Differences in DNA methylation profile of Th1 and Th2 cytokine genes are associated with tolerance acquisition in children with IgE-mediated cow’s milk allergy

Abstract

BackgroundEpigenetic changes in DNA methylation could regulate the expression of several allergy-related genes. We investigated whether tolerance acquisition in children with immunoglobulin E (IgE)-mediated cow’s milk allergy (CMA) is characterized by a specific DNA methylation profile of Th2 (IL-4, IL-5) and Th1 (IL-10, IFN-γ)-associated cytokine genes.ResultsDNA methylation of CpGs in the promoting regions of genes from peripheral blood mononuclear cells and serum level of IL-4, IL-5, IL-10 and INF-γ were assessed in children with active IgE-mediated CMA (group 1), in children who acquired tolerance to cow’s milk proteins (group 2) and in healthy children (group 3). Forty children (24 boys, aged 3 to 18 months) were enrolled: 10 in group 1, 20 in group 2, and 10 in the control group. The DNA methylation profiles clearly separated active CMA patients from healthy controls. We observed an opposite pattern comparing subjects with active IgE-mediated CMA with healthy controls and group 2 children who outgrew CMA. The IL-4 and IL-5 DNA methylation was significantly lower, and IL-10 and INF-γ DNA methylation was higher in active IgE-mediated CMA patients. Gene promoter DNA methylation rates of all cytokines and respective serum levels were strongly correlated. Formula selection significantly influenced cytokine DNA methylation profiles in group 2.ConclusionsTolerance acquisition in children with IgE-mediated CMA is characterized by a distinct Th1 and Th2 cytokine gene DNA methylation pattern. These results suggest that DNA methylation may be a target for CMA prevention and treatment.

Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

“…Aberrant DNA methylation profiles are associated with the pathogenesis of disease. Initially, DNA methylation was associated with tumor formation and progression [25], but later on, variations in DNA methylation have been associated with other diseases [26, 27] including chronic kidney disease (CKD) [28, 29] and immune-mediated diseases such as rheumatoid arthritis [30] and allergy [31, 32]. In addition, variations in DNA methylation of immune-related genes orchestrate the host immune response after organ transplantation [5–8].…”

The Implications of DNA Methylation on Food Allergy

“…Apart from FOXP3 methylation, the DNA methylation level of selected Th1 and Th2 cytokines genes can be used as potential biomarkers in predicting tolerance acquisition. In a clinical trial, it was observed that healthy subjects had different DNA methylation profiles in selected Th1 and Th2 cytokines, such as IL-4 , IL-5 , IL-10 , and IFN-γ , if compared to active cow's milk allergy patients [22]. In this way, DNA methylation analysis was clearly able to separate active cow's milk allergy patients from healthy controls.…”

“…In another study investigating the underlying mechanisms for the development of food allergy, Berni Canani et al [22] assessed the DNA methylation of CpGs in the promoter regions of genes from peripheral blood mononuclear cells as well as the serum levels of IL-4, IL-5, IL-10, and IFN-γ in 40 children. These children were divided into 3 groups: children with active IgE-mediated cow's milk allergy (group 1), children who acquired tolerance to cow's milk proteins (group 2), and healthy children (group 3).…”

Epigenome-wide association study links site-specific DNA methylation changes with cow's milk allergy

“…Alterations in DNAm play a key role in T-cell differentiation and in maintaining T H 1/T H 2 balance, 1, 2 and thus may offer a potential mechanistic explanation for the natural history of CMA. However, to date, research on the epigenetics of FA, 3 or CMA in particular, 4 has been very limited. Most of the available studies are based on small sample sizes (<60 children), and were not replicated in an independent sample.…”