Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis
Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis
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DOI：
10.1136/ard.2006.068320
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发表时间：
2007-09-01
影响因子：
27.4
通讯作者：
Radeke, Heinfried H.
中科院分区：
文献类型：
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作者：
Behrens, Frank;Himsel, Andrea;Radeke, Heinfried H.
目的：调节性T细胞(Tregs)主要通过细胞接触机制发挥抗炎作用。目的：研究类风湿关节炎(RA)患者外周血Tregs与滑膜组织细胞培养物接触后的调节能力，以及其在RA患者外周血、滑膜组织和滑液中的表达情况。用ELISPOT方法对滑膜组织细胞培养、CD3缺失的滑膜组织细胞培养、与自体CD4+和CD4+CD25+外周血T细胞共同培养的滑膜组织细胞中干扰素(IFN)γ分泌细胞的频率进行定量。用实时荧光定量聚合酶链式反应检测CD3e、T-bet和FoxP3基因的表达，免疫组织化学方法检测FoxP3蛋白的表达。结果：RA滑膜组织细胞可自发表达IFNc，这种表达可被CD3+T细胞耗尽所抑制，并可与自体外周血Treg共同培养而特异性减少。免疫组织化学证实，FoxP3基因在RA滑膜组织中的表达证实了Treg在RA滑膜炎中的存在。然而，FoxP3转录本在滑膜中的含量低于外周血或滑液中的含量。T-bet/FoxP3比值与滑膜组织淋巴细胞浸润程度和疾病活动性均呈正相关。结论：本研究首次证实了在人类RA中，自体Tregs能够降低体外培养的滑膜组织细胞的炎症活性，而在RA患者的滑膜中，FoxP3+Tregs的表达水平低于外周血和滑液。Th1和Treg的这种局部失衡可能是反复出现风湿性红斑的原因，因此将成为未来治疗的目标。
Objectives: Regulatory T cells (Tregs) exert their anti-inflammatory activity predominantly by cell contact-dependent mechanisms. A study was undertaken to investigate the regulatory capacity of autologous peripheral blood Tregs in contact with synovial tissue cell cultures, and to evaluate their presence in peripheral blood, synovial tissue and synovial fluid of patients with rheumatoid arthritis ( RA).Methods: 44 patients with RA and 5 with osteoarthritis were included in the study. The frequency of interferon (IFN)gamma-secreting cells was quantified in synovial tissue cell cultures, CD3-depleted synovial tissue cell cultures, synovial tissue cultures co-cultured with autologous CD4+ and with CD4+ CD25+ peripheral blood T cells by ELISPOT. Total CD3+, Th1 polarised and Tregs were quantified by real-time PCR for CD3e, T-bet and FoxP3 mRNA, and by immunohistochemistry for FoxP3 protein.Results: RA synovial tissue cell cultures exhibited spontaneous expression of IFNc which was abrogated by depletion of CD3+ T cells and specifically reduced by co-culture with autologous peripheral blood Treg. The presence of Treg in RA synovitis was indicated by FoxP3 mRNA expression and confirmed by immunohistochemistry. The amount of FoxP3 transcripts, however, was lower in the synovial membrane than in peripheral blood or synovial fluid. The T-bet/FoxP3 ratio correlated with both a higher grade of synovial tissue lymphocyte infiltration and higher disease activity.Conclusion: This study has shown, for the first time in human RA, the efficacy of autologous Tregs in reducing the inflammatory activity of synovial tissue cell cultures ex vivo, while in the synovium FoxP3+ Tregs of patients with RA are reduced compared with peripheral blood and synovial fluid. This local imbalance of Th1 and Treg may be responsible for repeated rheumatic flares and thus will be of interest as a target for future treatments.