Objective Takayasu’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. Methods We 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. Results Transcriptome 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. Conclusions JAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.

中文翻译：

---

靶向高安动脉炎中的 JAK/STAT 通路

目的 高安动脉炎（TAK）是一种大血管炎，主动脉及其主要分支有重要的促炎性T细胞浸润，但其病因尚不清楚。我们的工作旨在探索 Janus 激酶/信号转导器和转录激活剂 (JAK/STAT) 信号通路在 TAK 的促炎性 T 细胞分化和疾病活动中的参与。方法 我们分析了来自健康供体 (HD) 和 25 个 TAK（中位年龄 37.6 岁，包括 21 个在美国国立卫生研究院的活跃 TAK）中的荧光激活细胞分选（FACS 分选）CD4+ 和 CD8+ T 细胞的转录组和干扰素基因特征（ NIH) 得分 >1)。然后我们在体外和体内测试了 JAK 抑制剂（JAKinibs）对 TAK 的影响。结果 转录组分析显示，HD 和 TAK 之间的 CD4+ 和 CD8+ 样本分别有 248 和 432 个显着失调的基因。在失调的基因中，我们强调了与 I 型和 II 型干扰素、JAK/STAT 和 TAK 中细胞因子/趋化因子相关信号通路相关的通路的大量富集。我们通过实时逆转录聚合酶链反应 (RT-qPCR) 证实了与 HD 相比，TAK 中 I 型干扰素基因特征的上调。JAKinib 在体外和体内均诱导 CD4+ 和 CD8+ T 细胞的 CD25 表达显着降低，1 型辅助 T 细胞 (Th1) 和 Th17 细胞显着减少，TAK 中 Tregs 细胞增加。JAKinibs 还降低了 TAK 患者的 C 反应蛋白水平、NIH 评分和皮质类固醇剂量。