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FRI0268 Dna demethylation characterizes salivary gland epithelial cells from patients with primary sjögren’s syndrome
  1. D. Cornec1,2,
  2. Y. Thabet2,3,
  3. C. Le Dantec2,
  4. I. Ghedira3,
  5. V. Devauchelle-Pensec1,2,
  6. Y. Renaudineau2,
  7. J.-O. Pers2
  1. 1Rheumatology
  2. 2Immunology EA2216, Brest Teaching Hospital, Brest, France
  3. 3Research Unit 03UR/07-02 “Autoimmunity and Allergy”, Faculty of Pharmacy, Monastir, Tunisia

Abstract

Background Sjögren’s syndrome (SS) is an autoimmune exocrinopathy characterized by an epithelium injury with dense lymphocytic infiltrates composed of activated T and B cells. Present at the interface of genetic and environmental risk factors, epigenetic modifications are suspected to play a key role in SS.

Objectives to characterize DNA methylation in SS.

Methods 5 methyl cytosine (5MeCyt) ELISA tested global DNA methylation within long-term culture salivary gland epithelial cells (SGEC) and peripheral blood T and B cells from eight SS patients. DNA methylation/demethylation partners were tested by real time quantitative PCR (DNMT1, DNMT3a/b, PCNA, UHRF1, MBD2, MBD4, and Gadd45-alpha). Immunofluorescence was conducted on labial salivary gland biopsy. Co-culture experiments were performed using the human salivary gland cell line (HSG) and B cells.

Results Global DNA methylation was reduced in SGEC from SS patients (5MeCyt: 36.3±3.2% in SS versus 43.1±3.3% in controls, P=0.01), while no differences were 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 1.8-fold increase in Gadd45-alpha expression. The other DNA methylation/demethylation partners tested were not different from controls. Interestingly, SGEC demethylation may be attributed in part to the infiltrating B cells as suspected from the analysis of salivary gland biopsy in SS patients treated with rituximab (anti-CD20). Such hypothesis was confirmed using co-culture experiments with HSG cells and B cells revealing an alteration of the ERK/DNMT1 pathway. Finally, several SGEC genes were overexpressed due to DNA methylation changes including ICAM-1 and human endogenous retrovirus (HERV).

Conclusions As a consequence, part of the SGEC dysfunction in SS may be linked to epigenetic modifications and this tissue-specific defect may be ascribed in part to infiltrating B cells, thus opening new therapeutic perspectives in SS.

Disclosure of Interest: None Declared

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