title: Defective DNA methylation in salivary gland epithelial acini from patients with Sjögren's syndrome is associated with SSB gene expression, anti-SSB/LA detection, and lymphocyte infiltration.
abstract: The pathogenesis of primary Sjögren's syndrome (pSS) is complex, in part due to DNA methylation abnormalities. This study was undertaken to evaluate the importance of global DNA methylation ((5m)C) as determined in minor salivary glands (MSG) from well characterized pSS patients. Twenty-two pSS patients and ten controls were selected, and MSG were stained with anti-(5m)C, anti-(5m)C/anti-cytokeratin (KRT)19, or with anti-SSB/La antibodies (Ab). The DNA methylation status at the SSB gene promoter P1 and P1' was evaluated by methylation-sensitive restriction enzymes (MSRE) coupled with PCR. The effect of the DNA demethylating drug 5 azacytidine (5-Aza) was tested in the human salivary gland (HSG) cell line. In pSS, the reduction of global DNA methylation ((5m)C) was associated with lymphocyte infiltration, the emergence of (5m)C(low) and KRT19(high) acini, and the detection of circulating anti-SSB/La Ab, but not with disease activity (ESSDAI). Next, treating HSG cells with 5-Aza was effective in inducing SSB expression. Finally in pSS patients positive for anti-SSB/La Ab, we further observed DNA demethylation at the SSB gene promoter P1 with consequent SSB overexpression at both the transcriptional and protein levels in salivary gland epithelial cells. In conclusion, our results highlight the importance of DNA methylation in the pathophysiology of pSS and to the emergence of anti-SSB/La Ab.
authors.affiliation: INSERM ESPRI, ERI29/EA2216, SFR ScInBioS, LabEx IGO "Immunotherapy Graft Oncology", Innovative Medicines Initiative PRECISESADS, Réseau épigénétique et réseau canaux ioniques du Cancéropole Grand Ouest, European University of Brittany, Brest, France; Department of Pathophysiology, School of Medicine, National University of Athens, Greece.
authors.forename: O D
authors.initials: OD
authors.lastname: Konsta
authors.affiliation: INSERM ESPRI, ERI29/EA2216, SFR ScInBioS, LabEx IGO "Immunotherapy Graft Oncology", Innovative Medicines Initiative PRECISESADS, Réseau épigénétique et réseau canaux ioniques du Cancéropole Grand Ouest, European University of Brittany, Brest, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Dantec
authors.affiliation: INSERM ESPRI, ERI29/EA2216, SFR ScInBioS, LabEx IGO "Immunotherapy Graft Oncology", Innovative Medicines Initiative PRECISESADS, Réseau épigénétique et réseau canaux ioniques du Cancéropole Grand Ouest, European University of Brittany, Brest, France.
authors.forename: A
authors.initials: A
authors.lastname: Charras
authors.affiliation: INSERM ESPRI, ERI29/EA2216, SFR ScInBioS, LabEx IGO "Immunotherapy Graft Oncology", Innovative Medicines Initiative PRECISESADS, Réseau épigénétique et réseau canaux ioniques du Cancéropole Grand Ouest, European University of Brittany, Brest, France.
authors.forename: D
authors.initials: D
authors.lastname: Cornec
authors.affiliation: Department of Pathophysiology, School of Medicine, National University of Athens, Greece.
authors.forename: E K
authors.initials: EK
authors.lastname: Kapsogeorgou
authors.affiliation: Department of Pathophysiology, School of Medicine, National University of Athens, Greece.
authors.forename: A G
authors.initials: AG
authors.lastname: Tzioufas
authors.affiliation: INSERM ESPRI, ERI29/EA2216, SFR ScInBioS, LabEx IGO "Immunotherapy Graft Oncology", Innovative Medicines Initiative PRECISESADS, Réseau épigénétique et réseau canaux ioniques du Cancéropole Grand Ouest, European University of Brittany, Brest, France.
authors.forename: J O
authors.initials: JO
authors.lastname: Pers
authors.affiliation: INSERM ESPRI, ERI29/EA2216, SFR ScInBioS, LabEx IGO "Immunotherapy Graft Oncology", Innovative Medicines Initiative PRECISESADS, Réseau épigénétique et réseau canaux ioniques du Cancéropole Grand Ouest, European University of Brittany, Brest, France; Laboratory of Immunology and Immunotherapy, CHU Morvan, Brest, France. Electronic address: yves.renaudineau@univ-brest.fr.
authors.forename: Y
authors.initials: Y
authors.lastname: Renaudineau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001374:Azacitidine / Q000494:pharmacology; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics* / Q000276:immunology*; D012470:Salivary Glands, Minor / Q000276:immunology* / Q000378:metabolism*; D012859:Sjogren's Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
chemical_list: D000974:Antibodies, Antinuclear; C574674:La protein, human; D010750:Phosphoproteins; C035357:SS-B antibodies; D001374:Azacitidine
keywords: Anti-SSB antibodies; DNA demethylation; Lymphocytes; Sjögren's syndrome