News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2019)

Environmental exposures might promote atopic disease through dysregulation of gene expression by means of epigenetic modifications, including DNA methylation. To assess a potential role of DNA methylation in the pathogenesis of atopy or asthma, Forno et al (Lancet Respir Med 2018; https://doi.org/10.1016/S2213-2600(18)30466-1) generated genome-wide DNA methylome profiles in airway epitheliums of pediatric patients with atopy or atopic asthma. Samples were obtained from the nasal epithelium, a readily available surrogate for the bronchial epithelium. The authors identified more than 8000 differentially methylated CpGs in genes associated with atopy or atopic asthma. These CpG sites were present in loci relevant to multiple disease processes, including epithelial barrier function (CDHR3 and CDH26) and immune regulation (FBXL7, NTRK1, and SLC9A3). Importantly, most of these loci have not been associated with increased risk in genome-wide association studies. A 30-CpG panel was then created that accurately classified children according to the presence of atopy or atopic asthma. Collectively, these results show an important role for epigenetic regulation of the airway epithelium (through DNA methylation) in the pathogenesis of atopic disease and suggest that predictive nasal methylation profiles could be of clinical utility in the future. Image attribution: Figure by user Christoph Bock, Max Planck Institute for Informatics [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)].Important role for epigenetic regulation of the airway epithelium (through DNA methylation) Important role for epigenetic regulation of the airway epithelium (through DNA methylation) We contacted the authors of the study, and last author, Juan C. Celedón, MD, DrPh, of the University of Pittsburgh, Pittsburgh, Pennsylvania, writes, “We identified specific methylation profiles in airway epithelium that are -associated with atopy and atopic asthma in children of Puerto -Rican, African American, and European descent, as well as a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants.” Distinct commensal bacterial populations are present in infants with cow’s milk allergy compared with healthy subjects. To demonstrate a causal relationship, Feehley et al (Nat Med 2019; https://doi.org/10.1038/s41591-018-0324-z) colonized germ-free mice with feces obtained from human infants. Feces derived from healthy donors conferred greater protection against anaphylaxis on exposure to cow’s milk allergen compared with feces obtained from donors with known cow’s milk allergy. Gut microbial composition and gene expression in the ileum were also markedly different between the 2 groups. Correlation studies revealed a potential protective effect of Anaerostipes caccae, which was confirmed because monocolonization of germ-free mice with A caccae indeed protected against anaphylaxis and induced changes in gene expression associated with healthy microbiota. These results highlight the critical role of the gut microbiota in regulating food allergy and support continued study into selective modification of commensal bacterial populations for therapeutic benefit.The critical role of gut microbiota in regulating food allergy The critical role of gut microbiota in regulating food allergy We asked last author, Cathryn Nagler, PhD, of the University of Chicago, Chicago, Illinois, to comment on the study. She writes, “This study allows us to define a causal relationship and shows that the microbiota itself can dictate whether you have an allergic response in this model.” Retinoic acid (RA), a metabolite of dietary vitamin A, exerts diverse effects on immune cell differentiation and function through the action of its receptor, retinoic acid receptor α (RARα). Schwartz et al (Immunity 2019;50:106-20, e10; https://doi.org/10.1016/j.immuni.2018.12.014) dissected the effects of RA on the major TH cell subsets through genome-wide RNA sequencing, with the most dramatic effect being inhibition of the differentiation of TH9 cells. Mechanistic studies revealed that RA antagonized TH9-promoting transcription factors and triggered chromatin remodeling in the Il9 locus, as well in other loci associated with TH9 differentiation. Activation of the RA-RARα axis in vivo limited TH9-induced murine pulmonary immunopathology. This finding is likely generalizable because RA target genes exhibited reduced expression in human allergic tissue samples. In total, these findings further our understanding of the complex immunologic effects of RA by demonstrating repression of TH9 differentiation and amelioration of TH9-mediated -immunopathology.Repression of TH9 differentiation and amelioration of TH9-mediated immunopathology Repression of TH9 differentiation and amelioration of TH9-mediated immunopathology We asked author Daniella Schwartz, MD, of the National Institutes of Health, Bethesda, Maryland, to comment on the study. She writes, “We found that the vitamin A metabolite RA repressed a TH9 transcriptomic program, directly targeting the extended Il9 locus and broadly modifying the TH9 epigenome. Our results suggest that repression of the TH9 program is a major function of RA-RARα signaling in TH differentiation, arguing for a role for RA in IL-9–related diseases.” Differentiation and activation of TH2 cells are very complex, highly regulated processes that remain incompletely understood. To elucidate the underlying regulatory networks, Henriksson et al (Cell 2019; https://doi.org/10.1016/j.cell.2018.11.044) performed a genome-wide analysis using CRISPR, a recently developed gene-silencing technology. The authors assessed the effect of inhibiting expression of each single gene in the genome on the differentiation and activation of primary mouse TH2 cells. Gene-regulatory networks were then derived after incorporating results from additional cutting-edge genomic techniques (RNA sequencing, ATAC sequencing, and ChIP sequencing). TH2 cellular differentiation and activation were identified to be tightly coupled processes with joint control by a diverse array of transcription factors, metabolites, and cytokines. Strikingly, only a very small number of genes that regulated differentiation exhibited no identifiable role in activation. Collectively, the authors have generated an atlas of TH2 differentiation and activation that identifies new regulators and might aid in the future development of TH2-modulating therapeutic agents. Image attribution: National Human Genome Research Institute (NHGRI) from Bethesda, Maryland [CC BY 2.0 (https://creativecommons.org/licenses/by/2.0)] Wikimedia Commons.An atlas of TH2 differentiation and activation An atlas of TH2 differentiation and activation We asked author Sarah A. Teichmann, FMedSci, of the Wellcome Sanger Institute, Cambridge, United Kingdom, to comment on the study. She writes, “We have created an atlas of the most important genes involved in the regulation of TH cell immune response and highlighted particular genes for further study. This openly available resource will help drive forward our understanding of the immune system and could lead to finding new immune-activating therapeutics against tumors and infections or for damping down the immune response to relieve allergies in the future.” (Author photo credit: Wellcome Sanger Institute, GRL.)News items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.