Distinct DNA Methylation Patterns of Rheumatoid Arthritis Peripheral Blood and Synovial Tissue T Cells

Abstract

Objective To study epigenetic patterns in T lymphocytes that accumulate in the rheumatoid arthritis (RA) synovium, we characterized DNA methylation of CD3+ T cells in peripheral blood and synovial tissue in patients with RA and osteoarthritis (OA). Methods Genomic DNA of CD3+ T cells was isolated from patients with RA (n = 8) and OA (n = 5) from blood or the synovium at the time of an arthroplasty using antibodies and magnetic beads. Methylation was measured by using the Illumina Infinium MethylationEPIC Kit. Differentially methylated loci (DML) and differentially methylated genes (DMGs) were identified by using Welch’s t‐test. Principal component analysis, hierarchical clustering, and pathway analysis were used to determine relationships among groups. Results When we compared DNA methylation of CD3+ T cells between peripheral blood and synovial tissue within each disease, 4615 and 164 DML were identified in RA and OA samples, respectively, resulting in 832 and 36 DMGs. A principal component analysis showed that methylation differences in T cells were greater on the basis of on location (blood vs synovium) rather than disease (RA vs OA). Differentially modified pathways were significantly enriched between RA blood and synovial T cells, especially in genes related to complement, integrin cell surface interactions, and the P53 pathway. The limited number of DMGs identified between OA blood and synovial T cells did not conform to biologic pathways. Conclusion The patterns of DNA methylation in RA show location‐specific differences related to immune pathways, whereas methylation differences in OA are limited. The RA joint‐specific signatures could be due to selective accumulation of T‐cell populations or expansion of differentially marked adaptive immune cells. Understanding epigenetic patterns could provide clues to the types of T cells that accumulate in the RA joint and identify potential therapeutic targets.

New Targets and Strategies for Rheumatoid Arthritis: From Signal Transduction to Epigenetic Aspect

“…CD4 + T cells of RA patients show hypomethylation, and CD4 + CD8 + T cells have been found to have significantly hypomethylated IFNγ promoters, which can produce higher levels of IFNγ [126,127]. In a recent study, the DNA methylation of T cells in RA patients was significantly different between synovium and blood, which provided a strong support for the discovery of new therapeutic targets by targeting T cells [128]. In general, hypermethylation of gene promoter regions usually prevents transcription factor binding, leading to transcriptional repression.…”

Epigenetic Regulation in the Pathogenesis of Rheumatoid Arthritis

“…To investigate the epigenetic patterns of T lymphocytes in RA synovium, Firestein et al. analyzed the DNA sequence methylation patterns of CD3+ T cells in peripheral blood and synovial tissue from patients with RA and osteoarthritis (OA) ( 22 ). The differential sites of DNA methylation identified for RA and OA in the CD3+ T cells were 4615 and 164, respectively, while differentially methylated genes were 832 and 36, respectively.…”

Multi-omics molecular biomarkers and database of osteoarthritis

“…In addition, in the whole blood, HLA-B*27-dependent, independent DNA methylation changes ( 40 ), leukocyte LINE-1 hypomethylation and oxidative stress in knee OA were detected ( 41 ). In 2021, the distinct DNA methylation patterns of rheumatoid arthritis in peripheral blood T-cells were uncovered ( 42 ).…”