Genome-Wide DNA Methylation Analysis of CD19+ B Cells in Primary Sjögren’s Syndrome

Gunnel Nordmark¹, Juliana Imgenberg-Kreuz², Jonas Carlsson Almlöf², Jessica Nordlund², Roald Omdal³, Katrine B. Norheim³, Maija-Leena Eloranta⁴, Lars Rönnblom⁴ and Johanna K. Sandling², ¹Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, ²Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, ³Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway, ⁴Department of Medical Sciences, SciLife Lab, Rheumatology, Uppsala University, Uppsala, Sweden, Uppsala, Sweden

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: B cells, Sjogren's syndrome and methylation

Session Information

Title: Sjogren's Syndrome II: Insights into Pathophysiology

Session Type: Abstract Submissions (ACR)

Background/Purpose

Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren’s Syndrome (pSS) (1). A genome-wide DNA methylation study in T cells from patients with pSS and controls identified a large number of differentially methylated genes (2). B cells play an important role in pSS with production of autoantibodies and the potential development of B cell lymphomas. The aim of this study was to investigate DNA methylation profiles in purified CD19+ B cells from patients with pSS and healthy controls.

Methods

Seventeen female patients with pSS, mean age 53.2 years and 28 healthy blood donors, 11 females/17 males, mean age 46.7 years were included. All patients fulfilled the AECG criteria for pSS, 94.1 % were anti-SSA and/or -SSB positive and none of the patients had lymphoma. DNA was prepared from CD19+ B cells positively selected from fresh blood samples. Genome wide DNA methylation profiles were generated on the Illumina HumanMethylation450 BeadChip array. After quality control and normalization, 383 258 CpG sites remained. A threshold of 10% difference between cases and controls in average methylation level per CpG site was applied. Age and sex were included as covariates and a Bonferroni corrected p-value of <1x10^-7was considered significant.

Results

We identified 482 differentially methylated CpG sites, 91 hypomethylated annotated to 63 genes and 391 hypermethylated annotated to 316 genes. Pathway analysis of genes with hypomethylated sites showed over-representation in Interferon signalling genes, and for genes with hypermethylated sites Syndecan-1-mediated signalling events and the EGF receptor signalling pathway. Disease association of genes with differentially methylated sites showed enrichment for genes implicated in cancer, viral infections and B cell and follicular lymphomas. The most distinct difference in average methylation was observed in the interferon-induced gene IFI44L with 31 % decreased methylation in pSS CD19+ B cells compared to control B cells.

Conclusion

Our results demonstrate that DNA methylation is altered in CD19+ B cells from patients with pSS, which underscores the importance of these cells in the pathogenesis of the disease. The significance of genes in the interferon system is highlighted and the enrichment of genes involved in B cell lymphoma is intriguing and warrants further investigation.

References

1. Konsta OD, et al. The contribution of epigenetics in Sjogren’s Syndrome. Frontiers in Genetics 2014; 5: 71.

2.Altorok N, et al. Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjogren’s syndrome. Arthritis & Rheumatology 2014; 66(3): 731-739.

Disclosure:

G. Nordmark,
None;

J. Imgenberg-Kreuz,
None;

J. Carlsson Almlöf,
None;

J. Nordlund,
None;

R. Omdal,
None;

K. B. Norheim,
None;

M. L. Eloranta,
None;

L. Rönnblom,
None;

J. K. Sandling,
None.

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