Epigenetic dysregulation in salivary glands from patients with primary Sjögren's syndrome may be ascribed to infiltrating B cells

Yosra Thabet; Christelle Le Dantec; Ibtissem Ghedira; Valérie Devauchelle; Divi Cornec; Jacques-Olivier Pers; Yves Renaudineau

doi:10.1016/j.jaut.2013.02.002

Epigenetic dysregulation in salivary glands from patients with primary Sjögren's syndrome may be ascribed to infiltrating B cells

J Autoimmun. 2013 Mar:41:175-81. doi: 10.1016/j.jaut.2013.02.002. Epub 2013 Mar 7.

Authors

Yosra Thabet¹, Christelle Le Dantec, Ibtissem Ghedira, Valérie Devauchelle, Divi Cornec, Jacques-Olivier Pers, Yves Renaudineau

Affiliation

¹ Research Unit EA2216 Immunology and Pathology, European University of Brittany, Brest University Medical School Hospital, Brest, France.

PMID: 23478041
DOI: 10.1016/j.jaut.2013.02.002

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / pharmacology
Antigens, CD20 / immunology
B-Lymphocytes / drug effects
B-Lymphocytes / immunology*
B-Lymphocytes / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / immunology
Cell Line
Cells, Cultured
Coculture Techniques
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA (Cytosine-5-)-Methyltransferases / immunology
DNA Methylation / immunology
Epigenesis, Genetic / immunology*
Epithelial Cells / immunology
Epithelial Cells / metabolism
Extracellular Signal-Regulated MAP Kinases / immunology
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Expression / immunology
Humans
Intercellular Adhesion Molecule-1 / immunology
Intercellular Adhesion Molecule-1 / metabolism
Microscopy, Fluorescence
Nuclear Proteins / genetics
Nuclear Proteins / immunology
Protein Kinase C-delta / immunology
Protein Kinase C-delta / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Salivary Glands / immunology*
Salivary Glands / metabolism
Salivary Glands / pathology
Signal Transduction / immunology
Sjogren's Syndrome / genetics
Sjogren's Syndrome / immunology*
Sjogren's Syndrome / pathology

Substances

Antibodies, Monoclonal
Antigens, CD20
Cell Cycle Proteins
GADD45A protein, human
ICAM1 protein, human
Nuclear Proteins
Intercellular Adhesion Molecule-1
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNMT1 protein, human
Protein Kinase C-delta
Extracellular Signal-Regulated MAP Kinases