Decreased Histone Acetylation Levels at Th1 and Regulatory Loci after Induction of Food Allergy

Abstract

Immunoglobulin E (IgE)-mediated allergy against cow’s milk protein fractions such as whey is one of the most common food-related allergic disorders of early childhood. Histone acetylation is an important epigenetic mechanism, shown to be involved in the pathogenesis of allergies. However, its role in food allergy remains unknown. IgE-mediated cow’s milk allergy was successfully induced in a mouse model, as demonstrated by acute allergic symptoms, whey-specific IgE in serum, and the activation of mast cells upon a challenge with whey protein. The elicited allergic response coincided with reduced percentages of regulatory T (Treg) and T helper 17 (Th17) cells, matching decreased levels of H3 and/or H4 histone acetylation at pivotal Treg and Th17 loci, an epigenetic status favoring lower gene expression. In addition, histone acetylation levels at the crucial T helper 1 (Th1) loci were decreased, most probably preceding the expected reduction in Th1 cells after inducing an allergic response. No changes were observed for T helper 2 cells. However, increased histone acetylation levels, promoting gene expression, were observed at the signal transducer and activator of transcription 6 (Stat6) gene, a proallergic B cell locus, which was in line with the presence of whey-specific IgE. In conclusion, the observed histone acetylation changes are pathobiologically in line with the successful induction of cow’s milk allergy, to which they might have also contributed mechanistically.

Non–IgE- or Mixed IgE/Non–IgE-Mediated Gastrointestinal Food Allergies in the First Years of Life: Old and New Tools for Diagnosis

“…Classical epigenetic mechanisms, including DNA methylation and histone modifications, have been shown to be involved in the development of IgE-mediated food allergies such as CMA [ 171 , 172 , 173 ]. Differences in DNA methylation in different gene pathways have been observed in children who subsequently developed an IgE-mediated food allergy [ 174 ], suggesting their possible role as potential biomarkers.…”

The Interplay of Nutriepigenomics, Personalized Nutrition and Clinical Practice in Managing Food Allergy

“…After first exposure and allergic reaction and resolved, histone acetylation of Th2 genes was found lower in the raw milk when compared to processed milk [79]. In another study looking at the effect of cow's milk allergy, a reduced percentage of regulatory T (Treg) and T helper 17 (Th17) cells were prevalent, in parallel to decreased levels of H3 and/or H4 histone acetylation at Treg and Th17 loci [80]. This indicates that activating T cell-related genes can affect the tolerance to milk, and additionally the exposure to raw milk exhibits an allergy-protective effect through the epigenetic modifications of T cells.…”

“…This is suggested to be influenced by histone acetylation induced by the dietary substances which later activate the mast cells, especially in acute food allergy reactions that often correlate with severe gastrointestinal issues [81]. This effect is suggested to involve the cell signaling within the mast cells and is related to the activation of Th2 cells [80,82]. In the presence of whey-specific IgE, histone acetylation level is increased to further augment STAT6 gene expression [80].…”

“…This effect is suggested to involve the cell signaling within the mast cells and is related to the activation of Th2 cells [80,82]. In the presence of whey-specific IgE, histone acetylation level is increased to further augment STAT6 gene expression [80]. IgE is also related to varieties of IgE binding proteins that react well to parvalbumin in a fish allergen [83,84] and tropomyosin as crustacean allergen [85]; however, their molecular mechanisms and interaction have not been yet elucidated on how methylation and acetylation could lead to the rising of the allergies [86,87].…”

A High-Sodium Diet Modulates the Immune Response of Food Allergy in a Murine Model

“…A previous study demonstrated that the failure to induce oral tolerance, or the breakdown of oral tolerance as a result of the impaired generation or functioning of the suppressive Tregs, could contribute to food allergy [9]. Newly discovered evidence revealed that the epigenetic modifications, caused by decreased or increased levels of histone acetylation at key Th cell loci, contributed to the allergy to cow's milk protein or the allergy-protective effect of raw milk [10,11]. While it is well known that sodium is an immunomodulator of Th17 cells and Tregs [12], our understanding of the direct effect of sodium on Th2-dependent allergic diseases, such as food allergies, remains scarce.…”