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Atopic dermatitis (AD) is an inflammatory skin disorder affecting up to 20% of the paediatric population worldwide. AD patients commonly exhibit dry skin and pruritus and are at a higher risk for developing asthma as well as allergic rhinitis. Filaggrin loss‐of‐function variants are the most widely replicated genetic risk factor among >40 genes associated with AD susceptibility. The prevalence of AD has tripled in the past 30 years in industrial countries around the world. This urgent public health issue has prompted the field to more thoroughly investigate the mechanisms that underlie AD pathogenesis amidst environmental exposures. Epigenetics is the study of heritable, yet reversible, modifications to the genome that affect gene expression. The past decade has seen an emergence of exciting studies identifying a role for epigenetic regulation associated with AD and at the interface of environmental factors. Such epigenetic studies have been empowered by sequencing technologies and human genome variation and epigenome maps. miRNAs that post‐transcriptionally modify gene expression and circRNAs have also been discovered to be associated with AD. Here, we review our current understanding of epigenetics associated with atopic dermatitis. We discuss studies identifying distinct DNA methylation changes in keratinocytes and T cells, eQTLs as DNA methylation switches that impact gene expression, and histone modification changes associated with AD‐related microbial dysbiosis. We further highlight the need for integrative and collaborative analyses to elucidate the impact of these epigenetic findings as potential drivers for AD pathogenesis and the translation of this new knowledge to develop newer targeted treatments. [ABSTRACT FROM AUTHOR]

Abstract: Filaggrin (FLG) loss‐of‐function (LOF) variants are a major risk factor for the common inflammatory skin disease, atopic dermatitis (AD) and are often population‐specific. African‐American (AA) children are disproportionately affected with AD, often later developing asthma and/or allergic rhinitis and comprise an atopy health disparity group for which the role of FLG LOF is not well known. Discovery of FLG LOF using exome sequencing is challenging given the known difficulties for accurate short‐read alignment to FLG's high homology repeat variation. Here, we employed an array‐based sequencing approach to tile across each FLG repeat and discover FLG LOF in a well‐characterized cohort of AA children with moderate‐to‐severe AD. Five FLG LOF were identified in 23% of our cohort. Two novel FLG LOF singletons, c.488delG and p.S3101*, were discovered as well as p.R501*, p.R826* and p.S3316* previously reported for AD. p.S3316* (rs149484917) is likely an African ancestral FLG LOF, reported in African individuals in ExAC (Exome Aggregation Consortium), Exome Variant Server (ESP), and 4 African 1000G population databases (ESN, MSL, ASW, and ACB). The proportion of FLG LOF (11.5%) among the total FLG alleles in our cohort was significantly higher in comparisons with FLG LOF reported for African individuals in ExAC (2.5%; P = 4.3 × 10−4) and ESP (1.7%; P = 3.5 × 10−5) suggesting a disease‐enrichment effect for FLG LOF. Our results demonstrate the utility of array‐based sequencing in discovering FLG LOF, including novel and population‐specific, which are of higher prevalence in our AA severe AD group than previously reported. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17 + –producing cell counts in Asian patients with AD. Objective We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. Methods We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). Results Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD ( P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. T H 2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher T H 17 and T H 22 ( IL17A, IL19 , and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower T H 1/interferon ( CXCL9, CXCL10, MX1 , and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. Conclusion The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher T H 17 activation, and a strong T H 2 component. The relative pathogenic contributions of the T H 17 and T H 2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to TH2/TH22 cytokine activation. However, these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. Objective: We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. Methods: CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. Results: After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of TH2-, TH22-, and some TH17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. Conclusions: This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology. [Copyright &y& Elsevier]

Background: Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an “allergic”/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects. Objective: We sought to define whether both variants share a common pathogenesis. Methods: We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry. Results: A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10−5) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin). Conclusions: Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions. [Copyright &y& Elsevier]

Background: Atopic dermatitis (AD) is a common disease with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in the lack of specific treatments. AD is currently considered a biphasic disease, with TH2 predominating in acute disease and a switch to TH1 characterizing chronic disease. Elucidation of the molecular factors that participate in the onset of new lesions and maintenance of chronic disease is critical for the development of targeted therapeutics. Objectives: We sought to characterize the mechanisms underlying the onset and maintenance of AD. Methods: We investigated intrapersonal sets of transcriptomes from nonlesional skin and acute and chronic lesions of 10 patients with AD through genomic, molecular, and cellular profiling. Results: Our study associated the onset of acute lesions with a striking increase in a subset of terminal differentiation proteins, specifically the cytokine-modulated S100A7, S100A8, and S100A9. Acute disease was also associated with significant increases in gene expression levels of major TH22 and TH2 cytokines and smaller increases in IL-17 levels. A lesser induction of TH1-associated genes was detected in acute disease, although some were significantly upregulated in chronic disease. Further significant intensification of major TH22 and TH2 cytokines was observed between acute and chronic lesions. Conclusions: Our data identified increased S100A7, S100A8, and S100A9 gene expression with AD initiation and concomitant activation of TH2 and TH22 cytokines. Our findings support a model of progressive activation of TH2 and TH22 immune axes from the acute to chronic phases, expanding the prevailing view of pathogenesis with important therapeutic implications. [Copyright &y& Elsevier]

Atopic dermatitis (AD) is a chronic, itchy inflammatory skin disorder associated with multiple genetic risk loci [[1]]. The most widely replicated genetic risk factor for AD is loss-of-function (LoF) variants in the filaggrin gene (FLG; NM 002016.2). FLG sequencing from the Genetics of Atopic Dermatitis cohort identified 15 FLG LoF. [Extracted from the article]