Leipe Jan, Grunke Mathias, Dechant Claudia, Reindl Christiane, Kerzendorf Ulrike, Schulze-Koops Hendrik, Skapenko Alla
Medizinische Poliklinik and University of Munich, Munich, Germany.
Arthritis Rheum. 2010 Oct;62(10):2876-85. doi: 10.1002/art.27622.
To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides.
Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage-specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell-inducing conditions were analyzed in vitro.
The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients.
Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease.
阐明Th17细胞在自身免疫性关节炎发病机制中的作用。
在明确界定的同质性队列中分析Th17细胞，这些队列包括典型的自身免疫性关节炎类风湿关节炎（RA）和银屑病关节炎（PsA）患者，根据疾病持续时间极短的活动性RA患者（n = 36；平均病程2.8个月，28个关节疾病活动评分5.0）和疾病持续时间极短的活动性PsA患者（n = 20；平均病程2.3个月）进行分组，这些患者均未接受过糖皮质激素或改善病情抗风湿药物治疗，以及病情已确诊的RA患者（n = 21；平均病程68个月），这些患者被视为治疗反应者或无反应者。健康个体组和骨关节炎（一种非炎性关节炎）患者组作为对照队列。体外分析T细胞谱系特异性转录因子（RORC、T-bet、GATA-3和FoxP3）的表达以及CD4 T细胞对Th17细胞诱导条件的反应。
在RA或PsA发病和进展过程中，Th17细胞频率和白细胞介素-17水平均与全身疾病活动度密切相关。在疾病活动度得到治疗控制的患者中，这些值降至对照水平。Th17细胞在关节中富集，滑膜Th17细胞频率增加，且表达CCR4和CCR6，表明Th17细胞选择性迁移至关节。RA和PsA患者中RORC的内在表达升高，伴有Th17细胞发育偏向，且Th17细胞对天然细胞因子拮抗剂具有抗性，提示这些患者Th17活性失控的潜在分子机制。
Th17细胞在人类自身免疫性关节炎的炎症过程中，无论是在发病时还是在疾病确立后，均发挥重要作用。
