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DNA methylation represents an important regulatory event governing gene expression that is dysregulated in Sjögren's syndrome (SjS) and a number of autoimmune/inflammatory diseases. As disease-associated single-nucleotide polymorphisms (SNPs) have relevance in controlling DNA methylation, 94 non-HLA SjS-SNPs were investigated, among them 57 (60.6%) with widespread effects on 197 individual DNA methylation quantitative trait loci (meQTL) were selected. Typically, these SNPs are intronic, possess an active promoter histone mark, and control cis-meQTLs located around transcription start sites. Interplay is independent of the physical distance between SNPs and meQTLs. Using epigenome-wide association study datasets, SjS-meQTLs were characterized (41 genes and 13 DNA methylation CpG motifs) and for the most part map to a pro-inflammatory cytokine pathway, which is important for the control of DNA methylation in autoimmune diseases. In conclusion, exploring meQTLs represents a valuable tool to predict and investigate downstream effects of genetic factors in complex diseases such as SjS., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Historically, systemic self-inflammatory conditions were classified as either autoinflammatory and caused by the innate immune system or autoimmune and driven by adaptive immune responses. However, it became clear that reality is much more complex and that autoimmune/inflammatory conditions range along an "inflammatory spectrum" with primarily autoinflammatory vs. autoimmune conditions resembling extremes at either end. Epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. Methylation of CpG DNA dinucleotides and/or their hydroxymethylation, post-translational modifications to amino termini of histone proteins, and non-coding RNA expression are main epigenetic events. The pathophysiology of autoimmune/inflammatory diseases has been closely linked with disease causing gene mutations (rare) or a combination of genetic susceptibility and epigenetic modifications arising from exposure to the environment (more common). Over recent years, progress has been made in understanding molecular mechanisms involved in systemic inflammation and the contribution of innate and adaptive immune responses. Epigenetic events have been identified as (i) central pathophysiological factors in addition to genetic disease predisposition and (ii) as co-factors determining clinical pictures and outcomes in individuals with monogenic disease. Thus, a complete understanding of epigenetic contributors to autoimmune/inflammatory disease will result in approaches to predict individual disease outcomes and the introduction of effective, target-directed, and tolerable therapies. Here, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune/inflammatory disorders along the inflammatory spectrum choosing three examples: the autoinflammatory bone condition chronic nonbacterial osteomyelitis (CNO), the "mixed pattern" disorder psoriasis, and the autoimmune disease systemic lupus erythematosus (SLE).

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease facilitated by aberrant immune responses directed against cells and tissues, resulting in inflammation and organ damage. In the majority of patients, genetic predisposition is accompanied by additional factors conferring disease expression. While the exact molecular mechanisms remain elusive, epigenetic alterations in immune cells have been demonstrated to play a key role in disease pathogenesis through the dysregulation of gene expression. Since epigenetic marks are dynamic, allowing cells and tissues to differentiate and adjust, they can be influenced by environmental factors and also be targeted in therapeutic interventions. Here, we summarize reports on DNA methylation patterns in SLE, underlying molecular defects and their effect on immune cell function. We discuss the potential of DNA methylation as biomarker or therapeutic target in SLE.

The pathogenic origin of autoimmune diseases can be traced to both genetic susceptibility and epigenetic modifications arising from exposure to the environment. Epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. CpG-DNA methylation, histone tail modifications and microRNAs (miRNAs) are the main epigenetic mechanisms of gene regulation. Understanding the molecular mechanisms that are involved in the pathophysiology of autoimmune diseases is essential for the introduction of effective, target-directed and tolerated therapies. In this review, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune disorders while focusing on systemic lupus erythematosus. We also discuss future directions in basic research, autoimmune diagnostics and applied therapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

IL-10 plays a critical role in controlling inflammation and the anti-inflammatory functions of IL-10 are regulated based on its coordinated expression from various cellular sources, most notably T cells. Although nearly all CD4+ subpopulations can express IL-10, surprisingly little is known about the molecular mechanisms which control IL-10 induction, particularly in humans. To examine the regulation of human IL-10 expression, we created the hIL10BAC transgenic mouse. As previously reported, we observed conservation of myeloid-derived IL-10 expression but found that human IL-10 was only weakly expressed in splenic CD4+ T cells from hIL10BAC mice. Since DNA methylation is an important determinant of gene expression profiles, we assessed the patterns of DNA methylation in the human and mouse IL10 genes in naïve and activated CD4+ T cells. Across mouse and human IL10 there were no obvious patterns of CpG methylation in naïve CD4+ T cells following polyclonal activation. Overall however, the human IL10 gene had significantly higher levels of DNA methylation. Interestingly, coculture with the IL-10-inducing cytokine IL-27 lead to a site-specific reduction in methylation of the mouse but not human IL10 gene. Demethylation was specifically localized to an intronic site adjacent to a known regulatory region. Our findings indicate that while the mouse and human IL10 genes undergo variable changes in DNA methylation during CD4+ T cell activation, IL-27 appears to influence DNA methylation in a particular intronic region thus associating with IL-10 expression., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Psoriasis is an autoimmune/inflammatory disorder primarily affecting the skin. Chronic joint inflammation triggers the diagnosis of psoriatic arthritis (PsA) in approximately one-third of psoriasis patients. Although joint disease typically follows the onset of skin psoriasis, in around 15% of cases it is the initial presentation, which can result in diagnostic delays. The pathophysiological mechanisms underlying psoriasis and PsA are not yet fully understood, but there is evidence pointing towards epigenetic dysregulation involving CD4+ and CD8+ T-cells. Objectives: The aim of this study was to investigate disease-associated DNA methylation patterns in CD4+ T-cells from psoriasis and PsA patients that may represent potential diagnostic and/or prognostic biomarkers. Methods: PBMCs were collected from 12 patients with chronic plaque psoriasis and 8 PsA patients, and 8 healthy controls. CD4+ T-cells were separated through FACS sorting, and DNA methylation profiling was performed (Illumina EPIC850K arrays). Bioinformatic analyses, including gene ontology (GO) and KEGG pathway analysis, were performed using R. To identify genes under the control of interferon (IFN), the Interferome database was consulted, and DNA Methylation Scores were calculated. Results: Numbers and proportions of CD4+ T-cell subsets (naïve, central memory, effector memory, CD45RA re-expressing effector memory cells) did not vary between controls, skin psoriasis and PsA patients. 883 differentially methylated positions (DMPs) affecting 548 genes were identified between controls and "all" psoriasis patients. Principal component and partial leastsquares discriminant analysis separated controls from skin psoriasis and PsA patients. GO analysis considering promoter DMPs delivered hypermethylation of genes involved in "regulation of wound healing, spreading of epidermal cells", "negative regulation of cell-substrate junction organization" and "negative regulation of focal adhesion assembly". Comparing controls and "all" psoriasis, a majority of DMPs mapped to IFN-related genes (69.2%). Notably, DNA methylation profiles also distinguished skin psoriasis from PsA patients (2,949 DMPs/1,084 genes) through genes affecting "cAMP-dependent protein kinase inhibitor activity" and "cAMP-dependent protein kinase regulator activity". Treatment with cytokine inhibitors (IL-17/TNF) corrected DNA methylation patterns of IL-17/TNF-associated genes, and methylation scores correlated with skin disease activity scores (PASI). Conclusion: DNA methylation profiles in CD4+ T-cells discriminate between skin psoriasis and PsA. DNA methylation signatures may be applied for quantification of disease activity and patient stratification towards individualized treatment. [ABSTRACT FROM AUTHOR]

Abstract Epigenetic events have been linked with disease expression in individuals genetically predisposed to the development of systemic lupus erythematosus (SLE), a severe systemic autoimmune/inflammatory disease. Altered DNA methylation and hydroxymethylation as well as histone modifications mediate changes in chromatin accessibility and gene expression in immune cells from SLE patients. Defective epigenetic control contributes to uncontrolled expression of inflammatory mediators, including cytokines and co-receptors, resulting in systemic inflammation and tissue damage. While the pathophysiological involvement of epigenetic changes in SLE has been accepted for some time, we only recently started to investigate and understand molecular events contributing to epigenetic dysregulation. Here, epigenetic alterations will be discussed with a focus on underling molecular events that may be target of preventative measures or future treatment strategies. [ABSTRACT FROM AUTHOR]

The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options. [ABSTRACT FROM AUTHOR]

Epigenetic events play a central role in the priming, differentiation and subset determination of T lymphocytes. Through their influence on chromatin conformation and DNA-accessibility to transcription factors and RNA polymerases, epigenetic marks allow or prevent gene expression and control cellular functions including cytokine expression. CpG-DNA methylation and post-translational modifications to histone tails are the two most well accepted epigenetic mechanisms. The involvement of epigenetic mechanisms in the pathogenesis of systemic lupus erythematosus (SLE) has been suggested by the development of lupus-like symptoms by individuals who received procainamide or hydralazine treatment resulting in a reduction of CpG-DNA methylation. To date, a growing body of literature indicates that the deregulation of cytokine expression through epigenetic disturbances can result in altered immune responses and autoimmune reactions. Over the past decade, various global and regional epigenetic alterations have been reported in immune cells from patients with SLE and other autoimmune disorders. More recently, the molecular mechanisms that result in epigenetic disturbances have been addressed, and deregulated transcription factor networks have been demonstrated to mediate epigenetic alterations in B and T lymphocytes from SLE patients. A better understanding of the molecular events that contribute to epigenetic alterations and subsequent immune imbalance is essential for the establishment of disease biomarkers and identification of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract: IL-10 plays a critical role in controlling inflammation and the anti-inflammatory functions of IL-10 are regulated based on its coordinated expression from various cellular sources, most notably T cells. Although nearly all CD4+ subpopulations can express IL-10, surprisingly little is known about the molecular mechanisms which control IL-10 induction, particularly in humans. To examine the regulation of human IL-10 expression, we created the hIL10BAC transgenic mouse. As previously reported, we observed conservation of myeloid-derived IL-10 expression but found that human IL-10 was only weakly expressed in splenic CD4+ T cells from hIL10BAC mice. Since DNA methylation is an important determinant of gene expression profiles, we assessed the patterns of DNA methylation in the human and mouse IL10 genes in naïve and activated CD4+ T cells. Across mouse and human IL10 there were no obvious patterns of CpG methylation in naïve CD4+ T cells following polyclonal activation. Overall however, the human IL10 gene had significantly higher levels of DNA methylation. Interestingly, coculture with the IL-10-inducing cytokine IL-27 lead to a site-specific reduction in methylation of the mouse but not human IL10 gene. Demethylation was specifically localized to an intronic site adjacent to a known regulatory region. Our findings indicate that while the mouse and human IL10 genes undergo variable changes in DNA methylation during CD4+ T cell activation, IL-27 appears to influence DNA methylation in a particular intronic region thus associating with IL-10 expression. [ABSTRACT FROM AUTHOR]

Aicardi-Goutières Syndrome (AGS) is a rare neuro-inflammatory disease characterized by increased expression of interferon-stimulated genes (ISGs). Disease-causing mutations are present in genes associated with innate antiviral responses. Disease presentation and severity vary, even between patients with identical mutations from the same family. This study investigated DNA methylation signatures in PBMCs to understand phenotypic heterogeneity in AGS patients with mutations in RNASEH2B. AGS patients presented hypomethylation of ISGs and differential methylation patterns (DMPs) in genes involved in "neutrophil and platelet activation". Patients with "mild" phenotypes exhibited DMPs in genes involved in "DNA damage and repair", whereas patients with "severe" phenotypes had DMPs in "cell fate commitment" and "organ development" associated genes. DMPs in two ISGs (IFI44L, RSAD2) associated with increased gene expression in patients with "severe" when compared to "mild" phenotypes. In conclusion, altered DNA methylation and ISG expression as biomarkers and potential future treatment targets in AGS. • Aicardi-Goutières Syndrome (AGS) patients with the RNASEH2B p.A177T mutation exhibit variable disease severity. • DNA methylation profiles in PBMCs separate AGS patients and controls, and "severe" from "mild" AGS. • Molecular scores based on type I IFN expression or DNA methylation associate with disease severity. • Findings from this study may inform future molecular patient stratification and individualized care. [ABSTRACT FROM AUTHOR]