期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：13845-13850
DOI：10.1073/pnas.1524056113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceJuvenile idiopathic arthritis, a common chronic childhood rheumatic disease, is characterized by joint inflammation and synovial accumulation of activated autoreactive T cells. Although current therapies induce high rates of disease remission, 50-80% patients flare upon treatment withdrawal, thus requiring continued exposure to the safety risks and costs of an immunosuppressive biologic. Unfortunately, at the time of therapy withdrawal, patients who will maintain inactive disease are clinically indistinguishable from those who will not. We identified differences in the DNA methylation status of T-cell activation genes--detectable at a protein level and established at the time of therapy withdrawal--that were specifically associated with clinical outcome, demonstrating the mechanistic and diagnostic relevance of epigenetic features in autoimmune arthritis. Multifactorial diseases, including autoimmune juvenile idiopathic arthritis (JIA), result from a complex interplay between genetics and environment. Epigenetic mechanisms are believed to integrate such gene-environment interactions, fine-tuning gene expression, and possibly contributing to immune system dysregulation. Although anti-TNF therapy has strongly increased JIA remission rates, it is not curative and up to 80% of patients flare upon treatment withdrawal. Thus, a crucial unmet medical and scientific need is to understand the immunological mechanisms associated with remission or flare to inform clinical decisions. Here, we explored the CD4+ T-cell DNA methylome of 68 poly-articular and extended oligo-articular JIA patients, before and after anti-TNF therapy withdrawal, to identify features associated with maintenance of inactive disease. Individual CpG sites were clustered in coherent modules without a priori knowledge of their function through network analysis. The methylation level of several CpG modules, specifically those enriched in CpG sites belonging to genes that mediate T-cell activation, uniquely correlated with clinical activity. Differences in DNA methylation were already detectable at the time of therapy discontinuation, suggesting epigenetic predisposition. RNA profiling also detected differences in T-cell activation markers (including HLA-DR) but, overall, its sensitivity was lower than epigenetic profiling. Changes to the T-cell activation signature at the protein level were detectable by flow cytometry, confirming the biological relevance of the observed alterations in methylation. Our work proposes epigenetic discrimination between clinical activity states, and reveals T-cell-related biological functions tied to, and possibly predicting or causing, clinical outcome.
