P141 Differential DNA methylation in peripheral naÏve CD4+T-cells in early rheumatoid arthritis patients. (March 2019)

• Record Type: Journal Article
• Authors: Pitaksalee, R; Burska, AN; McInnes, I; Emery, P; Hodgett, R; Ponchel, F
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 1
• Page Start: A62
• Page End: A62
• Publication Date: 2019-03
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-EWRR2019.125
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Career situation of first and presenting author: Student for a master or a PhD. Introduction: Alterations in DNA methylation patterns (epimutations) have been related to several diseases, including Rheumatoid Arthritis (RA). We hypothesise that such epimutations occur early in the RA disease process. T-cells are important cells in early pathogenesis, therefore we choose to analyse patterns of differential methylation (DM) of the DNA of CD4+ T cells. Objectives: To identify changes in DNA methylation pattern of naïve CD4 +T cells in early, drug naïve RA patients, towards understanding early events in disease pathogenesis. Methods: DNA methylation of 480, 000 CpGs (Illumina methylation genome-wide array) were analysed in cell sorted, naïve CD4+ T cell from 6 healthy control (HC) and 10 RA patients. To priorities DM gene, we designed a scoring system. 1 We examined potential interactions between DM genes using the STRING-database of protein-protein network analysis. Flow cytometry was used to characterise subpopulations of naïve CD4+ T cells in early RA for 4 DM genes, coding for cell surface molecules. Results: We observed 648 DM-genes in naïve T-cells in early RA (354 hypo and 294 hyper-methylated). STRING analysis of these 648 genes/proteins revealed central of JAK1/STATs signalling, associated with an IL6/IL6R/STAT3 signalling node, a 2nd node for STAT2 linked to downstream interferon signalling, a 3rd node centred on IL2/IL15/STAT5, and many other associations notably related to TNF-alpha and TGF-beta signalling as well as a Th17 cell differentiation axis. Several genes were coding for cell surface proteins, notable CD4, IL2R, IL6R and CD62L. Analysis of CD4 and IL2R confirmed significant increased expression between RA and HC. CD62L identified 2 subpopulations of naïve T-cell in RA the classical naive CD62L+ cells and CD62L- naïve T-cells as previously reported 2 . IL6R expression was reduced in CD62L- naïve CD4+ T cell compared to CD62L+ cells. Conclusions: DNA methylation pattern in naïve CD4+ T cell point to a central role for JAK1/STAT3/IL6 signalling in very early RA pathogenesis, with a pivotal role in diversification towards other pathways (notably TNF, Th17, Th1), which may already contribute to patient heterogeneity at this stage. Our data provides more understanding of early RA pathogenesis and should facilitate novel therapeutic strategies by targeting the right pathways. References: Pitaksalee R, et al . P128 Analysis of DNA methylation patterns in rheumatoid arthritis patient: a system for prioritising meaningful difference. ARD 2018;77:A69. Ponchel F, et al . Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood 2002;100:4550–4556. Disclosure of Interest: None declared.