42. · 5.79 Impact Factor
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ABSTRACT: The cortisol circadian rhythm and response to stressful stimuli are altered in children and adults with allergic disease, including asthma. It is not known whether these alterations precede or follow the onset of allergic disease.
We sought to evaluate the cortisol circadian rhythm and stress response among infants at risk for the development of allergic disease.
Infants with and without risk factors for allergic disease were evaluated at age 6 months. Saliva was obtained at 8 am, 2 pm, and 8 pm at home (n = 68) by parents when their infants were comfortable and in the clinic (n = 88) before and after their physical examination and vaccinations. Information regarding parental allergy and exposure to other children at home or in child care were obtained by questionnaire.
In multivariate analysis the circadian rhythm of cortisol was flattened because of the lack of the expected morning surge of cortisol, resulting in decreased diurnal variation of cortisol in infants of mothers with allergy (P = .035) or asthma (P = .002) or an asthmatic father (P = .022). The cortisol stress response was greater in infants of mothers with allergy (P = .045) or asthma (P = .039), those with fewer siblings (P = .066), and those not entering day care early in life (P = .017).
These alterations in both basal and stress levels of endogenous cortisol among infants predisposed to allergic disease might affect the development of allergic immune responses early in life through interactions with inflammatory mediators.
Journal of Allergy and Clinical Immunology 03/2006; 117(2):306-11. · 11.00 Impact Factor
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ABSTRACT: Prenatal factors have been implicated in childhood eczema, but the relationship between maternal cytokine production during pregnancy and infant eczema is unknown. Non-selected women in their third trimester were enrolled in the Tucson Infant Immune Study. Data from three sources were used to define MD-eczema: parent-completed illness questionnaires at age 2, 3, 4, 6 and 9 months regarding physician-seen eczema, parent-completed questionnaires at 12 months regarding physician-diagnosed eczema, and medical record reviews. Blood samples were taken from mothers during their third trimester and from the umbilical cord at birth. Maternal peripheral blood mononuclear cells and cord blood mononuclear cells were stimulated with ConA/PMA, and supernatants were assayed for IFN-gamma and IL-4, -5, -10, and -13. Of 364 children, 28% were seen by a physician for eczema by 1 yr of age. After adjustment for potential confounders using logistic regression, the odds for development of eczema in infancy were significantly higher when mothers had active eczema in pregnancy (OR, 2.46, CI 1.0-5.8, p <0.042) and when mothers were in the highest tertile of serum IgE production (OR 2.28, CI 1.2-4.4, p <0.013). Colds in the third trimester were associated with lower odds of eczema (OR 0.32, CI 0.16-0.63, p <0.001). Our findings from this cohort study suggest that in utero factors, including maternal IgE, colds, and eczema, may influence the risk of infant eczema.
Pediatric Allergy and Immunology 02/2005; 16(1):19-26. · 2.46 Impact Factor
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ABSTRACT: Human decidua has been shown to produce a number of cytokines. We hypothesized that decidual cytokine production influences cord blood mononuclear cell (CBMC) cytokine production and that cytokine profiles of decidua from allergic women differ from those of decidua from nonallergic women. Using enzyme-linked immunosorbent assay, we measured unstimulated and concanavalin A/phorbol myristate acetate-stimulated production of interleukin-4 (IL-4), IL-5, IL-10, IL-13 and interferon- gamma (IFN-gamma) by decidual explants from 59 healthy women delivered by unlabored cesarean section and from corresponding CBMCs in 39 of the 59. Except for IL-10, there was little or no unstimulated cytokine production. There was a strong correlation between stimulated decidual and stimulated CBMC IFN-gamma production (p = 0.01). In allergic women the ratio of IL-13 to IL-4 production was increased in stimulated explants (p = 0.03). Stimulated CBMCs from infants of allergic mothers were more likely to produce detectable levels of IL-5 than those from infants of nonallergic mothers (p = 0.04) and had a tendency toward higher IL-13 levels as well (p = 0.07). These results suggest that maternal and fetal IFN-gamma production is closely linked and that maternal allergy appears to influence cytokine production in the neonate for IL-5 and possibly IL-13.
Human Immunology 12/2004; 65(11):1336-43. · 2.84 Impact Factor
