A comprehensive analysis of interleukin-4 receptor polymorphisms and their association with atopy and IgE regulation in childhood

BACKGROUND: The interleukin (IL) 4/IL13 pathway is involved in the regulation of IgE production associated with atopic diseases. Numerous polymorphisms have been identified in the coding region of the IL4 receptor alpha chain (IL4Ra) and previous association studies have shown conflicting results. Based on their putative functional role, polymorphisms A148G, T1432C and A1652G, located in the coding region of IL4Ra, were selected for association and haplotype studies in a large German population sample (n = 1,120). METHODS: Genotyping was performed using allele-specific PCR and restriction-enzyme-based assays. Haplotypes were estimated, and population-derived IgE percentiles (50% IgE >60 IU/ml, 66% IgE >115 IU/ml and 90% IgE >457 IU/ml) were calculated as outcome variables in a haplotype trend regression analysis. RESULTS: In our population, only polymorphism T1432C showed a trend for a protective effect against atopic rhinitis (odds ratio, OR: 0.52, 95% confidence interval, CI: 0.26-1.02, p = 0.05). When haplotypes were calculated, one haplotype was significantly associated with elevated serum IgE levels at the 50th percentile (OR 1.60, 95% CI 1.08-2.37, p = 0.02). CONCLUSIONS: These data indicate that IL4Ra polymorphisms, although suggested to be functionally relevant by in vitro studies, have only a minor influence on IgE regulation in our large population sample.     

Fatty acids in serum cholesteryl esters in relation to asthma and lung function in children

BACKGROUND: Dietary fatty acid intake has been proposed to contribute to asthma development with n-6 polyunsaturated fatty acids (PUFA) having a detrimental and n-3 PUFA a protective effect. OBJECTIVE: The aim of our analysis was to explore the relationship between fatty acid composition of serum cholesteryl esters as marker of dietary intake and prevalence of asthma, impaired lung function and bronchial hyper-responsiveness in children. METHODS: The study population consisted of 242 girls and 284 boys aged 8-11 years, living in Munich, Germany. Data were collected by parental questionnaire, lung function measurement and skin prick test according to the International Study of Asthma and Allergies in Childhood phase II protocol. Confounder-adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association between quartiles of fatty acid concentration and health outcomes with the first quartile as reference. RESULTS: n-3 PUFA: levels of eicosapentaenoic acid were not related to asthma and impaired lung function. Linolenic acid levels were positively associated with current asthma (OR for fourth quartile 3.35, 95% CI 1.29-8.66). Forced expiratory volume in 1 s (FEV(1)) values decreased with increasing levels of linolenic acid (p for trend=0.057). n-6 PUFA: there was a strong positive association between arachidonic acid levels and current asthma (OR(4th quartile) 4.54, 1.77-11.62) and a negative association with FEV(1) (P=0.036). In contrast, linoleic acid was negatively related to current asthma (OR(4th quartile) 0.34, 0.14-0.87) and FEV(1) values increased with increasing levels of linoleic acid (P=0.022). The ratio of measured n-6 to n-3 PUFA as well as levels of palmitic and oleic acid were not consistently related to asthma or lung function. CONCLUSION: Our data do not support the hypothesis of a protective role of n-3 PUFA. Elevated arachidonic acid levels in children with asthma may be because of a disturbed balance in the metabolism of n-6 PUFA or may be secondary to inflammation in these patients.     

Prevalence of respiratory and atopic disorders among children in the East and West of Germany five years after unification.

Living conditions in eastern Germany have changed rapidly since unification in 1990 and little is known about how these changes affect the prevalence of atopic diseases. This study describes methods and prevalences of a large epidemiological project investigating determinants of childhood asthma and allergies in eastern (Dresden and Leipzig) and western (Munich) Germany in 1995/1996. Community based random samples of 9-11 yr old children in Dresden (n=3,017) and Munich (n=2,612), and of 5-7 yr old children in Dresden (n=3,300), Leipzig (n=3,167) and Munich (n=2,165) were studied by parental questionnaires, bronchial challenges with hypertonic saline, skin examination, skin-prick tests, and measurements of specific and total serum immunoglobulin (Ig)E using Phase II modules of the International Study of Asthma and Allergies in Childhood (ISAAC). In 9-11 yr old children, the prevalence of physician diagnosed asthma (7.9% versus 10.3%; p<0.01) and bronchial hyperresponsiveness (15.7% versus 19.9%; p<0.05) was lower in Dresden than in Munich. No difference between Munich and Dresden was observed in the prevalence of diagnosed hay fever, skin test reactivity to > or = 1 allergen, and increased levels (>0.35 kU x L(-1)) of specific IgE against inhalant and food allergens. Symptoms and visible signs of atopic eczema tended to be more prevalent in Dresden. Similar East-West differences between the three study areas were seen in the younger age group. These findings are in line with recently observed increases in the prevalence of hay fever and atopic sensitization, but not of asthma and bronchial hyperresponsiveness, among 9-11 yr old children in Leipzig.     

Reduced risk of hay fever and asthma among children of farmers

BACKGROUND: The prevalence of atopic diseases is on the rise. Traditional lifestyles may be associated with a reduced risk of atopy. OBJECTIVES: To test the hypothesis that children living on a farm have lower prevalences of atopic diseases. To identify differences in living conditions between farmers and other families which are associated with the development of atopic conditions. DESIGN: Cross-sectional survey among children entering school (aged 5-7 years). A written questionnaire including the ISAAC core questions and asking for exposures on a farm and elsewhere was administered to the parents. Setting: School health entry examination in two Bavarian districts with extensive farming activity. Subjects: 10 163 children. MAIN OUTCOME MEASURES: The prevalence of doctor's diagnoses and symptoms of hay fever, asthma and eczema as assessed by parental report. RESULTS: Farmers' children had lower prevalences of hay fever (adjusted odds ratio = 0. 52, 95% CI 0.28-0.99), asthma (0.65, 0.39-1.09), and wheeze (0.55, 0. 36-0.86) than their peers not living in an agricultural environment. The reduction in risk was stronger for children whose families were running the farm on a full-time basis as compared with families with part-time farming activity. Among farmers' children increasing exposure to livestock was related to a decreasing prevalence of atopic diseases (aOR = 0.41, 95% CI 0.23-0.74). CONCLUSIONS: Factors related to environmental influences on a farm such as increased exposure to bacterial compounds in stables where livestock is kept prevent the development of allergic disorders in children.     

Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78

The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR messenger RNA. Conversely, suppression of TLRs was observed in placental tissue. To investigate further, the functional relevance of maternal TLR signaling was tested in TLR2/3/4/7/9^−/− knockout mice. The asthma-preventive effect was completely abolished in heterozygous offspring from A. lwoffii F78–treated TLR2/3/4/7/9^−/− homozygous mother mice. Furthermore, the mild local and systemic inflammatory response was also absent in these A. lwoffii F78–exposed mothers. These data establish a direct relationship between maternal bacterial exposures, functional maternal TLR signaling, and asthma protection in the progeny.Allergic bronchial asthma has become a major public health burden in industrialized countries, and the incidence of this chronic inflammatory disease has been steadily growing over the last decades. Although many susceptibility genes have been identified (Moffatt et al., 2007; Vercelli, 2008), genetics alone cannot explain the velocity of these changes. Additional factors must have contributed to the growing incidence of asthma. In agreement with the hygiene hypothesis, epidemiological studies indicate that lack of early childhood exposure to microbial agents may contribute to increased susceptibility to the development of allergic diseases (Strachan, 2000). Moreover, environments characterized by a diverse and concentrated microbial milieu, such as traditional farming sites, may protect from allergic diseases (Riedler et al., 2001; Majkowska-Wojciechowska et al., 2007; Midodzi et al., 2007; von Mutius and Radon, 2008). In this regard, analysis of cowshed dust samples has identified the Gram-negative, nonpathogenic bacterium Acinetobacter lwoffii F78 as a potential allergo-protective agent (Korthals et al., 2008). Although experimental approaches using a mouse model of acute allergic airway inflammation suggest a strong allergy protective potential of this bacterial strain (Debarry et al., 2007), nothing is known about the effects of prenatal exposure to A. lwoffii F78 and possible downstream mechanisms affecting allergic inflammatory responses in the progeny.Respiratory allergies, including bronchial asthma, are chronic inflammatory diseases that are based on a complex deregulated interaction of both innate and adaptive immune responses (Hammad and Lambrecht, 2008; Holgate and Polosa, 2008). Regarding the maturation of the adaptive immune system, it is now well established that the development of functionally active T cell subsets starts already prenatally (Warner et al., 2000), and it has been proposed that immunoprogramming by environmental influences may occur at this early developmental stage. Indeed, studies have demonstrated that many factors affecting the initiation and course of respiratory allergies appear to act within a narrow window of opportunity, either prenatally and/or early in life (Ege et al., 2006; Rowe et al., 2007). It is still unresolved, however, how protective signals are transferred from the mother to the developing fetus.Regarding mechanisms by which A. lwoffii F78 may exert its protective effects, consideration must be given to innate immune processes that participate in initial microbial recognition. Innate immunity functions as a first line of defense that uses, in addition to physical barriers, a pattern recognition receptor (PRR) system that can identify a broad spectrum of microbial components. Toll-like receptors (TLRs) are a major class of PRRs expressed by several cell types, including epithelium and immune cells, that play a vital role in the initiation of the immune response (Gon, 2008; Kawai and Akira, 2009).Combining prenatal exposure to the cowshed bacterium A. lwoffii F78 with a mouse model of allergic airway inflammation, we show in this report that prenatal exposure to farming-related microbes protects from the development of allergic phenotypes in the next generation. The process by which this protection is achieved involves a low level, local, and systemic maternal innate immune response, and the transference of protective immunity from the mother to the fetus is fully dependent on the action of the maternal TLR2, 3, 4, 7, and/or 9.