201. Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming
- Author
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Cooles, Faye, Tarn, Jessica, Lendrem, Dennis, Naamane, Najib, Lin, Chung Ma, Millar, Ben, Maney, Nicola, Anderson, Amy, Thalayasingam, Nishanthi, Diboll, Julie, Bondet, Vincent, Duffy, Darragh, Barnes, Michael, Smith, Graham, Ng, Sandra, Watson, David, Henkin, Rafael, Cope, Andrew, Reynard, Louise, Pratt, Arthur, Isaacs, John, Newcastle University [Newcastle], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), William Harvey Research Institute, Barts and the London Medical School, University College of London [London] (UCL), King‘s College London, RA-MAP Consortium: Adwoa Hughes-Morley, Alexandra Walker, Alexandru Cuza, Amaya Gallagher-Syed, Amy Anderson, Andrea Haynes, Andrew Filer, Andrew Long, Andrew P Cope, Angela Parke, Anthony Rowe, Arnaud Didierlaurent, Ashley Gilmour, Athula Herath, Ayako Wakatsuki, Pedersen Aysin, Tulunay Virlan, Ben Allen, Benjamin A Fisher, Blerina Kola, Bohdan Harvey, Brian Tom, Carl S Goodyear, Carolyn Cuff, Catharien Hilkens, Catharina Lindholm, Catherine T Mela, Christopher D Buckley, Chris Larminie, Chris Marshall, Christopher John, Christopher M Mela, Claudio Carini, Costantino Pitzalis, Coziana Ciurtin, Dan Baker, Daniel Ziemek, Daniela Dastros-Pitei, Dao Nguyen, David L Scott, David S Watson, Deborah Symmons, Dennis Lendrem, Denny Verbeeck, Desmond Padhji, Donna Finch, Duncan Porter, Emma Vernon, Faye Cooles, Feng Hong, Fiona Clarke, Fiona Stirling, Fowzia Ibrahim, Frances Humby, Francisco Bonachela Capdevila, Frederic Geissmann, Frederique Ponchel, Gemma Molyneux, Gemma Simpson, Georgina Thorborn, Gerry Parker, Gioia Altobelli, Graham R Smith, Hannah Edwards, Hannah Tipney, Hans-Dieter Zucht, Hayley Noble, Heidi Lempp, Humayara AliIain B McInnes, Ian C Scott, Ian N BruceIona Donnelly, Ivana Vranic, James A Butler, James Galloway, Jamie C Sergeant, Jane Worthington, Jehan El-Jawhari, Jessica Tarn, Joanne Ellis, John Casement, John Isaacs, Julie Diboll, Karim Raza, Katriona Goldmann, Kirsty Hicks, Liliane Fossati-Jimack, Lucy Rowell, Marc Levesque, Mark C Coles, Mark Coles, Mark Curran, Martin Hodge, Martin Jenkins, Mateusz Maciejewski, Matt Page, Matthew A Sleeman, Matthew J Loza, Maya Buch, Meilien Ho, Michael Binks, Michael F McDermott, Michael Macoritto, Michael R Barnes, Michael R Ehrenstein, Michele Bombardieri, Myles Lewis, Neil Gozzard, Neil Payne, Neil Ward, Nina Joseph, Paul Emery, Peter C Taylor, Peter Schulz-Knappe, Petra Budde, Philip Jones, Philip Stocks, Rachel Harry, Rafael Henkin, Ravi Rao, Ray Harris, Rekha Parmar, Ruth Toward, Sally Hollis, Samana Schwank, Samantha Lipsky, Samiul Hasan, Sandra Martins, Sandra Ng, Sarah Brockbank, Sarah Keidel, Scott Jelinsky, Sharmila Rana, Simon Read, Stephen Kelly, Stephen Wright, Steve P Young, Sukru Kaymakcalan, Susan Talbot, Suzanne Mm Verstappen, Tomi Lazarov, Tony Sabin, Valerie Ludbrook, Vernon Farewell, Wayne Tsuji, Wing Wu, Wivine Burny, Yujie Zhong, Zheng Liu, Zhilong Jia, and Vougny, Marie-Christine
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[SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,antirheumatic agents ,Rheumatology ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,inflammation ,[SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology ,immune system diseases ,Immunology ,arthritis, rheumatoid ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
ObjectivesAn interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.MethodsIn a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes.ResultsWe reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (pPARP9, STAT1,andEPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α).ConclusionsOur data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.
- Published
- 2022