OP0054 High-Throughput DNA Methylation Analysis of Cell Sorted Blood Cell Populations Reveals Widespread Epigenetic Deregulation in Sjogren’s Syndrome

ABSTRACTPrimary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overexpression effects, that also exhibit increased variability, in many already known IFN-regulated genes. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of novel genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified new genetic variants associated with SS that mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, DNA methylation, gene expression and SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

Download Full-text

Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren’s syndrome

RMD Open ◽

10.1136/rmdopen-2019-000995 ◽

2020 ◽

Vol 6 (1) ◽

pp. e000995 ◽

Cited By ~ 2

Author(s):

Albin Björk ◽

Elina Richardsdotter Andersson ◽

Juliana Imgenberg-Kreuz ◽

Gudny Ella Thorlacius ◽

Johannes Mofors ◽

...

Keyword(s):

Dna Methylation ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Primary Sjögren’S Syndrome ◽

Primary Sjogren’S Syndrome ◽

Primary Sjögren's Syndrome ◽

System Activity ◽

Sjögren‘S Syndrome

ObjectiveStandard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjögren’s syndrome (pSS).MethodsPatients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq).ResultsmRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62–0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as ‘high’ or ‘low’ IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89–0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001).ConclusionsWe describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.

Download Full-text

The effect of total glucoside of paeony on gut microbiota in NOD mice with Sjögren’s syndrome based on high-throughput sequencing of 16SrRNA gene

Chinese Medicine ◽

10.1186/s13020-020-00342-w ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Wen-Wen Lu ◽

Tian-Xiao Fu ◽

Qing Wang ◽

Yi-Lian Chen ◽

Tian-Yi Li ◽

...

Keyword(s):

Gut Microbiota ◽

Sjögren’S Syndrome ◽

High Throughput ◽

High Throughput Sequencing ◽

Sjögren's Syndrome ◽

Nod Mice ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

16Srrna Gene ◽

Sjögren‘S Syndrome

Download Full-text

The Clinical Relevance of IL-17-Producing CD4+CD161+ Cell and Its Subpopulations in Primary Sjögren’s Syndrome

Journal of Immunology Research ◽

10.1155/2015/307453 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 5

Author(s):

Linbo Li ◽

Jing He ◽

Lei Zhu ◽

Yuqin Yang ◽

Yuebo Jin ◽

...

Keyword(s):

T Cell ◽

Disease Activity ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Primary Sjögren’S Syndrome ◽

Cell Populations ◽

Primary Sjogren’S Syndrome ◽

Primary Sjögren's Syndrome ◽

Sjögren‘S Syndrome

Objective. Th17 cells have been demonstrated to play an important role in the onset and development of primary Sjögren’s syndrome (pSS). In this study, we evaluated the expansion and clinical significance of circulating CD4+CD161+ T cell and its “effector” (CD4+CD25−CD161+ T cell) and “regulatory” (CD4+CD25+CD161+ T cell) subpopulations.Methods. Fifty-eight pSS patients and 16 healthy controls (HCs) were recruited in our study. The cell populations and intracellular IL-17 expression were analyzed by flow cytometry. The disease activity was evaluated by the EULAR-SS Disease Activity Index (ESSDAI). Autoantibodies were measured by ELISA or indirect immunofluorescence assay.Results. The CD161+ T cell fractions showed higher proportions of IL-17-producing cells. The frequencies of the overall CD4+CD161+ T cell population and its effector subset were positively correlated with disease activity parameters and more severe disease manifestations. A significant elevation of the CD4+CD25+CD161+ T cell subpopulation was observed in the peripheral blood of pSS patients compared to HCs and this subset showed decreased regulatory functions compared with the CD4+CD25+CD161− population.Conclusion. Circulating CD4+CD161+ T cell populations associated with pSS disease activity and severity. These cells might be involved in the development of pSS and could be potential therapeutic targets in the treatment of pSS.

Download Full-text

B-cell populations and sub-populations in Sjögren's syndrome

La Presse Médicale ◽

10.1016/j.lpm.2012.05.021 ◽

2012 ◽

Vol 41 (9) ◽

pp. e475-e483 ◽

Cited By ~ 9

Author(s):

Nishath Hamza ◽

Nicolaas A. Bos ◽

Cees G.M. Kallenberg

Keyword(s):

B Cell ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Cell Populations ◽

Sjögren‘S Syndrome

Download Full-text

Hypomethylation mediates genetic association with the major histocompatibility complex genes in Sjögren’s syndrome

PLoS ONE ◽

10.1371/journal.pone.0248429 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0248429

Author(s):

Calvin Chi ◽

Kimberly E. Taylor ◽

Hong Quach ◽

Diana Quach ◽

Lindsey A. Criswell ◽

...

Keyword(s):

Dna Methylation ◽

Major Histocompatibility Complex ◽

Genetic Association ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Major Histocompatibility ◽

Causal Mediation ◽

Histocompatibility Complex ◽

Sjögren‘S Syndrome

Differential methylation of immune genes has been a consistent theme observed in Sjögren’s syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren’s International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.

Download Full-text