This review covers basic aspects of histone modification and the role of posttranslational histone modifications in the development of allergic diseases, including the immune mechanisms underlying this development. Together with DNA methylation, histone modifications (including histone acetylation, methylation, phosphorylation, ubiquitination, etc.) represent the classical epigenetic mechanisms. However, much less attention has been given to histone modifications than to DNA methylation in the context of allergy. A systematic review of the literature was undertaken to provide an unbiased and comprehensive update on the involvement of histone modifications in allergy and the mechanisms underlying this development. In addition to covering the growing interest in the contribution of histone modifications in regulating the development of allergic diseases, this review summarizes some of the evidence supporting this contribution. There are at least two levels at which the role of histone modifications is manifested. One is the regulation of cells that contribute to the allergic inflammation (T cells and macrophages) and those that participate in airway remodeling [(myo-) fibroblasts]. The other is the direct association between histone modifications and allergic phenotypes. Inhibitors of histone-modifying enzymes may potentially be used as anti-allergic drugs. Furthermore, epigenetic patterns may provide novel tools in the diagnosis of allergic disorders.
Asthma is a widespread chronic inflammatory disease, which has a highly heterogeneous etiopathogenesis, with predominance of either T‑helper cell type 2 (Th2; type 2) or non-Th2 (non-type 2) mechanisms. Together with cardiovascular or autoimmune diseases, obesity, and others, asthma belongs to so called noncommunicable diseases, a group of disorders with immunometabolic links as underlying mechanisms. So far, obesity and asthma have been considered mostly independently, but there are clear signs of relevant interactions. First, obese patients are at increased risk of asthma or asthma‑like symptoms. Second, asthma accompanied by obesity is more severe and more difficult to treat. A specific phenotype called obesity‑associated asthma has been also described, which is late‑onset, rather severe, non-type 2‑driven disease, present mostly in women. In addition, obesity can coincide with asthma also in children, and, although obesity generally skews the Th1/Th2 balance towards Th1, it can also accompany type 2‑driven asthma. However, those combinations represent less precisely defined disease entities. Despite a substantial increase in our knowledge on the mechanisms mediating the effects of obesity on the development of asthma in several recent years, still much needs to be done, especially on the molecular level.
Purpose of review Epigenetic mechanisms are known to play a crucial role in the pathogenesis of asthma, allergic rhinitis, atopic dermatitis, food allergy, and other allergic disorders, especially through mediating the effects of the environmental factors, well recognized allergy-risk modifiers. The aim of this work was to provide a concise but comprehensive review of the recent progress in the epigenetics of allergic diseases. Recent findings Recent few years have substantially expanded our knowledge on the role of epigenetics in the pathogenesis and clinical picture of allergies. Specifically, it has been shown that epigenetic marks, especially DNA methylation, possess a diagnostic potential for atopic sensitization, asthma, allergic rhinitis, and food allergy. DNA methylation can be a predictor of clinical responses in controlled allergen challenges, including oral food challenges. Furthermore, direct or indirect targeting epigenetic mechanisms, this time especially histone modifications, was able to favorably affect expression of the genes underlying allergies and generally improve airway biology in allergic diseases or their animal models. Summary Further studies are needed to explore the diagnostic and therapeutic potential of epigenetic modifications in allergies and to develop respective clinical tools.
Epidemiological studies identified raw cow’s milk consumption as an important environmental exposure that prevents allergic diseases. In the present study, we investigated whether raw cow’s milk has the capacity to induce tolerance to an unrelated, non-milk, food allergen. Histone acetylation of T cell genes was investigated to assess potential epigenetic regulation. Female C3H/HeOuJ mice were sensitized and challenged to ovalbumin. Prior to sensitization, the mice were treated with raw milk, processed milk, or phosphate-buffered saline for eight days. Allergic symptoms were assessed after challenge and histone modifications in T cell-related genes of splenocyte-derived CD4+ T cells and the mesenteric lymph nodes were analyzed after milk exposure and after challenge. Unlike processed milk, raw milk decreased allergic symptoms. After raw milk exposure, histone acetylation of Th1-, Th2-, and regulatory T cell-related genes of splenocyte-derived CD4+ T cells was higher than after processed milk exposure. After allergy induction, this general immune stimulation was resolved and histone acetylation of Th2 genes was lower when compared to processed milk. Raw milk reduces allergic symptoms to an unrelated, non-milk, food allergen in a murine model for food allergy. The activation of T cell-related genes could be responsible for the observed tolerance induction, which suggested that epigenetic modifications contribute to the allergy-protective effect of raw milk.
Effective and specific management of RV infections with Dua-01-L12R9 might be useful in preventing asthma exacerbations, which should be verified by clinical trials.
Extracellular vesicles (EVs) are membranous structures, which are secreted by almost every cell type analyzed so far. In addition to their importance for cell-cell communication under physiological conditions, EVs are also released during pathogenesis and mechanistically contribute to this process. Here we summarize their functional relevance in asthma, one of the most common chronic non-communicable diseases. Asthma is a complex persistent inflammatory disorder of the airways characterized by reversible airflow obstruction and, from a long-term perspective, airway remodeling. Overall, mechanistic studies summarized here indicate the importance of different subtypes of EVs and their variable cargoes in the functioning of the pathways underlying asthma, and show some interesting potential for the development of future therapeutic interventions. Association studies in turn demonstrate a good diagnostic potential of EVs in asthma.
In the era of personalized medicine, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index (BMI; 36.67 ± 6.90); 10 non-obese, non-atopic asthmatic adults with normal BMI (23.88 ± 2.73); and 10 healthy controls with normal BMI (23.62 ± 3.74). All asthmatic patients were considered to represent a low type-2 asthma phenotype according to selective clinical parameters. RNA sequencing (RNA-Seq) was conducted on peripheral blood CD4+ T cells. Thousands of differentially expressed genes were identified in both asthma groups compared with heathy controls. The expression of interferon (IFN)-stimulated genes associated with IFN-related signaling pathways was specifically affected in obese asthmatics, while the gap junction and G protein-coupled receptor (GPCR) ligand binding pathways were enriched in both asthma groups. Furthermore, obesity gene markers were also upregulated in CD4+ T cells from obese asthmatics compared with the two other groups. Additionally, the enriched genes of the three abovementioned pathways showed a unique correlation pattern with various laboratory and clinical parameters. The specific activation of IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in the development of new stratified therapeutic approaches.
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