Cord blood versus age 5 mononuclear cell proliferation on IgE and asthma
© Chang et al; licensee BioMed Central Ltd. 2010
Received: 3 February 2010
Accepted: 4 August 2010
Published: 4 August 2010
Fetal immune responses following exposure of mothers to allergens during pregnancy may influence the subsequent risk of childhood asthma. However, the association of allergen-induced cord blood mononuclear cell (CBMC) proliferation and cytokine production with later allergic immune responses and asthma has been controversial. Our objective was to compare indoor allergen-induced CBMC with age 5 peripheral blood mononuclear cell (PBMC) proliferation and determine which may be associated with age 5 allergic immune responses and asthma in an inner city cohort.
As part of an ongoing cohort study of the Columbia Center for Children's Environmental Health (CCCEH), CBMCs and age 5 PBMCs were cultured with cockroach, mouse, and dust mite protein extracts. CBMC proliferation and cytokine (IL-5 and IFN-γ) responses, and age 5 PBMC proliferation responses, were compared to anti-cockroach, anti-mouse, and anti-dust mite IgE levels, wheeze, cough, eczema and asthma.
Correlations between CBMC and age 5 PBMC proliferation in response to cockroach, mouse, and dust mite antigens were nonsignificant. Cockroach-, mouse-, and dust mite-induced CBMC proliferation and cytokine responses were not associated with allergen-specific IgE at ages 2, 3, and 5, or with asthma and eczema at age 5. However, after adjusting for potential confounders, age 5 cockroach-induced PBMC proliferation was associated with anti-cockroach IgE, total IgE, and asthma (p < 0.05).
In contrast to allergen-induced CBMC proliferation, age 5 cockroach-induced PBMC proliferation was associated with age 5 specific and total IgE, and asthma, in an inner-city cohort where cockroach allergens are prevalent and exposure can be high.
List of Abbreviations
Brief Respiratory Questionnaire
cord blood mononuclear cell
Columbia Center for Children's Environmental Health
counts per minute
enzyme-linked immunosorbent assay
environmental tobacco smoke
Fluorescence Allergosorbent Test
International Study of Asthma and Allergy in Childhood
mouse urinary protein
peripheral blood mononuclear cell
skin prick test
There has been longstanding controversy in the literature regarding whether biomarkers measured in cord blood may help predict subsequent childhood asthma or atopy [1–9]. Prospective birth cohorts studies have demonstrated that cord blood IgE is a better predictor of skin prick test (SPT) positivity to aeroallergens (dust mite, grass, cat and dog) than family history when assessed up to age 5 years [2, 6, 7]. A similar positive association with early asthma at age 5 years has been more difficult to demonstrate [2, 7]. However, others have shown a positive association between elevated cord blood IgE with risk of later asthma at age 10 years , and allergic rhinoconjunctivitis at age 20 years .
The findings continue to be mixed when comparing aeroallergen-induced cord blood mononuclear cell (CBMC) proliferation with the subsequent risk for developing asthma, eczema, and allergic rhinitis [10–12]. At birth, infants who developed allergic disease by age 1 year had significantly more positive CBMC responses to dust mite and food allergen proteins than newborns who did not develop allergy . Notably, one birth cohort that followed children as long as 6 years demonstrated no significant difference in aeroallergen-induced (dust mite, grass, mold, cat) CBMC proliferation among cord blood samples of children who subsequently developed atopic disease by 6 years of age compared with samples from children who did not . It has been argued that allergen-induced CBMC proliferation may represent a default immune response by recent thymic emigrants as opposed to a more mature T cell memory response . However, other approaches, such as those using MHC tetramer staining, have demonstrated antigen specific intrauterine T cell immune response following environmental exposures that display features of immunologic effector memory .
Only a few studies have reported on mitogen or antigen-induced CBMC T helper (Th) cytokine production, and compared their levels with the likelihood of later atopy. For example, increased phytohemagglutinin (PHA)-induced interleukin (IL)-5 and IL-13 was associated with increased total IgE during the first year of life . Dust mite-induced CBMC production of IL-13 was associated with SPT positivity in response to dust mite antigens at age 6 . However, associations between dust mite-induced CBMC production of IL-6 and IL-10 and subsequent atopic disease (i.e. asthma, eczema) or SPTs at age 6 years were absent [10, 18].
Despite this body of work, studies to date have not yet compared prospectively the association between antigen-induced lymphoproliferative responses in cord blood with repeat measures in later childhood, and assessed the relative strengths of their associations with childhood asthma or eczema. In addition, the roles of early immune responses following ex vivo stimulation with cockroach and mouse proteins, antigens associated with inner city asthma [19, 20], have not been fully elucidated. Our objective, using a longitudinal birth cohort designed to examine risk factors for the development of asthma in an inner city population, was to compare cockroach, mouse and dust mite antigen-induced lymphoproliferative response in cord blood with age 5 antigen-specific lymphoproliferative response among the same children, and determine whether either were associated with a greater likelihood of age 5 atopy. We hypothesized that indoor allergen-specific cord blood proliferation and Th2 cytokine production would be associated with subsequent childhood (ages 2, 3, and 5) IgE, asthma, and eczema. We report that, in contrast to allergen-induced CBMC proliferation, age 5 cockroach-induced PBMC proliferation was associated with age 5 specific and total IgE, and asthma, in an inner-city cohort where cockroach allergens are prevalent and exposure can be high.
As part of an ongoing longitudinal birth cohort study conducted under the auspices of the Columbia Center for Children's Environmental Health (CCCEH), women ages 18 to 35, living in Northern Manhattan and the South Bronx, were enrolled during pregnancy (n = 725) from clinics affiliated with New York Presbyterian Hospital (Columbia campus) or Harlem Hospital as described [19, 21, 22]. Exclusion criteria for pregnant women included smoking, illicit drug use, diabetes, hypertension, HIV infection, and residence in New York City for less than one year.
From this cohort of fully enrolled mothers, a sample based on the number of children from whom a blood sample was obtained (i.e. any time point from cord blood through age 5 years) was selected for inclusion (n = 609). For longitudinal analysis, a subset (n = 359) inclusive of all children for whom cord blood was collected and data were available for prospective analysis at age 2, 3 and 5 year was studied. For cross-sectional analysis, another overlapping subset (n = 352) inclusive of all children for whom age 5 blood was collected was assessed for concurrent (age 5) outcomes symptoms.
Written informed consent was obtained from all study participants and Columbia University's Institutional Review Board approved the study.
Detailed questionnaires were administered to women prenatally, every 3 months until the child was age 2, and every 6 months thereafter until age 5 [19, 22]. Questionnaires assessed demographics, maternal asthma, environmental tobacco smoke (ETS) exposure, and report of wheeze, cough and physician diagnosis of asthma and/or eczema. Furthermore, at age 5, parental report of eczema was determined using the validated International Study of Asthma and Allergy in Childhood (ISAAC) eczema questionnaire [23–25], and parental report of asthma was determined using the locally validated Brief Respiratory Questionnaire (BRQ) .
Home allergen measurements
Dust samples were vacuumed separately from kitchens and mothers' beds prenatally and were analyzed for mouse urinary protein (MUP), dust mite (Der f 1), and cockroach (Bla g 2) allergens by enzyme-linked immunosorbent assay (ELISA) as described [27–30].
Blood collection, mononuclear proliferation, cytokine assays, and IgE
Cord bloods were collected at delivery and maternal blood within 1 day postpartum [19, 21, 22, 31]. Peripheral blood samples at 2, 3 and 5 years of age were collected. Briefly, fresh mononuclear cells were isolated by density centrifugation and plated in triplicate for mononuclear proliferation and in duplicate for cytokine assays. Antigen-induced mononuclear cell proliferation and cytokine production were measured in cord blood and in peripheral blood at age 5 years.
Mononuclear cells (3 × 105 cells/well) were cultured in microtiter plates for 5 days with Blatella germanica (German cockroach; 10 μg/ml; Greer Laboratories, Lenoir, NC), Dermatophagoides farinae (dust mite; 10 μg/ml; Greer Laboratories, Lenoir, NC), Mus musculus (mouse protein extract; 10 μg/ml; Greer Laboratories, Lenoir, NC), or no antigen . Increased proliferation in response to German cockroach, dust mite, and mouse protein extract antigens were detected by tritiated thymidine incorporation. Increased mononuclear cell proliferation were defined as (1) a stimulation index [SI] (averaged counts per minute [cpm] in the presence of antigen divided by averaged cpm without antigen) greater than 2, and (2) antigen-induced cpm greater than 1,000 above background . Separate cell aliquots for cytokine analysis were cultured under identical conditions, and supernatants were collected at day 5 and analyzed in duplicates for IL-5 and IFN-γ via ELISA kits (Immunotech, Marseille, France) .
Anti-cockroach, anti-mouse, and anti-dust mite IgE levels were measured in sera initially by using the Fluorescence Allergosorbent Test (FAST) (Bio Whittaker, Walkersville, MD) until August 2002. Subsequently, all samples were measured by ImmunoCAP (Phadia, Uppsala, Sweden). Total IgE levels were measured initially by immunoradiometric assay (IRMA) (Total IgE IRMA; Diagnostics Products Corp, Los Angeles, CA), and subsequently (after August 2002) by ImmunoCAP (Phadia, Uppsala, Sweden). All samples were measured in duplicate and during the transition of one validated method to another, a subset was analyzed using both methods to ensure correlation of results, as previously described . Antigen-specific IgE levels of 0.35 IU/ml or greater (class I) were considered positive.
Data were analyzed with SPSS version 16.0 (SPSS, Inc, Chicago, Ill). Dust allergens levels were analyzed as natural logarithm-transformed continuous values and in tertiles. Mononuclear cell proliferation results were analyzed as continuous (antigen-induced cpm divided by background cpm) or dichotomous (positive versus negative SI) variables. Cytokine responses to cockroach, mouse, and dust mite antigens were measured as cytokine ratios: (measured response to antigen)/(measured response to background condition) and analyzed as continuous variables. Allergen-specific IgE levels were analyzed as dichotomous variables (≥0.35 IU/ml, <0.35 IU/ml). Total IgE and sum of allergen-specific IgE (sum of anti-cockroach, anti-mouse, and anti-dust mite IgE) were analyzed as continuous variables. The later approach was intended to study a derived indicator of allergic sensitization to indoor allergens, important to inner city asthma , with the benefit of greater statistical power. All values below limit of detection (LOD) were recoded as half LOD. Symptoms and diagnoses assessed by questionnaires were analyzed as dichotomous variables (yes or no). All continuous variables were natural log transformed.
Fisher's Exact Test and nonparametric tests, including Mann-Whitney U (MWU) Test, Kruskal-Wallis Test, and Spearman's rho correlation, were used to ensure data results were not distorted by failure to fulfill parametric distribution requirements. Unadjusted logistic and linear regression analyses were performed to assess whether allergen-specific mononuclear cell proliferation were significant predictors of atopy and asthma, eczema, allergen-specific IgE levels, and total IgE levels. Adjusted multivariate logistic and linear regression models were examined to adjust for (1) child's sex, (2) ethnicity, (3) any ETS exposure at home at age of interest, (4) maternal history of asthma, and (5) prenatal allergen levels in bed. Interaction terms also were examined between each independent variables of interest and each of the five covariates described above in order to differentiate between confounders and effect modifiers. Statistical significance was defined as a two-tailed p < 0.05.
Study population, age-related indoor antigen-induced proliferation
Characteristics of Study Children
Maternal History of Asthma
Prenatal ETS Exposure*
Postnatal ETS Exposure
Maternal Highest Degree
High School Diploma or More
Currently on Medicaid
Currently in Public Assistance
Childhood Symptoms at Ages 2, 3, and 5 Years
Physician Diagnosed Asthma 2
Itchy Rash Last 12 months 3
Ever Had Eczema 3
Correlation of Cord Blood and Age 5 Blood Antigen Specific Proliferation
Age 5 Blood
Cord blood proliferation, cytokine production, IgE and respiratory symptoms
Age 5 proliferation, IgE and respiratory symptoms
Age 5 Cockroach Antigen-Induced PBMC Proliferation and IgE at Age 5 years
Anti-cockroach IgE ≥ 0.35 IU/ml
Total IgE (IU/ml)
[n = 113]
[n = 78]
[n = 124]
[n = 85]
Positive cockroach-induced PBMC proliferation
1.75 (0.69, 4.42)
3.39 (1.05, 10.92)
0.63 (p = 0.02)
1.05 (p = 0.00)
0.64 (0.22, 1.87)
-0.80 (p = 0.02)
African American ethnicity
(Reference = Dominican)
01.12 (0.36, 3.46)
0.30 (p = 0.37)
Age 5 ETS exposed
0.83 (0.27, 2.53)
-0.22 (p = 0.51)
Maternal history of asthma
1.20 (0.38, 3.77)
0.31 (p = 0.39)
Prenatal cockroach allergen in bed (μg/g dust)
0.71 (0.46, 1.12)
-0.10 (p = 0.36)
Moreover, cockroach antigen-induced PBMC proliferation was correlated weakly with total IgE production at age 5 (n = 120, Spearman's rho r = 0.225, p = 0.01). Cockroach antigen-induced PBMC proliferation was associated significantly with total IgE levels, after adjusting for potential confounders (n = 85, β = 1.05, p = 0.00) (Table 4). In contrast, mouse- and dust mite-induced PBMC proliferation did not demonstrate significant associations with antigen-specific IgE or total IgE at age 5 years (MWU Test p > 0.05). Cockroach and mouse allergen levels in bed and kitchen were not associated with antigen-specific CBMC or age 5 PBMC proliferation ratios (Kruskal-Wallis Test p > 0.05).
Cockroach Antigen-Induced PBMC Proliferation and Asthma, Eczema at Age 5 Years
[n = 99]
OR (95% CI)
[n = 93]
OR (95% CI)
Positive cockroach-induced PBMC proliferation
3.08 (1.13, 8.37)
2.09 (0.76, 5.75)
0.35 (0.13, 0.92)
1.26 (0.47, 3.37)
African American ethnicity
(Reference = Dominican)
2.13 (0.81, 5.63)
1.28 (0.48, 3.40)
Age 5 ETS exposed
1.36 (0.51, 3.61)
1.93 (0.69, 5.40)
Maternal history of asthma
3.97 (1.43, 11.02)
3.48 (1.27, 9.56)
Prenatal cockroach allergen in bed (μg/g dust)
0.89 (0.62, 1.27)
0.99 (0.70, 1.39)
In light of research indicating that the development of eczema may be related to antigen-specific T cell immune responses , further cross-sectional comparisons between age 5 PBMC proliferation and prevalence of reported eczema were conducted. In univariate analysis, cockroach antigen-induced PBMC proliferation was associated with eczema at age 5 years (n = 141, OR 2.41, 95% CI 1.11, 5.22), but this association did not persist after adjusting for potential confounders (sex, ethnicity, current ETS exposure, maternal asthma, prenatal cockroach allergen levels in bed) (Table 5). Mouse- and dust mite-induced PBMC proliferation also were not associated with asthma or eczema at age 5. Moreover, concurrent cockroach-, mouse-, and dust mite-induced PBMC proliferation was not associated with cough or wheeze at age 5 (MWU Test p > 0.05 for both).
Finally, anti-cockroach, anti-mouse, but not anti-dust mite, IgE was associated significantly with concurrent asthma and wheeze at age 5 years (Asthma n = 281-283: anti-cockroach IgE, p = 0.00; anti-mouse IgE, p = 0.01; anti-dust mite IgE, p = 0.54; Wheeze n = 280-282: anti-cockroach IgE, p = 0.00; anti-mouse IgE, p = 0.00; anti-dust mite IgE, p = 0.12 by MWU Test).
The major objective of this study was to compare cord blood and age 5 year biomarkers such as indoor antigen-specific proliferation and cytokine production and determine whether either was associated with IgE and symptoms related to atopy and asthma in an inner city prospective cohort. We found that significant associations between antigen-specific cord blood and age 5 proliferation measures were absent. Instead, cockroach-specific proliferation assessed concurrently at age 5 years, but not in cord blood, was associated with asthma and IgE. Our focus on repeat measures and longitudinal assessment of indoor allergen responses important to inner city asthma [19, 21, 22] is novel.
A possible explanation for the association of age 5, but not cord blood, cockroach antigen-induced mononuclear cell proliferation with concurrent asthma and atopy may be that cord blood immune responses at birth are less mature or efficient. In support of this possibility is evidence of reduced CBMC proliferation and Th cytokine responses compared to adult responses after ex vivo stimulation with allergens, PHA, lipid A, and peptidoglycan [32, 33]. Furthermore, there is evidence of impaired function of T regulatory cells as well as reduced expression and immature phenotype of transcription factor Foxp3, in cord blood compared to adults [32, 34]. Also, T cell epitope mapping demonstrated that in response to allergen, CBMCs lack the fine specificity demonstrated by adult cells . Moreover, Woodfolk et al. demonstrated evidence of differing strengths of T cell proliferative responses to Trichophyton rubrum, related to changes in T cell epitope recognition of the immunodominant amino-terminal that occurred over the first 2 years of life, with no change in the peptide recognition pattern after age 20 months . However, it is becoming evident from our work  and others'  that the fetal adaptive immune system can be highly functional and capable of responding to antigens. Hence, an alternate explanation for the association of antigen-specific age 5 PBMC, but not CBMC, proliferation response with age 5 atopic status is that even though initial T cell priming to aeroallergens occurs across the placenta , clinically significant allergic sensitization to inhalant allergens occurs postnatally in early childhood . Cord blood T cell responses may be specific and functional, but not necessarily committed .
The finding that cockroach allergen-induced proliferation at age 5 years is associated with IgE and asthma-related symptoms, as opposed to responses to other indoor allergens, is consistent with substantial research indicating that cockroach allergen is important in the pathogenesis of inner city asthma [40, 41]. They also are consistent with evidence that allergen levels in home dust can be associated with allergen-induced proliferation . Our additional finding that anti-cockroach IgE at age 5 years is associated both with asthma and eczema lends further support to the observed association between cockroach allergen exposure, specific allergic immune responses, and risk for asthma and atopy. Importantly, there are regional differences, as demonstrated by Matsui et al., regarding the burden of household mouse allergens on inner-city childhood asthma in Baltimore, Maryland . Similarly, the association between indoor allergen-specific IgE and asthma and eczema was more apparent for dust mite in other cohorts, where dust mites thrive better, in comparison to New York City [43, 44]. Further, the absence of an association between any indoor antigen-induced proliferation and eczema suggests that indoor allergen-induced T cell proliferative responses, in contrast to B cell induced responses, may not modulate the risk of developing eczema in an inner city cohort . Notably, significant positive associations between age 5 cockroach-induced PBMC proliferation and age 5 anti-cockroach IgE among girls but not boys may be a result of sex specific genetic linkages as demonstrated by other groups [45, 46]. Nonetheless, given the wide array and repeated immune responses to indoor antigens demonstrated by our group and others [20, 40–42], public health interventions directed toward region-specific allergen reduction in the home may have health benefits to all inner-city children.
We acknowledge several limitations to this study. Atopic and respiratory symptom assessments were conducted via standardized questionnaires based upon maternal reporting. Parental report of physician diagnosis of asthma may not be standardized , potentially resulting in misclassification. Due to insufficient sample size, we were unable to compare antigen-specific CBMC and age 5 year cytokine responses with clinical outcomes. Furthermore, due to budgetary constraints, we were not able to measure IgE isotype class switching Th2 cytokines IL-4 and IL-13 and their association with IgE levels. In addition, due to repeated analyses, significant statistical interactions in regression models may represent type 1 error. Despite the prospective longitudinal design of the cohort, due to loss to follow-up, many data analyses were cross-sectional. Finally, host characteristics (i.e. genetics) may add to variations in the results as the development of atopy is influenced by genetic, developmental, and environmental factors [47–49].
In conclusion, in contrast to cord blood, age 5 PBMC cockroach antigen-induced proliferation was associated with anti-cockroach and total IgE production and asthma in an inner-city cohort where cockroach is a prevalent allergen. If corroborated by further studies, this finding lends to potential clinical significance for use of antigen-specific proliferation assays as a biomarker for current, but not future, atopic status in early childhood.
Funding was provided by: The National Institute of Environmental Health Science (P01ES09600, R01ES008977, R01ES13163), and U.S. Environmental Protection Agency (R827027).
- Goldstein IF, Perzanowski MS, Lendor C, Garfinkel RS, Hoepner LA, Chew GL, Perera FP, Miller RL: Prevalence of allergy symptoms and total IgE in a New York City cohort and their association with birth order. Int Arch Allergy Immunol. 2005, 137: 249-257. 10.1159/000086338View ArticlePubMed
- Edenharter G, Bergmann RL, Bergmann KE, Wahn V, Forster J, Zepp F, Wahn U: Cord blood-IgE as risk factor and predictor for atopic diseases. Clin Exp Allergy. 1998, 28: 671-678. 10.1046/j.1365-2222.1998.00241.xView ArticlePubMed
- Ruiz RG, Richards D, Kemeny DM, Price JF: Neonatal IgE: a poor screen for atopic disease. Clin Exp Allergy. 1991, 21: 467-472. 10.1111/j.1365-2222.1991.tb01687.xView ArticlePubMed
- Lilja G, Johansson SG, Kusoffsky E, Oman H: IgE levels in cord blood and at 4-5 days of age: relation to clinical symptoms of atopic disease up to 18 months of age. Allergy. 1990, 45: 436-444. 10.1111/j.1398-9995.1990.tb01094.xView ArticlePubMed
- Bergmann RL, Edenharter G, Bergmann KE, Guggenmoos-Holzmann I, Forster J, Bauer CP, Wahn V, Zepp F, Wahn U: Predictability of early atopy by cord blood-IgE and parental history. Clin Exp Allergy. 1997, 27: 752-760. 10.1046/j.1365-2222.1997.310899.xView ArticlePubMed
- Karmaus W, Arshad H, Mattes J: Does the sibling effect have its origin in utero? Investigating birth order, cord blood immunoglobulin E concentration, and allergic sensitization at age 4 years. Am J Epidemiol. 2001, 154: 909-915. 10.1093/aje/154.10.909View ArticlePubMed
- Tariq SM, Arshad SH, Matthews SM, Hakim EA: Elevated cord serum IgE increases the risk of aeroallergen sensitization without increasing respiratory allergic symptoms in early childhood. Clin Exp Allergy. 1999, 29: 1042-1048. 10.1046/j.1365-2222.1999.00594.xView ArticlePubMed
- Pesonen M, Kallio MJ, Siimes MA, Elg P, Bjorksten F, Ranki A: Cord serum immunoglobulin E as a risk factor for allergic symptoms and sensitization in children and young adults. Pediatr Allergy Immunol. 2009, 20: 12-18. 10.1111/j.1399-3038.2008.00736.xView ArticlePubMed
- Sadeghnejad A, Karmaus W, Davis S, Kurukulaaratchy RJ, Matthews S, Arshad SH: Raised cord serum immunoglobulin E increases the risk of allergic sensitisation at ages 4 and 10 and asthma at age 10. Thorax. 2004, 59: 936-942. 10.1136/thx.2004.024224PubMed CentralView ArticlePubMed
- Chan-Yeung M, Ferguson A, Chan H, Dimich-Ward H, Watson W, Manfreda J, Becker A: Umbilical cord blood mononuclear cell proliferative response to house dust mite does not predict the development of allergic rhinitis and asthma. J Allergy Clin Immunol. 1999, 104: 317-321. 10.1016/S0091-6749(99)70373-8View ArticlePubMed
- Smillie FI, Elderfield AJ, Patel F, Cain G, Tavenier G, Brutsche M, Craven M, Custovic A, Woodcock A: Lymphoproliferative responses in cord blood and at one year: no evidence for the effect of in utero exposure to dust mite allergens. Clin Exp Allergy. 2001, 31: 1194-1204. 10.1046/j.1365-2222.2001.01173.xView ArticlePubMed
- Prescott SL, Macaubes C, Yabuhara A, Venaille TJ, Holt BJ, Habre W, Loh R, Sly PD, Holt PG: Developing patterns of T cell memory to environmental allergens in the first two years of life. Int Arch Allergy Immunol. 1997, 113: 75-79. 10.1159/000237512View ArticlePubMed
- Miles EA, Warner JA, Jones AC, Colwell BM, Bryant TN, Warner JO: Peripheral blood mononuclear cell proliferative responses in the first year of life in babies born to allergic parents. Clin Exp Allergy. 1996, 26: 780-788. 10.1111/j.1365-2222.1996.tb00608.xView ArticlePubMed
- Prescott SL, King B, Strong TL, Holt PG: The value of perinatal immune responses in predicting allergic disease at 6 years of age. Allergy. 2003, 58: 1187-1194. 10.1034/j.1398-9995.2003.00263.xView ArticlePubMed
- Thornton CA, Upham JW, Wikstrom ME, Holt BJ, White GP, Sharp MJ, Sly PD, Holt PG: Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens. J Immunol. 2004, 173: 3084-3092.View ArticlePubMed
- Rastogi D, Wang C, Mao X, Lendor C, Rothman PB, Miller RL: Antigen-specific immune responses to influenza vaccine in utero. J Clin Invest. 2007, 117: 1637-1646. 10.1172/JCI29466PubMed CentralView ArticlePubMed
- Neaville WA, Tisler C, Bhattacharya A, Anklam K, Gilbertson-White S, Hamilton R, Adler K, Dasilva DF, Roberg KA, Carlson-Dakes KT: Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life. J Allergy Clin Immunol. 2003, 112: 740-746. 10.1016/S0091-6749(03)01868-2View ArticlePubMed
- Prescott SL, Taylor A, King B, Dunstan J, Upham JW, Thornton CA, Holt PG: Neonatal interleukin-12 capacity is associated with variations in allergen-specific immune responses in the neonatal and postnatal periods. Clin Exp Allergy. 2003, 33: 566-572. 10.1046/j.1365-2222.2003.01659.xView ArticlePubMed
- Donohue KM, Al-alem U, Perzanowski MS, Chew GL, Johnson A, Divjan A, Kelvin EA, Hoepner LA, Perera FP, Miller RL: Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort. J Allergy Clin Immunol. 2008, 122: 914-920. 10.1016/j.jaci.2008.08.034PubMed CentralView ArticlePubMed
- Matsui EC, Eggleston PA, Buckley TJ, Krishnan JA, Breysse PN, Rand CS, Diette GB: Household mouse allergen exposure and asthma morbidity in inner-city preschool children. Ann Allergy Asthma Immunol. 2006, 97: 514-520. 10.1016/S1081-1206(10)60943-XView ArticlePubMed
- Miller RL, Chew GL, Bell CA, Biedermann SA, Aggarwal M, Kinney PL, Tsai WY, Whyatt RM, Perera FP, Ford JG: Prenatal exposure, maternal sensitization, and sensitization in utero to indoor allergens in an inner-city cohort. Am J Respir Crit Care Med. 2001, 164: 995-1001.View ArticlePubMed
- Lendor C, Johnson A, Perzanowski M, Chew GL, Goldstein IF, Kelvin E, Perera F, Miller RL: Effects of winter birth season and prenatal cockroach and mouse allergen exposure on indoor allergen-specific cord blood mononuclear cell proliferation and cytokine production. Ann Allergy Asthma Immunol. 2008, 101: 193-199. 10.1016/S1081-1206(10)60209-8PubMed CentralView ArticlePubMed
- Jenkins MA, Clarke JR, Carlin JB, Robertson CF, Hopper JL, Dalton MF, Holst DP, Choi K, Giles GG: Validation of questionnaire and bronchial hyperresponsiveness against respiratory physician assessment in the diagnosis of asthma. Int J Epidemiol. 1996, 25: 609-616. 10.1093/ije/25.3.609View ArticlePubMed
- Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, Williams H, : Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006, 368: 733-743. 10.1016/S0140-6736(06)69283-0View ArticlePubMed
- Valery PC, Purdie DM, Chang AB, Masters IB, Green A: Assessment of the diagnosis and prevalence of asthma in Australian indigenous children. J Clin Epidemiol. 2003, 56: 629-635. 10.1016/S0895-4356(03)00081-7View ArticlePubMed
- Bonner S, Matte T, Rubin M, Sheares BJ, Fagan JK, Evans D, Mellins RB: Validating an asthma case detection instrument in a Head Start sample. J Sch Health. 2006, 76: 471-478. 10.1111/j.1746-1561.2006.00144.xView ArticlePubMed
- Chew GL, Perzanowski MS, Miller RL, Correa JC, Hoepner LA, Jusino CM, Becker MG, Kinney PL: Distribution and determinants of mouse allergen exposure in low-income New York City apartments. Environ Health Perspect. 2003, 111: 1348-1351. 10.1289/ehp.6124PubMed CentralView ArticlePubMed
- Luczynska CM, Arruda LK, Platts-Mills TA, Miller JD, Lopez M, Chapman MD: A two-site monoclonal antibody ELISA for the quantification of the major Dermatophagoides spp. allergens, Der p I and Der f I. J Immunol Methods. 1989, 118: 227-235. 10.1016/0022-1759(89)90010-0View ArticlePubMed
- Pollart SM, Smith TF, Morris EC, Gelber LE, Platts-Mills TA, Chapman MD: Environmental exposure to cockroach allergens: analysis with monoclonal antibody-based enzyme immunoassays. J Allergy Clin Immunol. 1991, 87: 505-510. 10.1016/0091-6749(91)90009-DView ArticlePubMed
- van Strien RT, Verhoeff AP, van Wijnen JH, Doekes G, de Meer GE, Brunekreef B: Der p I concentrations in mattress surface and floor dust collected from infants' bedrooms. Clin Exp Allergy. 1995, 25: 1184-1189. 10.1111/j.1365-2222.1995.tb03042.xView ArticlePubMed
- Boyum A: Isolation of lymphocytes, granulocytes and macrophages. Scand J Immunol. 1976, Suppl 5: 9-15.
- Schaub B, Liu J, Schleich I, Hoppler S, Sattler C, von Mutius E: Impairment of T helper and T regulatory cell responses at birth. Allergy. 2008, 63: 1438-1447. 10.1111/j.1398-9995.2008.01685.xView ArticlePubMed
- Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD, Holt PG: Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol. 1998, 160: 4730-4737.PubMed
- Ly NP, Ruiz-Perez B, McLoughlin RM, Visness CM, Wallace PK, Cruikshank WW, Tzianabos AO, O'Connor GT, Gold DR, Gern JE: Characterization of regulatory T cells in urban newborns. Clin Mol Allergy. 2009, 7: 8. 10.1186/1476-7961-7-8PubMed CentralView ArticlePubMed
- Yabuhara A, Macaubas C, Prescott SL, Venaille TJ, Holt BJ, Habre W, Sly PD, Holt PG: TH2-polarized immunological memory to inhalant allergens in atopics is established during infancy and early childhood. Clin Exp Allergy. 1997, 27: 1261-1269. 10.1111/j.1365-2222.1997.tb01170.xView ArticlePubMed
- Woodfolk JA, Platts-Mills TA: Diversity of the human allergen-specific T cell repertoire associated with distinct skin test reactions: delayed-type hypersensitivity-associated major epitopes induce Th1- and Th2-dominated responses. J Immunol. 2001, 167: 5412-5419.View ArticlePubMed
- Mold JE, Michaelsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, Lee TH, Nixon DF, McCune JM: Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008, 322: 1562-1565. 10.1126/science.1164511PubMed CentralView ArticlePubMed
- Holt PG: Primary allergic sensitization to environmental antigens: perinatal T cell priming as a determinant of responder phenotype in adulthood. J Exp Med. 1996, 183: 1297-1301. 10.1084/jem.183.4.1297View ArticlePubMed
- Rowe J, Kusel M, Holt BJ, Suriyaarachchi D, Serralha M, Hollams E, Yerkovich ST, Subrata LS, Ladyman C, Sadowska A: Prenatal versus postnatal sensitization to environmental allergens in a high-risk birth cohort. J Allergy Clin Immunol. 2007, 119: 1164-1173. 10.1016/j.jaci.2007.02.016View ArticlePubMed
- Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, Mitchell H, McNiff-Mortimer K, Lynn H, Ownby D, Malveaux F: The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med. 1997, 336: 1356-1363. 10.1056/NEJM199705083361904View ArticlePubMed
- Chew GL, Perzanowski MS, Canfield SM, Goldstein IF, Mellins RB, Hoepner LA, Ashby-Thompson M, Jacobson JS: Cockroach allergen levels and associations with cockroach-specific IgE. J Allergy Clin Immunol. 2008, 121: 240-245. 10.1016/j.jaci.2007.08.024View ArticlePubMed
- Finn PW, Boudreau JO, He H, Wang Y, Chapman MD, Vincent C, Burge HA, Weiss ST, Perkins DL, Gold DR: Children at risk for asthma: home allergen levels, lymphocyte proliferation, and wheeze. J Allergy Clin Immunol. 2000, 105: 933-942. 10.1067/mai.2000.106546View ArticlePubMed
- Wickman M, Ahlstedt S, Lilja G, van Hage Hamsten M: Quantification of IgE antibodies simplifies the classification of allergic diseases in 4-year-old children. A report from the prospective birth cohort study--BAMSE. Pediatr Allergy Immunol. 2003, 14: 441-447. 10.1046/j.0905-6157.2003.00079.xView ArticlePubMed
- Schafer T, Heinrich J, Wjst M, Adam H, Ring J, Wichmann HE: Association between severity of atopic eczema and degree of sensitization to aeroallergens in schoolchildren. J Allergy Clin Immunol. 1999, 104: 1280-1284. 10.1016/S0091-6749(99)70025-4View ArticlePubMed
- Hunninghake GM, Lasky-Su J, Soto-Quiros ME, Avila L, Liang C, Lake SL, Hudson TJ, Spesny M, Fournier E, Sylvia JS: Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans. Am J Respir Crit Care Med. 2008, 177: 830-836. 10.1164/rccm.200711-1697OCPubMed CentralView ArticlePubMed
- Raby BA, Soto-Quiros ME, Avila L, Lake SL, Murphy A, Liang C, Fournier E, Spesny M, Sylvia JS, Verner A: Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica. Hum Mol Genet. 2007, 16: 243-253. 10.1093/hmg/ddl447View ArticlePubMed
- Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG: Development of allergen-specific T-cell memory in atopic and normal children. Lancet. 1999, 353: 196-200. 10.1016/S0140-6736(98)05104-6View ArticlePubMed
- Schaub B, Tantisira KG, Gibbons FK, He H, Litonjua AA, Gillman MW, Weiss S, Perkins DL, Gold DR, Finn PW: Fetal cord blood: aspects of heightened immune responses. J Clin Immunol. 2005, 25: 329-337. 10.1007/s10875-005-4180-5PubMed CentralView ArticlePubMed
- Litonjua AA, Carey VJ, Burge HA, Weiss ST, Gold DR: Parental history and the risk for childhood asthma. Does mother confer more risk than father?. Am J Respir Crit Care Med. 1998, 158: 176-181.View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.