Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
Ann Rheum Dis. 2024 Jul 15;83(8):1034-1047. doi: 10.1136/ard-2023-224842.
Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated.
Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi.
RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-β, which were normalised by JAKi without cytotoxicity.
SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.
通过 Janus 激酶信号转导和转录激活因子（JAK-STAT）通路传递信号的炎症细胞因子，特别是干扰素（IFN），与干燥综合征（SjD）有关。虽然 JAK 抑制剂（JAKi）在其他自身免疫性疾病中具有抑制作用，但 IFN-JAK-STAT 信号通路的系统研究以及 JAKi 治疗 SjD 受累人体组织的效果尚未得到充分研究。
使用批量或单细胞（sc）RNA 测序（RNAseq）、免疫荧光（IF）显微镜和流式细胞术研究人小唾液腺（MSG）和外周血单核细胞（PBMC）。对 PBMC 和原代唾液腺上皮细胞（pSGEC）系进行体外培养实验，以模拟 JAKi 治疗前后靶组织的变化。
RNAseq 和 IF 显示 SjD MSG 中 JAK-STAT 通路激活。与临床变量（例如焦点评分、抗 SSA 阳性）相关的 IFN 刺激基因（ISG）表达升高。MSG 的 scRNAseq 显示 JAK-STAT 和 ISG 的细胞类型特异性上调；PBMC 也表现出相似的趋势，包括单核细胞中明显上调的 ISG。体外研究显示 SjD MSG 和 PBMC 中存在较高的基础 pSTAT 水平，而 JAKi 可纠正这种情况。源自 SjD 的 pSGEC 表现出更高的基础 ISG 表达和对 IFN-β 的过度反应，而 JAKi 无细胞毒性作用可使其正常化。
SjD 患者的组织表现出依赖于细胞类型的 ISG 表达增加和 JAK-STAT 通路激活。JAKi 可使组织水平和 PBMC 中的这种异常信号正常化，表明针对 SjD 可能具有可行的治疗方法，可同时针对腺体和腺体外症状。基于这些数据，启动了一项用托法替尼治疗 SjD 的 Ib/IIa 期随机对照试验。
