Background/Purpose: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by systemic inflammation. Although the understanding of the pathogenesis is incomplete, there is substantial evidence that an increased Th17 cell response plays an important role in the disease onset. Further attempts to understand the RA pathogenesis recently raised interest in elucidating cell specific epigenetic modifications. In the current study we investigated genome-wide DNA methylation patterns in Th1 and Th17 cells from RA patients.

Methods: Early treatment-naive RA patients (n=6) were included into the study. For control gender- and age-matched healthy controls (n=6, HC) were analyzed. CD4 memory T cells were separated from the peripheral blood using magnetic beads. After overnight stimulation with anti-CD3/CD28 sorting of Th1 and Th17 cells was performed by FACS based on cytokine secretion assay for IL-17 and IFNγ. Subsequently, DNA was isolated, bisulfite-converted and amplified. Epigenome-wide association analysis was performed using the Infinium HumanMethylation 450 Bead Chip Kit assessing more than 480,000 CpG positions. Data were normalized using an algorithm in R software and further analyzed based on an established pipeline.

Results: Comparative analysis of methylation status of Th17 cells from RA patients and HC revealed 853 differentially methylated CpGs located mostly in transcription factor encoding genes such as NFATC1 and TBX2 or in genes for cytokines/cytokine receptors such as LTB and IL4R. Comparison of methylation status of Th1 cells from RA patients and HC identified 1209 differentially methylated CpGs. Interestingly, the most prominent differences were found in several Th17-characteristic genes such as CCL20, IL17R, and IL1R or in LTBD1 and NFATC2 genes. Analysis of Th1 and Th17 cell methylation regardless of whether from RA patients or HC yielded 664 differentially methylated CpGs. Remarkably, methylation differences were found in transcription factor encoding genes such as RUNX3 and TBX21, and in chemokine and cytokine genes such as IL17A, CCL1, CCL20, CXCL14, CXCR5 and XCL2.

Conclusion: Thus, the identified differences were primarily localized in genes encoding cytokines/ chemokines or transcription factors indicating that transcriptional programs leading to different soluble mediator profile might contribute to Th17 prone autoimmune reaction in RA. These data might therefore identify epigenetic patterns associated with the unrestricted Th17 response in RA and might delineate an epigenetic mechanism contributing to disease pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-study-of-dna-methylation-in-th1-and-th17-cells-in-rheumatoid-arthritis/