Session Title: Sjögren's Syndrome: Basic Science
Session Type: Abstract Submissions (ACR)
Background/Purpose: Primary Sjögren’s syndrome (PSS) is a systemic autoimmune disease characterized by inflammation of the lacrimal and salivary glands and dryness of the eyes and mouth. There is evidence to suggest that PSS shares common pathogenic factors with other autoimmune diseases such as lupus, including common genetic susceptibility loci. Recent evidence strongly supports an epigenetic contribution to the pathogenesis of lupus, however, very little is known about the epigenetics of PSS.
Methods: We performed a genome-wide DNA methylation study in naïve CD4+ T cells in eleven PSS patients before receiving any treatment compared to age-, sex-, and ethnicity-matched healthy controls. Naïve CD4+ T cells were isolated from PBMCs by FACS or indirect labeling and magnetic bead separation. Cell purity was > 95%. DNA was isolated, and treated with sodium bisulfite. Cytosine methylation was quantified in more than 485,000 CpG sites that cover 99% of RefSeq genes, with an average of 17 CpG sites per gene region using the Illumina Infinium HumanMethylation450 BeadChip array. Differentially methylated CpG sites between PSS patients and controls with a fold difference ≥ 1.2 were identified. A false discovery rate (FDR) of 5% was applied to correct for multiple testing and differential methylation was considered statistically significant if the FDR corrected P value was ≤ 0.01.
Results: We identified 553 hypomethylated and 200 hypermethylated CpG sites in naïve CD4+ T cells from PSS patients compared to healthy matched controls, representing 311 hypomethylated and 115 hypermethylated gene regions. Hypomethylated genes in PSS include LTA, coding for Lymphotoxin α, which is involved in LTβ receptor signaling pathway, activation of follicular dendritic cells, and expression of interferon α. Other relevant genes such as GSTM1, CD247, TNFSF25, PTPRC and PDCD1 were also hypomethylated. The interferon signature pathway was represented by hypomethylation of STAT1, IFI44L, and IFITM1. A group of genes encoding for members of the solute carrier proteins, which are membrane transport proteins that are important for maintenance of cell function were hypomethylated (SLC11A1, SLC11A2, SLC22A23, SLC25A25, ALC25A3, SLC25A33, SLC6A20), whereas, SLC9A1, which is important for the maintenance of PH homeostasis was hypermethylated in PSS patients compared to controls. In addition, the transcription factor RUNX1was hypermethylated in patients, suggesting an impact on the differentiation of hematopoietic stem cells, and possible connection to lymphoma predisposition. Gene ontology (GO) analysis of hypomethylated genes demonstrated enrichment of genes involved in lymphocyte activation (P= 1.10E-04), and immune response (P= 2.20E-03). GO terms for hypermethylated genes included antigen processing and presentation (P= 8.00E-06), and positive regulation of RNA metabolic process (P= 2.10E-02).
Conclusion: This is the first epigenome-wide DNA methylation study in PSS. Our data suggest wide-spread DNA methylation changes in naïve CD4+ T cells in PSS, and highlight several genes and pathways that may be involved in the pathogenesis of this disease and that will be the subject for our future investigation.
N. I. Altorok,
P. S. Coit,
K. A. Koelsch,
R. H. Scofield,
K. L. Sivils,
A. D. Farris,
A. H. Sawalha,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-dna-methylation-patterns-in-naive-cd4-t-cells-from-patients-with-primary-sjogrens-syndrome/