Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment
Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment
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DOI：
10.2119/molmed.2015.00057
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发表时间：
2015-01-01
影响因子：
5.7
通讯作者：
Bokarewa, Maria I.
中科院分区：
文献类型：
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作者：
Andersson, Karin M. E.;Cavallini, Nicola Filluelo;Bokarewa, Maria I.
产生白细胞介素（IL）-17 A和IL-17 F细胞因子（Th 17细胞）的T辅助细胞被认为是类风湿关节炎（RA）中自身免疫的来源。在这项研究中，我们的特点是特定的Th 17细胞在类风湿关节炎的致病特点。利用纳米线技术，我们分析了14例RA患者和6名健康对照者外周血CCR 6（+）CXCR 3（-）CD 4（+）细胞中419个基因的转录，并鉴定了109个区分RA患者和对照者Th 17细胞的基因。RA患者的Th 17细胞具有侵袭性致病特征，除了标志性细胞因子IL-17、IL-23和IL-21以及T细胞的转录调节因子RAR相关孤儿受体γ外，（ROR γ t）和Janus激酶2（JAK 2），它们产生高水平的IL-23 R，C-C趋化因子配体20型（CCL 20），粒细胞-单核细胞集落刺激因子（GM-CSF）和转录因子Tbet是滑膜归巢所必需的。我们发现，Th 17细胞富含Helios生产Foxp 3和IL 2 RA缺陷细胞，表明改变的调节谱。滤泡性T辅助细胞（Tfh）呈现出衔接分子、转录调节因子Bcl-6和B细胞活化细胞因子IL-21、IL-31和白血病抑制因子（LIF）的功能谱。我们观察到，抗肿瘤坏死因子（TNF）治疗对Th 17细胞的转录特征的影响有限。缓解期患者保留了受体（IL-23 R和IL-1 R1）、促炎细胞因子（IL-17 F、IL-23、IL-21和TNF）和衔接分子（C-X-C趋化因子受体5 [CXCR 5]和细胞毒性T淋巴细胞相关蛋白4 [CTLA-4]）的机制，这些机制对于Th 17细胞的有效转分化和积累至关重要。这项研究令人信服地表明，RA患者外周血CCR 6（+）CXCR 3（-）CD 4（+）细胞含有Th 17和Tfh细胞的致病性亚群，它们可能从Tfh转分化而来，并有助于疾病的持续存在。
T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (ROR gamma t) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.