Division of Rheumatology and Clinical Immunology, Medizinische Klinik and Poliklinik IV, University of Munich, Munich, Germany.
Division of Rheumatology, Department of Medicine V, University Hospital Mannheim, Mannheim, Germany ∗Jan Leipe and Fausto Pirronello contributed equally to this work.
Rheumatology (Oxford). 2020 Oct 1;59(10):2754-2763. doi: 10.1093/rheumatology/kez660.
The predominance of differentiated Th17 cells has been implied as a key driver of autoimmune arthritis, including early RA. Because accumulating evidence suggests that Th cell differentiation is a plastic process, we investigated plasticity and underlying molecular mechanisms to address the shift towards the Th17 phenotype in early RA.
A cohort of 61 patients with early, active, untreated RA and 45 age- and sex-matched healthy controls were studied. Viable in vitro- and in vivo-generated Th1, Th2 and Th17 cells were FACS-sorted and transdifferentiated under Th1-, Th2- or Th17-inducing conditions. The cytokine Th profile of the transdifferentiated cells was assessed by flow cytometry. Th cell-associated cytokine and transcription factor gene loci were analysed by chromatin immunoprecipitation assay and their expression by quantitative real-time PCR.
In vitro-generated Th cells showed substantial plasticity, which was similar between RA and healthy controls, whereas in vivo-derived Th1 and Th2 cells from RA patients demonstrated an enhanced plasticity towards IL-17-expressing phenotypes compared with healthy controls. Further, in vivo-generated Th17 cells from RA patients showed a resistance to transdifferentiate into Th1 or Th2 cells. The serum/glucocorticoid-regulated kinase 1-forkhead box protein O1-IL-23 receptor (SGK1-FOXO1-IL-23R) axis together with increased RORC expression was associated with the predominant Th17 phenotype in early RA.
Our data indicate that in vivo-originated Th subsets are prone to Th17 cell transdifferentiation in early RA, while Th17 cells are resistant to changes in their phenotype. Together, the data imply that an altered plasticity contributes to the Th17 shift in early RA.
分化型 Th17 细胞的优势被认为是包括早期 RA 在内的自身免疫性关节炎的关键驱动因素。由于越来越多的证据表明 Th 细胞分化是一个可塑性过程，我们研究了可塑性及其潜在的分子机制，以解决早期 RA 中向 Th17 表型的转变。
本研究纳入了 61 例早期、活动期、未经治疗的 RA 患者和 45 名年龄和性别匹配的健康对照者。分离并体外扩增活的 Th1、Th2 和 Th17 细胞，然后在 Th1、Th2 或 Th17 诱导条件下进行转分化。通过流式细胞术评估转分化细胞的细胞因子 Th 谱。通过染色质免疫沉淀测定分析 Th 细胞相关细胞因子和转录因子基因座，并通过定量实时 PCR 分析其表达。
体外生成的 Th 细胞具有明显的可塑性，RA 患者和健康对照者之间的可塑性相似，而 RA 患者体内生成的 Th1 和 Th2 细胞比健康对照者更易向表达 IL-17 的表型发生可塑性变化。此外，RA 患者体内生成的 Th17 细胞对向 Th1 或 Th2 细胞的转分化具有抗性。血清/糖皮质激素调节激酶 1-叉头框蛋白 O1-IL-23 受体 (SGK1-FOXO1-IL-23R) 轴和 RORC 表达增加与早期 RA 中的主要 Th17 表型相关。
我们的数据表明，早期 RA 中体内起源的 Th 亚群易于向 Th17 细胞转分化，而 Th17 细胞对其表型变化具有抗性。综上所述，数据表明改变的可塑性有助于早期 RA 中 Th17 细胞的转移。
