The contribution of epigenetics in SjÃ¶grenâ€™s Syndrome

Konsta, Orsia D; Thabet, Yosra; Dantec, Christelle Le; Brooks, Wesley H.; Tzioufas, Athanasios G.; Pers, Jacques‐Olivier; Renaudineau, Yves

doi:10.3389/fgene.2014.00071

Cited by 65 publications

(49 citation statements)

References 77 publications

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“…Due to the progressive damage to the exocrine glands, patients with SjS typically present clinically xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes) [3]. Extraglandular manifestations, such as fatigue, arthritis, or Raynaud’s phenomenon are commonly seen in SjS in addition to symptoms of dryness [4].…”

Section: Sjogren’s Syndromementioning

confidence: 99%

Mouse Models of Primary Sjogren’s Syndrome

Park¹,

Gauna²,

Cha

2015

CPD

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Sjögren’s syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS and describe them under three categories of spontaneous, genetically engineered, and experimentally induced development of SjS-like disease. In addition, we discuss future perspectives of SjS mouse models highlighting pros and cons of utilizing mouse models and demands for improved models.

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Section: Sjogren’s Syndromementioning

confidence: 99%

Mouse Models of Primary Sjogren’s Syndrome

Park¹,

Gauna²,

Cha

2015

CPD

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“…11 Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including pSS. 12 Epigenetic modifications constitute an additional layer of genomic regulation, and may serve as a dynamic link between genotype, environment and phenotype, for example by modulating gene expression. Methylation of the DNA base cytosine (5mC) can be studied in large sample sets with array-based methods such as the Illumina HumanMethylation450K array (HM450K), which allows for quantification of DNA methylation of 485 577 CpG sites across the human genome.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

et al. 2016

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ObjectivesIncreasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.MethodsGenome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.ResultsWe identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.ConclusionsOur study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

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“…The fundamental mechanisms and causative pathology remain unclear but likely involve environmental [4], genetic [5, 6, 7] and epigenetic [8, 9] factors, dysregulation of innate and adaptive immunity [5, 10] and epithelial cell defects [11]. In addition to sicca symptoms, autoantibodies to Ro/SS-A and La/SS-B [12, 13] and focal lymphocytic infiltration of the salivary and lacrimal glands are cardinal features of SS [14, 15].…”

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confidence: 99%

Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren’s syndrome

et al. 2017

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Objective Determine the presence and assess the extent of fatty infiltration of the minor salivary glands (SG) of primary SS patients (pSS) as compared to those with non SS sicca (nSS). Methods Minor SG biopsy samples from 134 subjects with pSS (n= 72) or nSS (n = 62) were imaged. Total area and fatty replacement area for each glandular cross-section (n=4–6 cross-sections per subject) were measured using Image J (National Institutes of Health, Bethesda, MD, USA). The observer was blinded to subject classification status. The average area of fatty infiltration calculated per subject was evaluated by logistic regression and general linearized models (GLM) to assess relationships between fatty infiltration and clinical exam results, extent of fibrosis and age. Results The average area of fatty infiltration for subjects with pSS (median% (range) 4.97 (0.05–30.2)) was not significantly different from that of those with nSS (3.75 (0.087–41.9). Infiltration severity varied widely, and subjects with fatty replacement greater than 6% were equivalently distributed between pSS and nSS participants (χ2 p=0.50). Age accounted for all apparent relationships between fatty infiltration and fibrosis or reduced saliva flow. The all-inclusive GLM for prediction of pSS versus non-SS classification including fibrosis, age, fatty replacement and focus score was not significantly different from any desaturated model. In no iteration of the model did fatty replacement exert a significant effect on the capacity to predict pSS classification. Conclusions Fatty infiltration is an age-associated phenomenon and not a selective feature of Sjögren’s syndrome. Sicca patients who do not fulfill pSS criteria have similar rates of fatty infiltration of the minor SG.

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The contribution of epigenetics in SjÃ¶grenâ€™s Syndrome

Cited by 65 publications

References 77 publications

Mouse Models of Primary Sjogren’s Syndrome

Mouse Models of Primary Sjogren’s Syndrome

Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren’s syndrome

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