Anderson Amy E, Pratt Arthur G, Sedhom Mamdouh A K, Doran John Paul, Routledge Christine, Hargreaves Ben, Brown Philip M, Lê Cao Kim-Anh, Isaacs John D, Thomas Ranjeny
National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK.
The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia.
Ann Rheum Dis. 2016 Feb;75(2):466-73. doi: 10.1136/annrheumdis-2014-205850. Epub 2015 Feb 3.
A previously identified signal transduction and activator of transcription-3 (STAT3) target-enriched gene signature in circulating CD4+ T cells of patients with early rheumatoid arthritis (RA) was prominent in autoantibody-negative individuals. Here, interleukin (IL)-6-mediated STAT signalling was investigated in circulating lymphocytes of an independent early arthritis patient cohort, seeking further insight into RA pathogenesis and biomarkers of potential clinical utility.
Constitutive and IL-6-induced expression of phosphorylated STAT1 (pSTAT1) and pSTAT3 was determined in T and B cells using Phosflow cytometric analysis in patients with RA and controls. Contemporaneous levels of serum cytokines were measured by immunoassay. Induced gene expression was measured in cultured CD4+T cells by quantitative real-time PCR.
Among circulating lymphocytes of 187 patients with early arthritis, constitutive pSTAT3 correlated with serum IL-6 levels maximally in CD4+ T cells. Increased constitutive pSTAT3, but not pSTAT1, was observed in circulating CD4+ T cells of patients with early anticitrullinated peptide autoantibody (ACPA)-negative RA compared with disease controls, and these levels decreased alongside markers of disease activity with IL-6R-targeted treatment. Among patients presenting with seronegative undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells contributed substantially to an algorithm for predicting progression to classifiable RA during a median of 20 months follow-up (area under receiver operator characteristic curve=0.84; p<0.001).
Our findings support a particular role for IL-6-driven CD4+ T cell activation via STAT3 during the induction of RA, particularly as a feature of ACPA-negative disease. CD4+ T cell pSTAT measurements show promise as biomarkers of UA-RA progression and now require independent validation.
先前在早期类风湿关节炎（RA）患者循环CD4+ T细胞中鉴定出的富含信号转导和转录激活因子3（STAT3）靶点的基因特征，在自身抗体阴性个体中尤为显著。在此，我们对一个独立的早期关节炎患者队列的循环淋巴细胞中白细胞介素（IL）-6介导的STAT信号进行了研究，以进一步深入了解RA的发病机制以及具有潜在临床应用价值的生物标志物。
采用磷酸化流式细胞术分析RA患者和对照组T细胞及B细胞中磷酸化STAT1（pSTAT1）和pSTAT3的组成性及IL-6诱导表达。通过免疫测定法检测同期血清细胞因子水平。采用定量实时PCR检测培养的CD4+ T细胞中的诱导基因表达。
在187例早期关节炎患者的循环淋巴细胞中，组成性pSTAT3在CD4+ T细胞中与血清IL-6水平相关性最强。与疾病对照组相比，早期抗瓜氨酸化肽自身抗体（ACPA）阴性RA患者的循环CD4+ T细胞中组成性pSTAT3升高，而pSTAT1未升高，并且这些水平随着IL-6R靶向治疗后疾病活动标志物的下降而降低。在血清阴性未分化关节炎（UA）患者中，CD4+ T细胞中组成性pSTAT3:pSTAT1的比值在中位20个月的随访期间对预测进展为可分类RA的算法有很大贡献（受试者操作特征曲线下面积=0.84；p<0.001）。
我们的研究结果支持IL-6通过STAT3驱动CD4+ T细胞激活在RA诱导过程中发挥特定作用，尤其是作为ACPA阴性疾病的一个特征。CD4+ T细胞pSTAT测量有望作为UA-RA进展的生物标志物，目前需要独立验证。
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