Atopic dermatitis (AD) is one of the most common chronic, inflammatory skin disorders with a complex etiology and a broad spectrum of clinical phenotypes. Despite its high prevalence and effect on the quality of life, safe and effective systemic therapies approved for long-term management of AD are limited. A better understanding of the pathogenesis of atopic dermatitis in recent years has contributed to the development of new therapeutic approaches that target specific pathophysiological pathways. Skin barrier dysfunction and immunological abnormalities are critical in the pathogenesis of AD. Recently, the importance of the downregulation of epidermal differentiation complex (EDC) molecules caused by external and internal stimuli has been extensively emphasized. The purpose of this review is to discuss the innovations in the therapy of atopic dermatitis, including biologics, small molecule therapies, and other drugs by highlighting regulatory mechanisms of skin barrier-related molecules, such as filaggrin (FLG) as a crucial pathway implicated in AD pathogenesis.

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.

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. 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. 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. 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. 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.

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-1591 TLR4 +896A/G and TLR2 A-169341 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 +8% 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-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. 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). 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. 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. 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.