Th17 Cells, but Not Th1 Cells, From Patients With Early Rheumatoid Arthritis Are Potent Inducers of Matrix Metalloproteinases and Proinflammatory Cytokines Upon Synovial Fibroblast Interaction, Including Autocrine Interleukin-17A Production
Th17 Cells, but Not Th1 Cells, From Patients With Early Rheumatoid Arthritis Are Potent Inducers of Matrix Metalloproteinases and Proinflammatory Cytokines Upon Synovial Fibroblast Interaction, Including Autocrine Interleukin-17A Production
复制标题
DOI：
10.1002/art.30093
复制
发表时间：
2011-01-01
影响因子：
--
通讯作者：
Lubberts, E.
中科院分区：
文献类型：
--
作者：
van Hamburg, J. P.;Asmawidjaja, P. S.;Lubberts, E.
目标。Th1细胞和Th17细胞已在类风湿关节炎（RA）中得到确认；然而，尚不清楚Th1细胞和/或Th17细胞是否参与驱动疾病的慢性和破坏性。本研究的目的是鉴定和表征Th17细胞在早期ra中的功能作用。流式细胞术分析了未接受治疗的早期RA患者和年龄匹配的健康志愿者的外周血单核细胞（PBMCs）。在早期RA患者（RASFs）滑膜成纤维细胞缺失或存在的情况下，对这些患者的PBMCs、幼稚T细胞、CCR6- Th1细胞和CCR6+ Th17细胞进行分类和培养，分析细胞因子表达和基因转录。同时进行肿瘤坏死因子α (TNF α)和白细胞介素17a （IL-17A）阻断实验。在未接受治疗的早期RA患者的pbmc中，观察到il - 17a和产生TNF α的CCR6+ Th17细胞的比例增加。当与rasf共培养时，这些原代Th17细胞是IL-6和IL-8以及组织破坏酶基质金属蛋白酶1 （MMP-1）和MMP-3的有效诱导剂，而原代Th1细胞或幼稚T细胞则不是。重要的是，在RASF/Th17细胞共培养中观察到IL-17A特异性上调，而TNF - α或干扰素- γ没有特异性上调。在RASF/Th17细胞共培养中，除了TNF α阻断外，IL-17A中和还需要进一步下调Th17活性。Th17细胞而非Th1细胞与rasf共同参与促炎反馈回路，揭示了人类Th17细胞驱动RA患者慢性破坏性疾病的潜在机制。此外，IL-17A活性的中和在当前的抗tnf治疗中抑制早期RA患者和潜在的其他Th17细胞介导的疾病的Th17细胞活性是必不可少的。
Objective. Both Th1 cells and Th17 cells have been recognized in rheumatoid arthritis (RA); however, it remains unclear whether Th1 cells and/or Th17 cells are involved in driving disease chronicity and destructiveness. The aim of this study was to identify and characterize the functional role of Th17 cells in early RA.Methods. Flow cytometry analysis was performed on peripheral blood mononuclear cells (PBMCs) from treatment-naive patients with early RA and age-matched healthy volunteers. PBMCs from these patients, naive T cells, and primary CCR6- Th1 cells and CCR6+ Th17 cells were sorted and cultured in the absence or presence of synovial fibroblasts from patients with early RA (RASFs), and cytokine expression and gene transcription were analyzed. In addition, tumor necrosis factor alpha (TNF alpha)-and interleukin-17A (IL-17A)-blocking experiments were performed.Results. In the PBMCs of treatment-naive patients with early RA, an increased fraction of IL-17Aand TNF alpha-producing CCR6+ Th17 cells was observed. When cocultured with RASFs, these primary Th17 cells were potent inducers of IL-6 and IL-8 and the tissue-destructive enzymes matrix metalloproteinase 1 (MMP-1) and MMP-3, whereas primary Th1 cells or naive T cells were not. Importantly, specific up-regulation of IL-17A but not TNF alpha or interferon-gamma was observed in RASF/Th17 cell cocultures. In addition to TNF alpha blocking, IL-17A neutralization was required to further down-regulate Th17 activity in RASF/Th17 cell cocultures.Conclusion. Th17 cells, but not Th1 cells, cooperated with RASFs in a proinflammatory feedback loop, revealing a potential mechanism by which human Th17 cells drive chronic destructive disease in patients with RA. Furthermore, the neutralization of IL-17A activity is essential in current anti-TNF therapies to suppress Th17 cell activity in patients with early RA and potentially other Th17 cell-mediated disorders.