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.

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