title: Epipolymorphisms associated with the clinical outcome of autoimmune arthritis affect CD4+ T cell activation pathways.
abstract: 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.
authors.affiliation: SingHealth Translational Immunology and Inflammation Centre, SingHealth, Singapore 169856; roberto.spreafico@gmail.com.|Duke-National University of Singapore Graduate Medical School, Singapore 169856.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: SingHealth Translational Immunology and Inflammation Centre, SingHealth, Singapore 169856.|Duke-National University of Singapore Graduate Medical School, Singapore 169856.
authors.forename: Maura
authors.initials: M
authors.lastname: Rossetti
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093.
authors.forename: John W
authors.initials: JW
authors.lastname: Whitaker
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lovell
authors.affiliation: SingHealth Translational Immunology and Inflammation Centre, SingHealth, Singapore 169856.|Duke-National University of Singapore Graduate Medical School, Singapore 169856.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Albani
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics* / Q000276:immunology; D044127:Epigenesis, Genetic / Q000235:genetics / Q000276:immunology; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D059467:Transcriptome / Q000235:genetics*
keywords: DNA methylation signature; T-cell activation; arthritis; epigenetics; transcriptomics