A small proline-rich protein (SPRR) gene variant contributes to atopic eczema and eczema-associated asthma susceptibility.

Introduction: There is some evidence that genetic variants in the epidermal differentiation complex (EDC) genes on chromosome 1q21 may be involved in the pathogenesis of atopic eczema (AE) similar to the well-known filaggrin gene (FLG) mutations. Aim: To evaluate the association of SNP in the small proline-rich protein 2B (SPRR2B) gene with atopic eczema and other allergic phenotypes and to investigate its possible interaction with FLG mutations. Material and methods: One hundred and eighty-eight children less than 2 years old were screened for the variant of allele rs6693927 in the SPRR2B gene and for 4 most prevalent FLG mutations. The variant of allele rs6693927 and all FLG mutations were genotyped by real-time polymerase chain reaction assays with subsequent melting curve analysis using SimpleProbe® probes. Results: The allele rs6693927[A] was associated with a significantly increased risk of AE (OR = 3.02; 95% CI: 1.17-8.00; p = 0.011) and the effect was independent of FLG risk alleles. The largest effects were observed in patients with a combined asthma-plus-eczema phenotype (OR = 5.44; 95% CI: 1.17-25.16; p = 0.029). Finally, in eczema, we found interactions of rs6693927[A] with FLG mutations, the risk of eczema was the most increased in the subjects who combined both rs6693927[A] allele and FLG mutations. Conclusions: The SPRR2B risk variant may play an important role in the development of atopic eczema and the particular eczema-associated asthma phenotype in young children. The effect seems to be independent of, and supplementary to, the well-known FLG mutations and may be modulated by gene-gene interactions.

Pet ownership in pregnancy and methylation pattern in cord blood.

Having pets in the house during the first years of life has been shown to protect against allergies. However, the result of different studies is heterogeneous. The aim of this study was to evaluate the methylation pattern in cord blood in relation to pet ownership during pregnancy.We investigated the methylation patterns of 96 cord blood samples, participants of the Epigenetic Hallmark of Maternal Atopy and Diet-ELMA project, born to mothers who either owned pets (n = 32) or did not own pets (n = 64) during their pregnancy. DNA from cord blood was analysed using the Infinium methylation EPIC. For statistical analysis, RnBeads software was applied.We found 113 differentially methylated sites (DMs) in the covariate-adjusted analysis (FDR p < 0.05), with small methylation differences. The top DMs were associated with genes: UBA7, THRAP3, GTDC1, PDE8A and SBK2. In the regional analysis, two promoter regions presented with significance: RN7SL621P and RNU6-211P. Cis-regulatory element analysis revealed significant associations with several immune-related pathways, such as regulation of IL18, Toll signalling, IL6 and complement.We conclude that pet exposure during pregnancy causes subtle but significant changes in methylation patterns in cord blood, which are reflected in the biological processes governing both innate and adaptive immune responses.

Asthma in farm children is more determined by genetic polymorphisms and in non-farm children by environmental factors.

BACKGROUND: The asthma syndrome is influenced by hereditary and environmental factors. With the example of farm exposure, we study whether genetic and environmental factors interact for asthma. METHODS: Statistical learning approaches based on penalized regression and decision trees were used to predict asthma in the GABRIELA study with 850 cases (9% farm children) and 857 controls (14% farm children). Single-nucleotide polymorphisms (SNPs) were selected from a genome-wide dataset based on a literature search or by statistical selection techniques. Prediction was assessed by receiver operating characteristics (ROC) curves and validated in the PASTURE cohort. RESULTS: Prediction by family history of asthma and atopy yielded an area under the ROC curve (AUC) of 0.62 [0.57-0.66] in the random forest machine learning approach. By adding information on demographics (sex and age) and 26 environmental exposure variables, the quality of prediction significantly improved (AUC = 0.65 [0.61-0.70]). In farm children, however, environmental variables did not improve prediction quality. Rather SNPs related to IL33 and RAD50 contributed significantly to the prediction of asthma (AUC = 0.70 [0.62-0.78]). CONCLUSIONS: Asthma in farm children is more likely predicted by other factors as compared to non-farm children though in both forms, family history may integrate environmental exposure, genotype and degree of penetrance.

Chromosome 11q13.5 variant as a risk factor for atopic dermatitis in children.

INTRODUCTION: Atopic dermatitis is a chronic inflammatory skin disease with a strong genetic basis. Recent GWASs have identified a single nucleotide polymorphism on chromosome 11q13.5 (rs7927894) as novel susceptibility loci of atopic dermatitis. AIM: To evaluate the association of this genetic variant with atopic dermatitis and to investigate its possible interaction with filaggrin null mutations in children population. MATERIAL AND METHODS: One hundred eighty-eight children less than 2 years old were screened for the variant of allele of rs7927894 on chromosome 11q13.5 and for the 4 most prevalent filaggrin mutations. The variant of allele of rs7927894 and all filaggrin mutations were genotyped by real-time PCR assays with subsequent melting curve analysis using SimpleProbe® probes. RESULTS: The allele of rs7927894[T] was associated with a significantly increased risk of atopic dermatitis (OR = 2.21; 95% CI: 1.14-4.28; p = 0.015). Both allergic and non-allergic patient groups had rs7927894[T] allele significantly more frequently than the control group, however, the frequency of alleles did not differ in these two groups. Interestingly, when rs7927894 variant and filaggrin mutations were considered together, the risk of atopic dermatitis was the most increased in the subjects who combined both rs7927894[T] allele and filaggrin mutations (OR = 16.41; p = 0.003). CONCLUSIONS: Our results indicate that the rs7927894 variant on chromosome 11q13.5 may play a role in the development of atopic dermatitis, but this effect seems to be independent of allergic sensitization and of the well-established filaggrin risk alleles, but may be modulated by gene-gene interactions.

Identification of fungal candidates for asthma protection in a large population-based study.

BACKGROUND: Exposure to molds has been related to asthma risk both positively and negatively, depending on the environmental setting. The pertinent results are based on generic markers or culturing methods although the majority of present fungi cannot be cultured under laboratory conditions. The aim of the present analysis was to assess environmental dust samples for asthma-protective fungal candidates with a comprehensive molecular technique covering also non-cultivable and non-viable fungi. METHODS: Mattress dust samples of 844 children from the GABRIELA study were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) of the fungus-specific internal transcribed spacer (ITS) region. Known asthma candidate species were tested for their associations with asthma, and further gel positions were sought to explain the above. As a second, data-driven, analysis, we tested the association of each individual gel position with asthma. RESULTS: In the hypothesis-driven approach, Penicillium chrysogenum emerged with an odds ratio of 0.80 (95% confidence interval 0.66-0.96; p = 0.020). The effect size was changed by 39% toward the null when adjusting for the two bands 683 (DNA of Metschnikowia sp., Aureobasidium spp.) and 978 (DNA of Epicoccum spp., Galactomyces spp., uncultured Penicillium). The data-driven approach yielded an additional band (containing DNA of Pseudotaeniolina globosa) with reduced risk of asthma (OR = 0.80 [0.66-0.96], p = 0.012). CONCLUSIONS: A large population-based study revealed several fungal taxa with inverse associations with childhood asthma. Molds produce a variety of bioactive compounds with detrimental but also beneficial immunoregulatory capacities, which renders them promising targets for further asthma research.

[The role of Toll-like receptors in the pathogenesis of allergic diseases - where is the truth?]. / Rola receptorów Toll-podobnych (TLR) w patogenezie schorzen alergicznych ­ gdzie lezy

Toll-like receptors (TLRs) are pattern recognition receptors crucial for the innate and adaptive immune response to pathogen-associated molecular patterns (PAMPs). TLR stimulation via microbial products activates antigen-presenting cells, influences the function of T regulatory cells (Treg), determines the Th1/Th2 balance and Th17 cell differentiation, and controls cytokine production in mast cells and activation of eosinophils. The role of TLR receptors in pathogenesis of allergic diseases results from the biological function that they play in activation and regulation of the immune response. However, the exact role still remains a controversial area. Whereas numerous epidemiological studies mainly indicate a protective effect of microbial exposure, experiments show that innate immune stimulation via TLRs may be involved in both development of and protection against allergic diseases. Timing, dose, site and intensity of exposure to environmental factors and host genetic predisposition are clearly crucial to understanding the interaction between innate immune stimulation and allergy development.Furthermore, extensive clinical trials suggest that ligands for TLRs provide new therapeutic targets for protection against and treatment of asthma and allergic rhinitis. The aim of this review is to summarize the current knowledge about the role of TLRs in pathogenesis of allergic diseases. We will further discuss how we can reconcile inconsistencies in the results of existing studies and review information on the potential use of ligands for TLRs in allergy prevention and therapy.

The combined effects of family size and farm exposure on childhood hay fever and atopy.

BACKGROUND: Exposure to farming environments and siblings is associated with reduced risks of childhood hay fever and atopy. We explored the independence and interaction of these protective effects in the GABRIELA study. METHODS: Questionnaire surveys on farming, asthma, and allergies were conducted in four central European areas among 79,888 6-12-yr-old children. Aeroallergen-specific serum IgE was measured in a stratified sample of 8,023 children. Multiple logistic regression was used to compare gradients in allergy prevalence by sibship size across three categories of exposure to farming environments. RESULTS: The prevalence of hay fever ranged from 2% (95% confidence interval 1.6%; 2.7%) among farmers' children with more than two siblings to 12% (11.2%; 13.0%) among children with no farm exposure and no siblings. Farming families were larger on average. More siblings and exposure to farming environments independently conferred protection from hay fever and atopy. There was no substantial effect modification between family size and exposure to farming environments. The odds ratios for hay fever per additional sibling were 0.79 among unexposed non-farm children, 0.77 among farm-exposed non-farm children, and 0.72 among children from farming families (2df interaction test: p = 0.41). CONCLUSION: The inverse association of exposure to farming environments with hay fever is found in all sizes of family, with no substantial tendency to saturation or synergism. This suggests that different biological mechanisms may underlie these two protective factors. Combinations of a large family and exposure to farming environments markedly reduce the prevalence of hay fever and indicate the strength of its environmental determinants.

Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide.

BACKGROUND: Previous studies have demonstrated that children raised on farms are protected from asthma and allergies. It is unknown whether the farming effect is solely mediated by atopy or also affects nonatopic wheeze phenotypes. OBJECTIVE: We sought to study the farm effect on wheeze phenotypes and objective markers, such as lung function and exhaled nitric oxide, and their interrelation with atopy in children. METHODS: The GABRIEL Advanced Studies are cross-sectional, multiphase, population-based surveys of the farm effect on asthma and allergic disease in children aged 6 to 12 years. Detailed data on wheeze, farming exposure, and IgE levels were collected from a random sample of 8023 children stratified for farm exposure. Of those, another random subsample of 858 children was invited for spirometry, including bronchodilator tests and exhaled nitric oxide measurements. RESULTS: We found effects of exposure to farming environments on the prevalence and degree of atopy, on the prevalence of transient wheeze (adjusted odds ratio, 0.78; 95% CI, 0.64-0.96), and on the prevalence of current wheeze among nonatopic subjects (adjusted odds ratio, 0.45; 95% CI, 0.32-0.63). There was no farm effect on lung function and exhaled nitric oxide levels in the general study population. CONCLUSIONS: Children living on farms are protected against wheeze independently of atopy. This farm effect is not attributable to improved airway size and lung mechanics. These findings imply as yet unknown protective mechanisms. They might include alterations of immune response and susceptibility to triggers of wheeze, such as viral infections.

Protection from childhood asthma and allergy in Alpine farm environments-the GABRIEL Advanced Studies.

BACKGROUND: Studies on the association of farm environments with asthma and atopy have repeatedly observed a protective effect of farming. However, no single specific farm-related exposure explaining this protective farm effect has consistently been identified. OBJECTIVE: We sought to determine distinct farm exposures that account for the protective effect of farming on asthma and atopy. METHODS: In rural regions of Austria, Germany, and Switzerland, 79,888 school-aged children answered a recruiting questionnaire (phase I). In phase II a stratified random subsample of 8,419 children answered a detailed questionnaire on farming environment. Blood samples and specific IgE levels were available for 7,682 of these children. A broad asthma definition was used, comprising symptoms, diagnosis, or treatment ever. RESULTS: Children living on a farm were at significantly reduced risk of asthma (adjusted odds ratio [aOR], 0.68; 95% CI, 0.59-0.78; P< .001), hay fever (aOR, 0.43; 95% CI, 0.36-0.52; P< .001), atopic dermatitis (aOR, 0.80; 95% CI, 0.69-0.93; P= .004), and atopic sensitization (aOR, 0.54; 95% CI, 0.48-0.61; P< .001) compared with nonfarm children. Whereas this overall farm effect could be explained by specific exposures to cows, straw, and farm milk for asthma and exposure to fodder storage rooms and manure for atopic dermatitis, the farm effect on hay fever and atopic sensitization could not be completely explained by the questionnaire items themselves or their diversity. CONCLUSION: A specific type of farm typical for traditional farming (ie, with cows and cultivation) was protective against asthma, hay fever, and atopy. However, whereas the farm effect on asthma could be explained by specific farm characteristics, there is a link still missing for hay fever and atopy.

Gene-environment interaction for childhood asthma and exposure to farming in Central Europe.

BACKGROUND: Asthma is a disease in which both genetic and environmental factors play important roles. The farming environment has consistently been associated with protection from childhood asthma and atopy, and interactions have been reported with polymorphisms in innate immunity genes. OBJECTIVE: To detect gene-environment interactions for asthma and atopy in the farming environment. METHODS: We performed a genome-wide interaction analysis for asthma and atopy by using 500,000 genotyped single nucleotide polymorphisms (SNPs) and farm-related exposures in 1708 children from 4 rural regions of Central Europe. We also tested selectively for interactions between farm exposures and 7 SNPs that emerged as genome-wide significant in a large meta-analysis of childhood asthma and 5 SNPs that had been reported previously as interacting with farm exposures for asthma or atopy. RESULTS: Neither the asthma-associated SNPs nor the SNPs previously published for interactions with asthma showed significant interactions. The genome-wide interaction study did not reveal any significant interactions with SNPs within genes in the range of interacting allele frequencies from 30% to 70%, for which our study was well powered. Among rarer SNPs, we identified 15 genes with strong interactions for asthma or atopy in relation to farming, contact with cows and straw, or consumption of raw farm milk. CONCLUSION: Common genetic polymorphisms are unlikely to moderate the protective influence of the farming environment on childhood asthma and atopy, but rarer variants, particularly of the glutamate receptor, metabotropic 1 gene, may do so. Given the limited statistical power of our study, these findings should be interpreted with caution before being replicated in independent farm populations.

The GABRIEL Advanced Surveys: study design, participation and evaluation of bias.

Exposure to farming environments has been shown to protect substantially against asthma and atopic disease across Europe and in other parts of the world. The GABRIEL Advanced Surveys (GABRIELA) were conducted to determine factors in farming environments which are fundamental to protecting against asthma and atopic disease. The GABRIEL Advanced Surveys have a multi-phase stratified design. In a first-screening phase, a comprehensive population-based survey was conducted to assess the prevalence of exposure to farming environments and of asthma and atopic diseases (n = 103,219). The second phase was designed to ascertain detailed exposure to farming environments and to collect biomaterial and environmental samples in a stratified random sample of phase 1 participants (n = 15,255). A third phase was carried out in a further stratified sample only in Bavaria, southern Germany, aiming at in-depth respiratory disease and exposure assessment including extensive environmental sampling (n = 895). Participation rates in phase 1 were around 60% but only about half of the participating study population consented to further study modules in phase 2. We found that consenting behaviour was related to familial allergies, high parental education, wheeze, doctor diagnosed asthma and rhinoconjunctivitis, and to a lesser extent to exposure to farming environments. The association of exposure to farm environments with asthma or rhinoconjunctivitis was not biased by participation or consenting behaviour. The GABRIEL Advanced Surveys are one of the largest studies to shed light on the protective 'farm effect' on asthma and atopic disease. Bias with regard to the main study question was able to be ruled out by representativeness and high participation rates in phases 2 and 3. The GABRIEL Advanced Surveys have created extensive collections of questionnaire data, biomaterial and environmental samples promising new insights into this area of research.

IL4RA gene expression in relation to I50V, Q551R and C-3223T polymorphisms.

BACKGROUND: Interleukin 4 (IL-4) and its receptor play important roles in the pathologies of asthma and atopy. The alpha subunit of the IL-4 receptor (IL-4RA) is included in 2 types of receptors which have different modulatory effects on immune responses. This distinct pattern reflects involvement in the immunopathology of both asthma and atopy. A number of studies have proven the association between IL4RA gene polymorphisms and asthma and atopy, but it is still an open question whether these variants are functional. OBJECTIVES: To analyze the data from IL4RA gene expression in PBMC in relation to specific polymorphisms - the most frequently studied I50V and Q551R and the less known C-3223T. MATERIAL AND METHODS: The analysis was performed for 36 subjects, both atopic and non-atopic. Real-time polymerase chain reaction (PCR) was used with specific primers for the quantification and genotyping. Delta Ct (ΔCT) and delta-delta Ct (ΔΔCT) values were used for the relative quantification of IL4RA expression in PBMC. RESULTS: We observed no significant differences in the IL4RA expression profile between the 3 genotypes. A trend toward higher relative expression was observed for homozygous minor I50V and C-3223T genotypes. CONCLUSIONS: We did not find a statistically significant relationship between the genetic polymorphisms and the relative expression of IL4RA. The effect of genetic polymorphism on IL4RA mRNA expression could interfere with other factors, such as environmental stimuli, and should be evaluated in future studies.

Maternal atopy and offspring epigenome-wide methylation signature.

The increase in the prevalence of allergic diseases is believed to partially depend on environmental changes. DNA methylation is a major epigenetic mechanism, which is known to respond to environmental factors. A number of studies have revealed that patterns of DNA methylation may potentially predict allergic diseases.Here, we examined how maternal atopy is associated with methylation patterns in the cord blood of neonates.We conducted an epigenome-wide association study in a cohort of 96 mother-child pairs. Pregnant women aged not more than 35 years old, not currently smoking or exposed to environmental tobacco smoke, who did not report obesity before conception were considered eligible. They were further tested for atopy. Converted DNA from cord blood was analysed using Infinium MethylationEPIC; for statistical analysis, RnBeads software was applied. Gestational age and sex were included as covariates in the final analysis.83 DM sites were associated with maternal atopy. Within the top DM sites, there were CpG sites which mapped to genes SCD, ITM2C, NT5C3A and NPEPL1. Regional analysis revealed 25 tiling regions, 4 genes, 3 CpG islands and 5 gene promoters, (including PIGCP1, ADAM3A, ZSCAN12P1) associated with maternal atopy. Gene content analysis revealed pointwise enrichments in pathways related to purine-containing compound metabolism, the G1/S transition of the mitotic cell cycle, stem cell division and cellular glucose homoeostasis.These findings suggest that maternal atopy provides a unique intrauterine environment that may constitute the first environment in which exposure is associated with methylation patterns in newborn.

Sensitisation patterns and allergy outcomes in pregnant women living in the urban area.

BACKGROUND: Worldwide, allergy affects more than one billion people, with particularly rising prevalence in industrialised areas. Specifically, young adults appear to be predominantly targeted for an allergy diagnosis. Allergic diseases in pregnancy are mainly pre-existing but could also occur de novo. The immunological changes while pregnant, with increased Th2 lymphocyte activity, can facilitate allergen sensitisation. OBJECTIVE: The aim of this study was to evaluate the pattern of specific IgE (sIgE) sensitisation to common inhalant and food allergens in pregnancy, and assess its relationship to self-reported allergic disease. METHODS: We assessed 200 pregnant women, aged 20-38 years (mean age = 29 years), participant of ELMA (Epigenetic Hallmark of Maternal Atopy and Diet) study, living in a metropolitan area, with no pregnancy associated metabolic complications, for total IgE and allergen specific IgE to 20 allergens. RESULTS: 48% of pregnant women were sensitised to at least one allergen, at a cut-off point of 0.35 kU/L and they were assigned as atopic. However 42% in atopic group were not reporting any allergic disease. The most common inhalant allergens were: pollen (24.5%) and animal dander (23.5%). The most common food allergens were: cow's milk (5.5%) and apples (4.5%). 7.5% of women reported asthma, 21.5% allergic rhinitis, 11.5% atopic dermatitis and 18.5% food allergy. 8.5% of were taking medication for asthma or allergies. Atopic dermatitis had the highest tendency to become more severe during pregnancy. Total IgE values were significantly higher in atopic women. CONCLUSIONS: Allergic sensitisation is a common phenomenon in pregnancy. Some sensitisations could be asymptomatic. Further studies should investigate if sensitisation in mothers confers risks for immune alterations in their children.

Genetic polymorphisms in pattern recognition receptors are associated with allergic diseases through gene-gene interactions.

BACKGROUND: There is evidence that suggests variation in gene encoding pattern recognition receptors, the essential components of innate immunity, might be associated with atopic diseases. However, results have been inconclusive. OBJECTIVES: The aim of the study was to determine the individual associations and possible interactive effects of the CD14 (cluster of differentiation 14), TLR4 (toll-like receptor 4) and TLR2 (toll-like receptor 2) polymorphisms on allergic diseases. MATERIAL AND METHODS: The CD14 C-159T, TLR4 +896A/G and TLR2 A-16934T polymorphisms were identified in 115 children aged from 6 to 17 years. All subjects were selected using a detailed questionnaire which included questions on symptoms and each one underwent skin prick testing. All single-nucleotide polymorphisms (SNPs) were determined using real-time polymerase chain reaction (PCR) assays. RESULTS: There was no statistically significant correlation between the 3 polymorphisms (CD14 C-159T, TLR4 +896A/G and TLR2/-16934A/T) and either asthma, allergic rhinitis or atopy. We observed that children who were heterozygous or homozygous for both the CD14/-159T and TLR2/-16934A alleles had a 4-fold lower risk for asthma than children who were carriers of the T allele of CD14 but non-carriers of the A allele of TLR2, and an almost 3-fold lower risk for asthma when compared to all other groups. Concerning allergic rhinitis, a similar trend was observed. In addition, the presence of at least 1 A allele in the TLR2/-16934 polymorphism reduced the risk for asthma and allergic rhinitis, but only in children who were homozygous for the common A allele in the TLR4 +896 polymorphism. CONCLUSIONS: Our study supports the idea that the CD14, TLR2 and TLR4 polymorphisms may not be directly involved in the development of atopic diseases. However, our results suggest that their impact on the risk of asthma and allergic rhinitis might be modulated by gene-gene interactions.

IL-4RA gene expression in PBMC with regard to place of living and atopy status.

BACKGROUND: IL-4 and IL-4RA are key factors in allergic inflammation. IL-4 stimulates both IgE production and Th2 lymphocyte differentiation. Increased levels of IL-4 and IL-4RA have been shown in allergic patients. Genetic analyses have confirmed that polymorphisms within the IL-4RA gene influence the risk of allergy and can change the expression of the protein. Due to gene-environment interactions, this process is also likely to be modified by environmental exposure. OBJECTIVES: The aim of the study was to evaluate the IL-4RA gene expression in peripheral blood mononuclear cells (PBMC) from atopic and non-atopic subjects with regard to place of living (urban vs rural). MATERIAL AND METHODS: We enrolled 38 subjects into the study, 18 of whom were atopic. Atopy was estimated according to the results of a skin prick test. PBMC were isolated from whole blood, total RNA was extracted and reverse transcribed into cDNA. We performed real-time PCR to measure gene expression, the ACTB gene was chosen as a reference and the delta-delta Ct (ΔΔCT) method was applied for relative quantification. The Mann-Whitney U test was used for statistics. RESULTS: We did not observe any statistically significant differences in the gene expression profile between atopic and non-atopic subjects regardless of their place of living. However, a trend was observed for atopic rural inhabitants to have lower levels of IL-4RA gene expression than atopic subjects living in the town. CONCLUSIONS: The regulation of IL-4RA gene expression is complex and probably influenced by both genetic and environmental factors, such as farming exposures, which could provide the counterbalance to atopy.

Filaggrin loss-of-function mutations as a predictor for atopic eczema, allergic sensitization and eczema-associated asthma in Polish children population.

BACKGROUND: Loss-of-function mutations in the filaggrin (FLG) gene were identified as a major risk factor for atopic eczema. OBJECTIVES: The aim of the study was to investigate the importance of 4 common FLG null mutations in the susceptibility to atopic eczema and other allergic phenotypes in Polish children population. MATERIAL AND METHODS: The FLG mutations were determined in 158 children younger than 2 years of age. All subjects were selected using a detailed questionnaire and blood samples for total and specific IgE measurements were obtained. Cases of atopic eczema were diagnosed according to the criteria of Hanifin and Rajka and skin examination. All FLG mutations were genotyped by real-time PCR assays with a subsequent melting curve analysis using a SimpleProbe® probes. RESULTS: The combined genotype of all 4 mutations (carriage of ≥ 1 FLG mutation) was significantly associated with atopic eczema (p = 0.016). The odds ratio (OR) for individuals carrying 1 of these 4 null mutations was 5.52 (95% CI; 1.11 ÷ 37.12). The significant association between either the combined FLG genotype or 2282del14 deletion and eczema was seen only in the allergic group. The association with asthma was restricted to asthma occurring in the context of eczema (OR, 6.27; 95% CI, 0.89 ÷ 53.56; p = 0.042). CONCLUSIONS: Our study confirms the previous findings that FLG mutations are strongly associated with atopic eczema and confer a significant risk of allergic sensitization and asthma in the context of eczema. These results underline the role of the epidermal barrier and filaggrin insufficiency in the pathogenesis of atopic eczema and eczema-associated asthma.

The role of vitamin D in atopic dermatitis.

Vitamin D has been suggested to have an important impact on a much wider aspects on human health than calcium homeostasis and mineral metabolism, specifically in the field of human immunology. It has been reported that vitamin D influences the regulation of both innate and adaptive immune systems, which makes the association between vitamin D and allergic diseases a field of interest. Although many studies have sought to determine whether vitamin D has an influence on progression of allergic disease, the impact of vitamin D on atopic dermatitis development and severity remains unclear. In this review, we summarize recent studies relating vitamin D to atopic dermatitis and discuss its possible role in the pathogenesis of allergic skin diseases, emphasizing the need for well-designed, prospective trials on vitamin D supplementation in the context of prevention and treatment for allergic conditions.

Safety and efficacy of pimecrolimus in atopic dermatitis: a 5-year randomized trial.

BACKGROUND AND OBJECTIVES: Atopic dermatitis (AD) primarily affects infants and young children. Although topical corticosteroids (TCSs) are often prescribed, noncorticosteroid treatments are needed because compliance with TCSs is poor due to concerns about their side effects. In this longest and largest intervention study ever conducted in infants with mild-to-moderate AD, pimecrolimus 1% cream (PIM) was compared with TCSs. METHODS: A total of 2418 infants were enrolled in this 5-year open-label study. Infants were randomized to PIM (n = 1205; with short-term TCSs for disease flares) or TCSs (n = 1213). The primary objective was to compare safety; the secondary objective was to document PIM's long-term efficacy. Treatment success was defined as an Investigator's Global Assessment score of 0 (clear) or 1 (almost clear). RESULTS: Both PIM and TCSs had a rapid onset of action with >50% of patients achieving treatment success by week 3. After 5 years, >85% and 95% of patients in each group achieved overall and facial treatment success, respectively. The PIM group required substantially fewer steroid days than the TCS group (7 vs 178). The profile and frequency of adverse events was similar in the 2 groups; in both groups, there was no evidence for impairment of humoral or cellular immunity. CONCLUSIONS: Long-term management of mild-to-moderate AD in infants with PIM or TCSs was safe without any effect on the immune system. PIM was steroid-sparing. The data suggest PIM had similar efficacy to TCS and support the use of PIM as a first-line treatment of mild-to-moderate AD in infants and children.

[The role of immunoglobulin preparations in treatment of allergic diseases]. / Rola preparatów immunoglobulin w leczeniu chorób alergicznych.

Intravenous immunoglobulin (IVIG) has been used for many years to treat patients with primary immunodeficiencies. More recently, IVIG has been shown to have antiinflammatory activity when used at substantially higher concentrations. A number of studies have examined the efficacy of IVIG in allergic diseases. For patients with severe refractory asthma, sinusitis, atopic dermatitis, and urticaria, IVIG offers an alternative therapy with relatively few side effects. Although the mechanism by which IVIG may attenuate the allergic response is still undetermined, clinical studies have shown that immunoglobulin therapy can decrease serum IgE levels and increase glucocorticoid binding affinity, while in vitro studies have shown that IVIG can decrease T-cell secretion of TH2 cytokines.