title: Epigenetic dysregulation in salivary glands from patients with primary Sjögren's syndrome may be ascribed to infiltrating B cells.
abstract: Sjögren's syndrome (SS) is an autoimmune exocrinopathy characterized by an epithelium injury with dense lymphocytic infiltrates, mainly composed of activated T and B cells. Present at the interface of genetic and environmental risk factors, DNA methylation is suspected to play a key role in SS. To clarify this point, global DNA methylation was tested within salivary gland epithelial cells (SGEC), peripheral T cells and B cells from SS patients. Global DNA methylation was reduced in SGEC from SS patients, while no difference was observed in T and B cells. SGEC demethylation in SS patients was associated with a 7-fold decrease in DNA methyl transferase (DNMT) 1 and a 2-fold increase in Gadd45-alpha expression. The other DNA methylation/demethylation partners, tested by real time PCR (DNMT3a/b, PCNA, UHRF1, MBD2, and MBD4), were not different. Interestingly, SGEC demethylation may be attributed in part to the infiltrating B cells as suspected in patients treated with anti-CD20 antibodies to deplete B cells. Such hypothesis was confirmed using co-culture experiments with human salivary gland cells and B cells. Furthermore, B cell-mediated DNA demethylation could be ascribed to an alteration of the PKC delta/ERK/DNMT1 pathway. As a consequence, part of the SGEC dysfunction in SS may be linked to epigenetic modifications, thus opening new therapeutic perspectives in SS.
authors.affiliation: Research Unit EA2216 Immunology and Pathology, European University of Brittany, Brest University Medical School Hospital, Brest, France.
authors.forename: Yosra
authors.initials: Y
authors.lastname: Thabet
authors.forename: Christelle
authors.initials: C
authors.lastname: Le Dantec
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Ghedira
authors.forename: Valérie
authors.initials: V
authors.lastname: Devauchelle
authors.forename: Divi
authors.initials: D
authors.lastname: Cornec
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Pers
authors.forename: Yves
authors.initials: Y
authors.lastname: Renaudineau
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D051745:Protein Kinase C-delta / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012469:Salivary Glands / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000097642:GADD45 Proteins
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D018797:Cell Cycle Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D048049:Extracellular Signal-Regulated MAP Kinases; D018799:Intercellular Adhesion Molecule-1; D009687:Nuclear Proteins; D051745:Protein Kinase C-delta; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C573420:ICAM1 protein, human; C000619380:DNMT1 protein, human