Targeting JAK/STAT pathway in Takayasu’s arteritis

• Published in: Annals of the rheumatic diseases Vol. 79; no. 7; pp. 951 - 959
• Main Authors: Régnier, Paul, Le Joncour, Alexandre, Maciejewski-Duval, Anna, Desbois, Anne-Claire, Comarmond, Cloé, Rosenzwajg, Michelle, Klatzmann, David, Cacoub, Patrice, Saadoun, David
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.07.2020; BMJ Publishing Group
• Subjects: Adult; Aorta; Arteritis; C-reactive protein; CD25 antigen; CD4 antigen; CD8 antigen; Cell differentiation; Chemokines; Coronary vessels; Corticosteroids; Cytokines; Female; Flow cytometry; Gene expression; Helper cells; Humans; Immunomodulators; Inflammation; Interferon; Interferons; Janus kinase; Janus Kinase Inhibitors - pharmacology; Janus Kinases - metabolism; Kinases; Life Sciences; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Male; MAP Kinase Signaling System - genetics; Middle Aged; Patients; Polymerase chain reaction; Reverse transcription; Signal transduction; STAT Transcription Factors - metabolism; Takayasu Arteritis - drug therapy; Takayasu Arteritis - genetics; Th1 Cells; Th17 Cells; Transcription factors; Vasculitis; Vein & artery diseases; systemic vasculitis; cytokines; T cells; chemokines; inflammation
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2019-216900

ObjectiveTakayasu’s arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK.MethodsWe analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK.ResultsTranscriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients.ConclusionsJAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.