Epigenetic Features of FoxP3 in Children With Cow's Milk Allergy

Epigenetic mechanisms have been implicated in the pathogenesis of food allergy. The investigators previously demonstrated that tolerance acquisition in children with Immunoglobulin E- (IgE) mediated cow's milk allergy (CMA) is driven by epigenetic modulation of the Th1 and Th2 cytokine genes. A regulatory T cell (Treg) suppressive phenotype, characterized by stable expression of the transcription factor "Forkhead box Protein 3" (FoxP3), plays a pivotal role in food tolerance. FoxP3 mRNA expression is lower in children with atopic asthma or IgE-mediated food allergy than in healthy children. FoxP3 stable expression requires full CpG demethylation of its transcriptional regulatory regions, and, moreover, hypermethylation of the FoxP3 gene has been associated with reduced Treg function and allergy.

DNA methylation is a biologically and chemically stable epigenetic modification that locks in long-term gene expression patterns. The demethylation status of FoxP3 at a highly conserved region within the Treg-specific-demethylated-region (TSDR), a CpG-rich, located on the 2nd conserved non-coding sequence of FoxP3 (CNS2), is restricted to Tregs. Transcriptional activity of the TSDR is essentially determined by its methylation status : it is completely inactive in its methylated state, but when the TSDR is demethylated, transcription factors such as Ets-1 and Creb can bind to the TSDR. TSDR demethylated and open chromatin conformation in the Foxp3 locus leads to stable phenotype differentiated Foxp3+ Treg. FoxP3 TSDR demethylation in peripheral blood mononuclear cells (PBMCs) has been associated with reduced atopic sensitization and asthma in children. Epigenetic regulation of antigen-induced T-cell subsets may predict a state of immune tolerance in food allergy. Indeed, DNA methylation of the FoxP3 gene in Tregs decreased during oral tolerance acquisition in patients with peanut allergy undergoing oral immunotherapy. The aim of this study was to evaluate further the epigenetic regulation of FoxP3 gene in children with IgE-mediated CMA.