A translational perspective on epigenetics in allergic diseases

doi:10.1016/j.jaci.2018.07.009

Journal of Allergy and Clinical Immunology

Volume 142, Issue 3, September 2018, Pages 715-726

https://doi.org/10.1016/j.jaci.2018.07.009 Get rights and content

Information for Category 1 CME Credit

Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.

Date of Original Release: September 2018. Credit may be obtained for these courses until August 31, 2019.

Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.

Target Audience: Physicians and researchers within the field of allergic disease.

Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

List of Design Committee Members: Jörg Tost, PhD (author); Zuhair K. Ballas, MD (editor)

Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: Work on food allergy in the laboratory of J. Tost is partially funded by DBV Technologies, and J. Tost had conference and travel fees covered by DBV Technologies. The work in the laboratory of J. Tost is further supported by the following grants unrelated to the presented work: ANR (ANR-13-EPIG-0003-05 and ANR-13-CESA-0011-05), Aviesan/INSERM (EPIG2014-01 and EPlG2014-18), INCa (PRT-K14-049), a Sirius research award (UCB Pharma S.A.), a Passerelle research award (Pfizer), iCARE (MSD Avenir), and the institutional budget of the CNRGH. Z. K. Ballas (editor) disclosed no relevant financial relationships.

Activity Objectives:

1.
To understand the concept of epigenetics and the role of epigenetic modifications in shaping the incidence and phenotype of allergic diseases.
2.
To know the cellular and molecular processes involved in modification of the epigenome.
3.
To understand the ways by which the environment, nutrients, and the microbiome can affect the development and course of allergic diseases through alterations in the epigenetic code.

Recognition of Commercial Support: This CME activity has not received external commercial support.

List of CME Exam Authors: Christin Deal, MD, Lisa Kohn, MD, Mona Liu, MD, Monica Tsai, MD, and Maria Garcia-Lloret, MD

Disclosure of Significant Relationships with Relevant Commercial

Companies/Organizations: The exam authors disclosed no relevant financial relationships.

The analysis of epigenetic modifications in allergic diseases has recently attracted substantial interest because epigenetic modifications can mediate the effects of the environment on the development of or protection from allergic diseases. Furthermore, recent research has provided evidence for an altered epigenomic landscape in disease-relevant cell populations. Although still in the early phase, epigenetic modifications, particularly DNA methylation and microRNAs, might have potential for assisting in the stratification of patients for treatment and complement or replace in the future biochemical or clinical tests. The first epigenetic biomarkers correlating with the successful outcome of immunotherapy have been reported, and with personalized treatment options being rolled out, epigenetic modifications might well play a role in monitoring or even predicting the response to tailored therapy. However, further studies in larger cohorts with well-defined phenotypes in specific cell populations need to be performed before their implementation. Furthermore, the epigenome provides an interesting target for therapeutic intervention, with microRNA mimics, inhibitors, and antisense oligonucleotides being evaluated in clinical trials in patients with other diseases. Selection or engineering of populations of extracellular vesicles and epigenetic editing represent novel tools for modulation of the cellular phenotype and responses, although further technological improvements are required. Moreover, interactions between the host epigenome and the microbiome are increasingly recognized, and interventions of the microbiome could contribute to modulation of the epigenome with a potential effect on the overall goal of prevention of allergic diseases.

Section snippets

DNA methylation

A number of epigenome-wide association studies (EWASs) have been performed and have identified, at least in asthmatic patients, common themes, such as the importance of eosinophils and regulatory T (Treg) cells and probably an altered epigenetic state of these cells.9, 10, 11 Large-scale EWASs have also shown that disease-predisposing environmental factors, such as prenatal maternal smoking or prenatal or postnatal air pollution, lead to DNA methylation changes at genes with relevance for

miRNAs and extracellular vesicles

miRNAs constitute an additional level of epigenetic regulation influencing gene expression without altering the genomic sequence. miRNAs are small noncoding RNA molecules (22-25 nucleotides) that posttranscriptionally regulate gene expression by blocking mRNA translation and/or altering the stability of the mRNA by binding perfectly or with mismatches to the 3′ untranslated region of the mRNA (Fig 2).⁸⁷ Each miRNA can potentially directly or indirectly regulate many target genes, and each gene

Conclusions

Investigating epigenetics will further our understanding of the disease mechanisms, and some epigenetic marks might be useful as biomarkers to guide clinical decisions for personalized management of allergic diseases, including the detection, management, and ideally prevention of these diseases. Because most published studies are limited to small exploratory cohorts and therefore had low statistical power, systematic inclusion of the analysis of epigenetic modifications, in particular DNA

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Epigenetics functions as a bridge between host genetic & environmental factors, aiding in human health and diseases. Many immune-related diseases, including infectious and allergic diseases, have been linked to epigenetic mechanisms, particularly DNA methylation. In this review, we summarized an updated overview of DNA methylation and its importance in personalized medicine, and demonstrated that DNA methylation has excellent potential for disease prevention, diagnosis, and treatment in a personalized manner. The future implications and limitations of the DNA methylation study have also been well-discussed.
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Allergic disease is still a serious global public health problem, affecting 30–40% of world population. The rapid increase in prevalence indicates gene-by-environment interaction, in which epigenetics may be the underlying mechanism. We reviewed recent epidemiological studies about the association between prenatal exposure to air pollution and childhood allergies. On the other hand, we reviewed the evidence that maternal exposure to air pollution caused epigenetic alterations that changed the gene expression or transcription in offspring. We further discussed the challenges of the global warming and COVID-19 to the childhood allergies especially in developing countries and suggested the opportunities to prevention or control by early intervention, immunotherapy, and epigenetic therapy.
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CircRNA expression profiles and circRNA-miRNA-mRNA crosstalk in allergic rhinitis
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Citation Excerpt :
Indeed, circRNAs can function as ceRNAs to sponge miRNAs14 and thereby manipulate transcription and alternative splicing,20 cooperate with RNA-binding proteins,21 and affect protein translation.22 CircRNAs can also control the cellular levels of specific miRNAs,23 the majority of which harbor highly conserved sequences and act in multiple cellular processes via post-transcriptional regulation. Thus, disturbed miRNA activity can be partly explained by circRNA involvement.24
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A total of 264 DEcircRNAs were identified by HTS, including 120 upregulated and 144 downregulated in AR compared to controls. A DEcircRNA-DEmiRNA-DEmRNA crosstalk network was constructed with 17 miRNAs, 11 circRNAs, 29 mRNAs, and 64 interaction pairs. These genes were involved in the Wnt signaling pathway, TNF biosynthesis, inflammatory responses, the PI3K-Akt signaling pathway, and Toll-like receptors. Of the 11 DEcircRNAs, hsa_circ_0008668 and circTRIQK were upregulated, whereas hsa_circ_0029853 and circRNA_01002 were downregulated in AR tissues. Sanger sequencing confirmed the back-splicing junctions of these circRNAs.
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Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema.
We sought to identify DNA methylation profiles associated with childhood allergy.
Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses.
We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium.
Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.

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Reviews and feature articleA translational perspective on epigenetics in allergic diseases

Information for Category 1 CME Credit

Section snippets

DNA methylation

miRNAs and extracellular vesicles

Conclusions

J Allergy Clin Immunol

J Allergy Clin Immunol

Cell

Lancet Respir Med

Am J Hum Genet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet Gastroenterol Hepatol

Lancet

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

Cell

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunity

J Allergy Clin Immunol

Chest

Cell

Curr Opin Immunol

J Allergy Clin Immunol

Immunity

Mucosal Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Semin Cell Dev Biol

Food allergy

Nat Rev Dis Primers

Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants

J Allergy Clin Immunol

The economic impact of childhood food allergy in the United States

JAMA Pediatr

Perceptions of epigenetics

Nature

Epigenetics and allergy: from basic mechanisms to clinical applications

Epigenomics

Epigenome-wide association study of asthma and wheeze in childhood and adolescence

Clin Epigenet

Forkhead box protein 3 (FOXP3) hypermethylation is associated with diesel exhaust exposure and risk for childhood asthma

J Allergy Clin Immunol

Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure

Environ Health Perspect

DNA methylation in lung cells is associated with asthma endotypes and genetic risk

JCI Insight

The nasal methylome: a key to understanding allergic asthma

Am J Respir Crit Care Med

Gata3 hypermethylation and Foxp3 hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut-sensitized mice

Allergy

An epigenome-wide association study of total serum immunoglobulin E concentration

Nature

Cow's milk allergy in Dutch children: an epigenetic pilot survey

Clin Transl Allergy

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

Epigenetics

DNA methylation changes separate allergic patients from healthy controls and may reflect altered CD4+ T-cell population structure

PLoS Genet

Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants

J Allergy Clin Immunol

The use of omalizumab in allergen immunotherapy

Clin Exp Allergy

Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care

J Allergy Clin Immunol

Reviews and feature article
A translational perspective on epigenetics in allergic diseases