ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2087

Defective Regulation of L1 Endogenous Retroelements in Primary Sjogren’s Syndrome and Systemic Lupus Erythematosus: Role of Methylating Enzymes

Clio Mavragani1, Adrianos Nezos2, Irina Sagalovskiy3, Surya V. Seshan4, Kyriakos A. Kirou5, Haralampos M. Moutsopoulos6 and Mary K. Crow3, 1Department of Physiology, School of Medicine, University of Athens, Athens, Greece, 2Department of Physiology, School of Medicine, University of Athens, Athens, Greece, 3Department of Medicine, Hospital for Special Surgery, New York, NY, 4Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY, 5Hospital for Special Surgery, New York, NY, 6Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Genetics, Genomics and Proteomics

Session Type: Abstract Submissions (ACR)

Background/Purpose: To investigate whether deranged methylating mechanisms are involved in the inappropriate expression of LINE-1 (L1) retroelements in primary Sjogren’s syndrome (SS) and systemic lupus erythematosus (SLE). 

Methods: Minor salivary glands (MSG) were obtained from 35 patients with primary SS [23 without adverse predictors for lymphoma development (SS-low risk) and 12 complicated by B-cell lymphoma (SS-lymphoma)] and 17 sicca controls (SC). Additionally, kidney biopsy specimens and PBMCs were obtained from 23 and 73 lupus patients respectively. Relative mRNA expression was quantified for full-length L1 transcripts, along with mediators of methylation. In an independent set of 22 MSG samples (8 SS-low risk, 11 SS-lymphoma and 3 SC), methylation levels of the L1 promoter were determined by bisulphite pyrosequencing.

Results: A strong positive correlation was demonstrated between L1 transcripts and gene products that mediate de novo and constitutive DNA methylation, DNA methyltransferase (DNMT)3B, DNMT1, and methyl CpG binding protein 2 (MeCP2), in both SS MSG and lupus renal tissues. A significantly negative correlation was observed between expression of L1 and lymphoid-specific helicase (LSH, encoded by HELLS) in both SS MSG and SLE kidney tissues, as well as between DNMT3A transcripts and L1 expression in SLE kidney tissues and PBMCs. Reduced levels of L1 promoter methylation along with increased DNMT3B, DNMT1, and MeCP2, but reduced LSH levels were detected in SS-low risk patients compared to both SS-lymphoma and SC. The SS-lymphoma group was also characterized by a profound decrease of MeCP2 and DNMT3B compared to SC.

Conclusion: Our data support a contributory role of altered methylation mechanisms in the pathogenesis of systemic autoimmune disorders and related lymphoproliferative processes and suggest that LSH and DNMT3A should be investigated as candidate upstream mediators of decreased L1 promoter methylation and increased L1 expression.

Disclosure:

C. Mavragani,
None;

A. Nezos,
None;

I. Sagalovskiy,
None;

S. V. Seshan,
None;

K. A. Kirou,
None;

H. M. Moutsopoulos,
None;

M. K. Crow,
None.

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