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ABSTRACT: BACKGROUND: IL10 encodes for IL-10, an important anti-inflammatory cytokine with pleiotropic effects. It is crucial for development of immune tolerance, downregulates expression of T(H)1 cytokines, and is relevant for T-cell regulation. Several IL10 single nucleotide polymorphisms (SNPs) were associated with inflammatory diseases, such as atopic diseases, which might have their onset during early immune maturation. OBJECTIVE: We hypothesized that IL10 SNPs are associated with decreased regulatory T (Treg) cell numbers, T(H)2-skewed immune responses, and decreased IFN-γ levels in cord blood parallel with increased proinflammatory markers, subsequently leading to increased atopic diseases until 3 years. METHODS: Eight genetic IL10 variants, represented by 4 linkage disequilibrium blocks (R(2) > 0.80) and 2 distal promoter SNPs, were genotyped in cord blood mononuclear cells of 200 healthy neonates. Cord blood mononuclear cells were cultured unstimulated or after stimulation with lipid A, peptidoglycan, PHA, house dust mite (Der p 1), or Der p 1 plus lipid A. mRNA expression of Treg cell-associated genes (forkhead box protein P3 [FOXP3], glucocorticoid-induced TNF receptor [GITR], lymphocyte activation gene 3 [LAG3]), T(H)1/T(H)2 cytokines, TNF-α, and GM-CSF were assessed. Atopic and respiratory outcomes (atopic dermatitis [AD] and wheeze) were assessed by means of questionnaire at age 3 years. RESULTS: Carriers of 3 IL10 SNP blocks and both distal promoter SNPs showed reduced expression of Treg cell markers, reduced IL-5 levels, proinflammatory TNF-α and GM-CSF, and partially increased IFN-γ levels. The same SNPs presented as determinant for AD, wheeze, or symptoms of AD, wheeze, or both at age 3 years. CONCLUSIONS: Polymorphisms in IL10 influenced Treg cell marker expression and T(H)1/T(H)2 and proinflammatory cytokine secretion early in life. This was relevant for further development of immune-mediated diseases, such as AD and wheeze, in early childhood.
The Journal of allergy and clinical immunology 09/2012; · 9.17 Impact Factor
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Laura Hatzler,
Valentina Panetta,
Susanne Lau,
Petra Wagner,
Renate L Bergmann, Sabina Illi,
Karl E Bergmann,
Thomas Keil,
Stephanie Hofmaier,
Alexander Rohrbach,
Carl Peter Bauer,
Ute Hoffman,
Johannes Forster,
Fred Zepp,
Antje Schuster,
Ulrich Wahn,
Paolo Maria Matricardi
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ABSTRACT: IgE sensitization against grass pollen is a cause of seasonal allergic rhinitis.
We sought to investigate the evolution at the molecular level and the preclinical predictive value of IgE responses against grass pollen.
The German Multicentre Allergy Study examined a birth cohort born in 1990. A questionnaire was administered yearly, and blood samples were collected at 1, 2, 3, 5, 6, 7, 10, and 13 years of age. Grass pollen-related seasonal allergic rhinitis (SARg) was diagnosed according to nasal symptoms in June/July. Serum IgE antibodies to Phleum pratense extract and 8 P pratense molecules were tested with immune-enzymatic singleplex and multiplex assays, respectively.
One hundred seventy-seven of the 820 examined children had SARg. A weak monomolecular/oligomolecular IgE response to P pratense was observed very frequently before SARg onset. These initial IgE responses increased in concentration and molecular complexity during the preclinical and clinical process. A typical progression of IgE sensitization was observed: Phl p 1 (initiator in >75% of cases); then Phl p 4 and Phl p 5; then Phl p 2, Phl p 6, and Phl p 11; and then Phl p 12 and Phl p 7. At age 3 years, IgE sensitization predicted SARg by age 12 years (positive predictive value, 68% [95% CI, 50% to 82%]; negative predictive value, 84% [95% CI, 80% to 87%]). At this preclinical prediction time, the number of recognized molecules and the serum levels of IgE to P pratense were significantly lower than at 3 or more years after SARg onset.
The IgE response against grass pollen molecules can start years before disease onset as a weak monosensitization or oligosensitization phenomenon. It can increase in serum concentration and complexity through a "molecular spreading" process during preclinical and early clinical disease stages. Testing IgE sensitization at a preclinical stage facilitates prediction of seasonal allergic rhinitis at its molecular monosensitization or oligosensitization stage.
The Journal of allergy and clinical immunology 07/2012; 130(4):894-901.e5. · 9.17 Impact Factor
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ABSTRACT: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects.
We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding.
For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping.
If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression.
Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets.
PLoS ONE 01/2012; 7(10):e46423. · 4.09 Impact Factor
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ABSTRACT: TBX21 (T cell specific T-box transcription factor) and HLX1 (H.20-like homeobox 1) are crucial transcription factors of T(H)1-cells, inducing their differentiation and suppressing T(H)2 commitment, particularly important for early life immune development. This study investigated the influence of TBX21 and HLX1 single nucleotide polymorphisms (SNPs), which have previously been shown to be associated with asthma, on T(H)1/T(H)2 lineage cytokines at birth.
Cord blood mononuclear cells (CBMCs) of 200 neonates were genotyped for two TBX21 and three HLX1 SNPs. CBMCs were stimulated with innate (Lipid A, LpA; Peptidoglycan, Ppg), adaptive stimuli (house dust mite Dermatophagoides pteronyssinus 1, Derp1) or mitogen (phytohemagglutinin, PHA). Cytokines, T-cells and mRNA expression of T(H)1/T(H)2-related genes were assessed. Atopic diseases during the first 3 years of life were assessed by questionnaire answered by the parents. Carriers of TBX21 promoter SNP rs17250932 and HLX1 promoter SNP rs2738751 showed reduced or trendwise reduced (p≤0.07) IL-5, IL-13 and TNF-α secretion after LpA-stimulation. Carriers of HLX1 SNP rs2738751 had lower IL-13 levels following Ppg-stimulation (p = 0.08). Carriers of HLX1 exon 1 SNP rs12141189 showed increased IL-5 (LpA, p = 0.007; Ppg, p = 0.10), trendwise increased IL-13 (LpA), higher GM-CSF (LpA/Ppg, p≤0.05) and trendwise decreased IFN-γ secretion (Derp1+LpA-stimulation, p = 0.1). Homozygous carriers of HLX1 promoter SNP rs3806325 showed increased IL-13 and IL-6 (unstimulated, p≤0.03). In carriers of TBX21 intron 3 SNP rs11079788 no differences in cytokine secretion were observed. mRNA expression of T(H)1/T(H)2-related genes partly correlated with cytokines at protein level. TBX21 SNP rs11079788 carriers developed less symptoms of atopic dermatitis at 3 years of age (p = 0.03).
Polymorphisms in TBX21 and HLX1 influenced primarily IL-5 and IL-13 secretion after LpA-stimulation in cord blood suggesting that genetic variations in the transcription factors essential for the T(H)1-pathway may contribute to modified T(H)2-immune responses already early in life. Further follow-up of the cohort is required to study the polymorphisms' relevance for immune-mediated diseases such as childhood asthma.
PLoS ONE 01/2012; 7(1):e31069. · 4.09 Impact Factor
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ABSTRACT: In a genome-wide association study, genetic variants on chromosome 17q21 were strongly associated with childhood asthma and orosomucoid 1-like 3 (ORMDL3) gene expression. Regulation of the 17q21 locus and its immunologic relevance early in life have not been well characterized.
We investigated the relation between polymorphisms and mRNA expression of 17q21 locus genes and their influence on T-cell subsets in cord blood.
In 200 children of our cord blood study, 17q21 polymorphisms were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Gene expression was assessed for ORMDL3; gasdermin A (GSDMA, alias GSDM1); gasdermin B (GSDMB, alias GSDML); Ikaros family zinc finger 3 (ZNFN1A3), zona pellucida binding protein 2 (ZPBP2); and proteasome (prosome, macropain) 26S subunit, non-ATPase, 3 (PSMD3), in cord blood mononuclear cells (CBMCs) and for ORMDL3 in peripheral blood (real-time RT-PCR). Mononuclear cells were assessed before and after microbial (lipid A/peptidoglycan), phytohemagglutinin, or allergen (Der p 1) stimulation. Regulatory T-associated markers (forkhead box protein 3, glucocorticoid-induced TNF receptor, lymphocyte activation gene 3 mRNA expression) and T(h)2/T(h)1/T(h)17 cytokines were examined.
In CBMCs, single genetic risk variants within 17q21 were associated with increased ORMDL3 (Der p 1 stimulation; P ≤ .01) and GSDMA expression (phytohemagglutinin/Der p 1 stimulation; P ≤ .05). Children homozygous for all 4 risk alleles for 17q21 tagging single nucleotide polymorphisms showed increased expression for ORMDL3 (Der p 1; P = .002) and GSDMA (phytohemagglutinin; P = .0009/Der p 1; P = .004). CBMC ORMDL3 expression was lower compared with PBMCs (P ≤ .0003) and increased in both CBMC and PBMC after stimulation (phytohemagglutinin/lipid A/peptidoglycan/Der p 1; P ≤ .006 and phytohemagglutinin/peptidoglycan; P < .05, respectively). No correlation between 17q21 polymorphisms and regulatory T/T(h)2/T(h)1 lineages was detectable. However, 17q21 risk allele carriers showed significantly increased IL-17 secretion (unstimulated, phytohemagglutinin-stimulated).
Our results suggest an association of 17q21 polymorphisms with ORMDL3, GSDMA expression, and IL-17 secretion early in life. These observations may imply a functional role of the 17q21 locus affecting T-cell development during immune maturation.
The Journal of allergy and clinical immunology 06/2011; 127(6):1587-94.e6. · 9.17 Impact Factor
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ABSTRACT: Rhinitis in older children and adults has been shown to be a predictor for adolescent- and adult-onset asthma. These findings suggest an interaction between the upper and lower airways. Whether rhinitis is a predictor for childhood-onset asthma is unknown.
We sought to investigate whether rhinitis in early childhood is an independent predictor for wheezing between the ages of 5 and 13 years in the German Multicentre Allergy Study birth cohort.
The German Multicentre Allergy Study cohort initially included 1314 healthy children. They were followed from birth to the age of 13 years with regular questionnaires and interviews. Specific IgE levels were measured at yearly intervals. Airway hyperresponsiveness was assessed at 7 years.
Allergic rhinitis until the age of 5 years was found to be a predictor for developing wheezing between the ages of 5 and 13 years, with an adjusted relative risk of 3.82 (P < .001). This association was not attributable to the type of sensitization, the severity of sensitization, or atopic dermatitis during the first 2 years of life. In this group of children, 41.5% of all new cases of wheezing occurred among children with preceding allergic rhinitis.
The first manifestation of allergic rhinitis occurs in preschool children in whom it is a predictor for subsequent wheezing onset. Preschool children with rhinitis might thus benefit from early assessment of allergic sensitization to identify the children at high risk of wheezing.
The Journal of allergy and clinical immunology 11/2010; 126(6):1170-5.e2. · 9.17 Impact Factor
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ABSTRACT: Regulatory T-cells (Tregs), characterized as CD4+CD25(hi) T-cells expressing FOXP3, play a crucial role in controlling healthy immune development during early immune maturation. Recently, FOXP3 demethylation was suggested to be a novel marker for natural Tregs in adults. In cord blood, the role and function of Tregs and its demethylation is poorly understood. We assessed FOXP3 demethylation in cord blood in relation to previously used Treg markers such as CD4+CD25(hi), FOXP3 mRNA, protein expression, and suppressive Treg function.
Cord blood mononuclear cells (CBMC) were isolated from 70 healthy neonates, stimulated for 3 days with the microbial stimulus lipid A (LpA), and allergen Dermatophagoides pteronyssinus (Derp1). Tregs (CD4+CD25(hi), intracellular, mRNA FOXP3 expression, isolated cells), DNA methylation of the FOXP3-locus and suppressive Treg function were assessed.
Demethylation of FOXP3 in whole blood was specific for isolated CD4+CD25(hi) Tregs. Demethylation of FOXP3 was positively correlated with unstimulated and LpA-stimulated FOXP3 mRNA-expression (p≤0.05), and CD4+CD25(hi) T-cells (p≤0.03). Importantly, increased FOXP3 demethylation correlated with more efficient suppressive capacity of Tregs (r = 0.72, p = 0.005). Furthermore, FOXP3 demethylation was positively correlated with Th2 cytokines (IL-5, IL-13) following LpA-stimulation (p = 0.006/0.04), with Th2 and IL-17 following Derp1+LpA-stimulations (p≤0.009), but not Th1 cytokines (IFN-γ).
FOXP3 demethylation reliable quantifies Tregs in cord blood. FOXP3 demethylation corresponds well with the suppressive potential of Tregs. The resulting strict correlation with functionally suppressive Tregs and the relative ease of measurement render it into a valuable novel marker for large field studies assessing Tregs as qualitative marker indicative of functional activity.
PLoS ONE 01/2010; 5(10):e13267. · 4.09 Impact Factor
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ABSTRACT: Cross-sectional studies suggest that maternal exposure to farming decreases the risk of allergic diseases in offspring. The potential underlying immunologic mechanisms are not understood.
We sought to assess whether maternal farm exposure activates regulatory T (Treg) cells in cord blood, exerting T(H)2-suppressive effects after microbial stimulation.
Eighty-four pregnant mothers were recruited before delivery. Detailed questionnaires (60 nonfarming and 22 farming mothers with 2 exclusions) assessed the farming exposures. Cord blood was stimulated with the microbial stimulus peptidoglycan (Ppg), the mitogen PHA, house dust mite extracts (Der p 1), and combinations. Treg cells (CD4+CD25(high) cells; intracellular forkhead/winged-helix family transcriptional repressor p3 [FOXP3] expression, FOXP3 levels, lymphocyte activation gene 3 mRNA expression, functional studies, and DNA methylation of the FOXP3 locus), proliferation, and T(H)2/T(H)1/T(H)17 cytokines were examined.
Cord blood Treg cell counts (both unstimulated and PHA stimulated) were increased with maternal farming exposures and associated with higher FOXP3 (Der p 1 + Ppg stimulation) and trendwise higher lymphocyte activation gene 3 (Ppg) expression. Furthermore, Treg cell function was more efficient with farming exposure (effector cell suppression, P = .004). In parallel, T(H)2 cytokine (IL-5) levels were decreased and associated with decreased lymphoproliferation and increased IL-6 levels (Ppg stimulation, Der p 1 + Ppg stimulation, or both; P < .05). Maternal exposure to increasing numbers of farm animals and stables was discovered to exert distinct effects on Treg cells, T(H)1/T(H)2 cells, or both. Additionally, FOXP3 demethylation in offspring of mothers with farm milk exposure was increased (P = .02).
Farm exposures during pregnancy increase the number and function of cord blood Treg cells associated with lower T(H)2 cytokine secretion and lymphocyte proliferation on innate exposure. One fascinating speculation is that maternal farm exposure might reflect a natural model of immunotherapy, potentially including a selection of innate stimuli in addition to allergen, shaping a child's immune system at an early stage.
The Journal of allergy and clinical immunology 04/2009; 123(4):774-82.e5. · 9.17 Impact Factor
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The Journal of allergy and clinical immunology 11/2008; 122(4):841. · 9.17 Impact Factor
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ABSTRACT: The inducible co-stimulatory molecule, ICOS, is an important regulator of T cell differentiation and effector function. Previously, it was reported that two variants in the ICOS promotor region, g.1-1413G>A and g.1-693G>A, were associated with sensitization to airborne allergens, elevated serum IgE levels and Th2 cytokine production in a Hutterite population. The aim of this study was to evaluate these two and four other selected ICOS variants for association with atopic phenotypes in two large European prospective pediatric cohorts. We investigated subjects from the German Multicenter Allergy Study (MAS), which followed over 800 children with atopic family history from birth until 13 yr of age, and from the Early Treatment of the Allergic Child Study (ETAC), which collected DNA and clinical data of over 330 children with atopic dermatitis during their first 2 yr of life. We genotyped DNA from these children by melting curve analysis using fluorescence resonance energy transfer (FRET) probes. We could not confirm the previously reported association of g.1-1413G>A and g.1-693G>A with atopic phenotypes in our pediatric cohorts. Also four other ICOS variants at putative binding sites for transcription factors showed no association with atopic dermatitis, asthma, allergic sensitization and allergic rhinitis. Our data suggest that these ICOS variants do not play a major role in the development of atopy in European children.
Pediatric Allergy and Immunology 10/2008; 20(3):242-5. · 2.46 Impact Factor
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ABSTRACT: Maternal atopy is a strong predictor for the development of childhood allergic diseases. The underlying mechanisms are ill defined, yet regulatory T (Treg) and T(H)17 cells may play a key role potentially shaping the early immune system toward a proallergic or antiallergic immune regulation.
We examined T(H)1/T(H)2, Treg, and T(H)17 cell responses to innate (lipid A/peptidoglycan) and mitogen/adaptive (phytohemagglutinin/Dermatophagoides pteronyssinus 1) immune stimulation in cord blood from offspring of atopic/nonatopic mothers.
Cord blood mononuclear cells from 161 healthy neonates (59% nonatopic, 41% atopic mothers) were investigated regarding Treg and T(H)17 cells (mRNA/surface markers), suppressive function, and proliferation/cytokine secretion.
Cord blood from offspring of atopic mothers showed fewer innate-induced Treg cells (CD4(+)CD25(+)high), lower mRNA expression of associated markers (glucocorticoid-induced tumor necrosis factor receptor-related protein/lymphocyte activation gene 3; P < .05), and a trend toward lower Forkhead box transcription factor 3 (Foxp3) expression. Treg cell function was impaired in mitogen-induced suppression of T effector cells in cord blood of offspring from atopic mothers (P = .03). Furthermore, IL-10 and IFN-gamma secretion were decreased in innate-stimulated cord blood of offspring from atopic mothers (P = .04/.05). Innate-induced IL-17 was independent of maternal atopy and highly correlated with IL-13 secretion.
In offspring of atopic mothers, Treg cell numbers, expression, and function were impaired at birth. T(H)17 cells were correlated with T(H)2 cells, independently of maternal atopy.
The Journal of allergy and clinical immunology 07/2008; 121(6):1491-9, 1499.e1-13. · 9.17 Impact Factor
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ABSTRACT: Reduced lung function is a feature of chronic asthma, which becomes apparent at school age. Unknown factors between birth and school age determine the progressive loss of pulmonary function in children with persistent asthma. We investigated the role of allergic sensitisation and allergen exposure early in life.
The German Multicentre Allergy Study followed 1314 children from birth to 13 years of age. We regularly interviewed parents about their child's asthma and measured IgE levels. Allergen exposure was assessed at age 6 months, 18 months, and at 3, 4, and 5 years; lung function was assessed at 7, 10, and 13 years; post-bronchodilator response at 10 and 13 years; and a bronchial histamine challenge was done at 7 years.
90% of children with wheeze but no atopy lost their symptoms at school age and retained normal lung function at puberty. By contrast, sensitisation to perennial allergens (eg, house dust mite, cat and dog hair) developing in the first 3 years of life was associated with a loss of lung function at school age. Concomitant exposure to high levels of perennial allergens early in life aggravated this process: forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio was 87.4 (SD 7.4) for those sensitised and with high exposure compared with 92.6 (6.0) for those not sensitised, p<0.0001; and maximal expiratory flow at 50% (MEF50) 86.4 (25.1) for sensitised and with high exposure compared with 101.5 (23.2; p=0.0031) for those not sensitised. Such exposure also enhanced the development of airway hyper-responsiveness in sensitised children with wheeze. Sensitisation and exposure later in life had much weaker effects and sensitisation to seasonal allergens did not play a part.
The chronic course of asthma characterised by airway hyper-responsiveness and impairment of lung function at school age is determined by continuing allergic airway inflammation beginning in the first 3 years of life. However, children with a non-atopic wheezing phenotype lose their symptoms over school age and retain normal lung function at puberty.
The Lancet 09/2006; 368(9537):763-70. · 38.28 Impact Factor
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ABSTRACT: Atopic dermatitis (AD) is considered to be one of the first manifestations in the atopic march. However, few prospective studies on AD and its association with childhood asthma exist.
The aim of this study was to prospectively investigate the natural course of AD to determine factors influencing its prognosis and to analyze the relationship of AD with childhood asthma.
The Multicenter Allergy Study, a German birth cohort, followed 1314 children from birth to age 7 years. Physical examinations, parental interviews on atopic symptoms and diagnoses, and determination of specific IgE levels were performed regularly.
The cumulative prevalence of AD in the first 2 years of life was 21.5%. Of these children with early AD, 43.2% were in complete remission by age 3 years, 38.3% had an intermittent pattern of disease, and 18.7% had symptoms of AD every year. Severity (adjusted cumulative odds ratio, 5.86; 95% CI, 3.04-11.29) and atopic sensitization (adjusted cumulative odds ratio, 2.76; 95% CI, 1.29-5.91) were major determinants of prognosis. Early wheeze and a specific sensitization pattern were significant predictors for wheezing at school age, irrespective of AD. Early AD without these cofactors constituted no increased risk of subsequent wheeze (adjusted odds ratio, 1.11; 95% CI, 0.56-2.20) or bronchial hyperreactivity.
AD is a common condition in infancy but disappears around age 3 years in a significant proportion of children. The prognosis is mostly determined by the severity and the presence of atopic sensitization. Early AD is associated with asthma at school age, but in many of these asthmatic children, wheezing manifests before or with the onset of AD. Children with AD and wheeze have a marked loss in lung function, suggesting a distinct phenotype rather than a progressive development from AD to asthma.
Journal of Allergy and Clinical Immunology 06/2004; 113(5):925-31. · 11.00 Impact Factor
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ABSTRACT: To analyze prevalences of allergic sensitization and atopic disease in relation to vaccination coverage.
A German atopy risk-enhanced birth cohort of 1314 neonates who were born in 1990 in 5 German cities was studied. A total of 943 children participated in the follow-up visit at 5 years of age. Atopic symptoms and diagnoses (derived from structured interviews), total serum immunoglobulin E, and specific immunoglobulin E against 9 common allergens (CAP Radio-Allergo-Sorbent Test Fluoro-Enzyme Immunoassay) were evaluated. Children were grouped into dose percentiles according to cumulative doses of any vaccine given up to 5 years of age (<10%, 0-11 doses; 10%-50%, 12-14 doses; 51%-90%, 15-20 doses; >90%, 21-27 doses).
The cumulative vaccine dose was inversely related to atopic dermatitis prevalences at 6 months (13.8%, 5.2%, 5.1%, and 4.5%), 2 years (16.9%, 10.9%, 7.4%, and 3.7%), 3 years (27.6%, 16.4%, 13.5%, and 4.5%), and 5 years (28.3%, 16.0%, 9.3%, and 11.9%). Asthma followed a similar pattern at age 3 (22.4%, 8.6%, 6.7%, and 6.3%), age 4 (20.0%, 8.6%, 8.9%, and 8.1%), and age 5 (20.8%, 12.6%, 10.3%, and 5.5%). Allergic sensitization rates were inversely related to the cumulative vaccine dose at age 2 (37.5%, 29.1%, 23.8%, and 12.9%).
Children with a higher vaccination coverage seemed to be transiently better protected against development of atopy in the first years of life.
PEDIATRICS 03/2003; 111(3):e282-8. · 4.47 Impact Factor
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Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 02/2003; 90(1):6-7. · 2.83 Impact Factor
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Susanne Lau,
Renate Nickel,
Bodo Niggemann,
Christoph Grüber,
Christine Sommerfeld, Sabina Illi,
Michael Kulig,
Johannes Forster,
Ulrich Wahn,
Marketa Groeger,
Fred Zepp,
Wolfgang Kamin,
Imke Bieber,
Uta Tacke,
Volker Wahn,
Carl-Peter Bauer,
Renate Bergmann,
Erika von Mutius
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ABSTRACT: Epidemiological surveys have indicated that there has been a notable increase in the prevalence of both asthma and other allergic symptoms in children and young adults. Since it seems unlikely that genetic factors would contribute to the rising trend, environmental factors might play a major part in the development of childhood asthma. In a prospective birth-cohort study, we assessed the relevance of different exposures such as mite and cat allergen exposure, environmental tobacco smoke (ETS) exposure, early infectious diseases and vaccinations for the development of childhood asthma up to the age of 10 years. Data up to 7 years of age have been evaluated. Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 7 years were available for 939 children (72%). Assessments included repeated measurements of specific IgE to food and inhalant allergens, measurement of indoor allergen exposure at 6 months, 18 months and 3 years of age and yearly interviews by a paediatrician. At age 7 years, pulmonary function was tested and bronchial responsiveness was determined in 645 children. At age 7, the prevalence of wheezing in the past 12 months was 10% (94 out of 938), and 6.1% (57 out of 939) parents reported a doctor's diagnosis of asthma in their children. Sensitisation to indoor allergens was associated with asthma, wheeze and increased bronchial responsiveness. However, no relationship between early indoor allergen exposure and the prevalence of asthma, wheeze and bronchial responsiveness was seen. During the first 3 years of life, intra-uterine tobacco and consistent ETS exposure have an adjuvant effect on allergic sensitisation that is transient and restricted to children with a genetic predisposition for allergy. Children sensitised to any allergen early in life and sensitised to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at this age (odds ratio (OR) = 10.12; 95% confidence interval (CI) = 3.81-26.88). Children with repeated episodes (> or =2) of runny nose before the age of 1 year were less likely to develop asthma by the age of 7 years (OR = 0.52; 95% CI = 0.29-0.92). Our data do not support the hypothesis that exposure to environmental allergens directly causes asthma in childhood but that induction of specific IgE responses and the development of childhood asthma are determined by independent factors. Indoor allergen avoidance is recommended as first line treatment in secondary and tertiary prevention; however, conclusions should be drawn with caution about the possible effect of primary preventative measures. Since allergic asthma seems to be a Th2-disease, immunomodulating factors such as early childhood infections, LPS-exposure or other factors influencing gene-environment interaction and individual susceptibility seem to be relevant for the development of childhood asthma.
Paediatric respiratory reviews 09/2002; 3(3):265-72. · 2.20 Impact Factor
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ABSTRACT: Lower prevalence rates for childhood respiratory allergies have been reported in eastern Germany than in western Germany.
Because allergic phenotypes are thought to be associated with an unbalanced T(H)1/T(H)2 T cell effector response, a cross-sectional investigation was carried out as part of the German ISAAC Phase II study to determine whether T(H)1/T(H)2 capacity might have developed in different directions during the separation between the 2 parts of the country.
In a community-based random sample of 9- to 11-year-old (n = 6399) and 5- to 7-year-old (n = 6202) children in eastern and western Germany, the prevalence of atopy was assessed. Heparinized blood samples were collected from a subgroup of children stratified according to the number of older siblings. T(H)1 and T(H)2 cytokine productivity was determined after stimulation with phorbol ester plus ionomycin.
Individuals who grew up in eastern Germany had a marked bias toward T(H)0 responsiveness (>60%), regardless of whether they were atopic. In contrast, the children of western Germany, particularly when they were atopic, showed T(H)2 polarization.
This is the first epidemiologic survey to demonstrate regional differences in the T(H)1/T(H)2 response pattern and their relation to atopic disease between regions.
Journal of Allergy and Clinical Immunology 02/2002; 109(2):338-42. · 11.00 Impact Factor
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ABSTRACT: Several birth cohort studies have been initiated during the past two decades to study environmental and genetic risk factors for atopic dermatitis, asthma and allergic rhinitis. This article summarizes results from the German Multicentre Allergy Study (MAS), which has followed children (initially 1,314) from birth (in 1990) to the present time. The effects of immunizations, allergen exposure, early sensitization patterns as well as upper airway infections on the subsequent development of asthma and atopy at school age are described. Furthermore, candidate gene studies of atopic dermatitis and increased total serum IgE levels on chromosomes 5q, 12q and 17q in MAS-children and their parents are outlined.
Pediatric Allergy and Immunology 02/2002; 13 Suppl 15:7-10. · 2.46 Impact Factor
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ABSTRACT: Objective: To investigate the association between early childhood infections and subsequent development of asthma.
Design: Longitudinal birth cohort study.
Setting: Five children's hospitals in five German cities.
Participants: 1314 children born in 1990 followed from birth to the age of 7 years.
Main outcome measures: Asthma and asthmatic symptoms assessed longitudinally by parental questionnaires; atopic sensitisation assessed longitudinally by determination of IgE concentrations to various allergens; bronchial hyperreactivity assessed by bronchial histamine challenge at age 7 years.
Results: Compared with children with 1 episode of runny nose before the age of 1 year, those with 2 episodes were less likely to have a doctor's diagnosis of asthma at 7 years old (odds ratio 0.52 (95% confidence interval 0.29 to 0.92)) or to have wheeze at 7 years old (0.60 (0.38 to 0.94)), and were less likely to be atopic before the age of 5 years. Similarly, having 1 viral infection of the herpes type in the first 3 years of life was inversely associated with asthma at age 7 (odds ratio 0.48 (0.26 to 0.89)). Repeated lower respiratory tract infections in the first 3 years of life showed a positive association with wheeze up to the age of 7 years (odds ratio 3.37 (1.92 to 5.92) for 4 infections v 3 infections).
Conclusion: Repeated viral infections other than lower respiratory tract infections early in life may reduce the risk of developing asthma up to school age.
BMJ 02/2001; 322(7283):390 - 395. · 14.09 Impact Factor
