髓系来源抑制细胞在幼年特发性关节炎中的表达水平及临床意义

The levels and clinical significance of myeloid-derived suppressor cell in peripheral blood from juvenile idiopathic arthritis

目的目前髓系来源抑制细胞（MDSC）在幼年特发性关节炎（JIA）中表达水平和功能还未被证实。本研究通过检测JIA外周血中MDSC的表达量，分析其与炎症细胞因子的相关性，为研究JIA中MDSC的生成和功能提供临床依据。方法JIA和对照组外周血中MDSC的表达量，信号转导与转录活化因子3（STAT3）、IL-17A mRNA的表达水平分别用流式细胞术和RT-qPCR检测；血浆中IL-1β、IL-6、IL-10和IL-17A细胞因子通过ELISA法测定，2组间比较和相关性分析分别采用Munn-Wwhntrey检验和Spearman分析法。结果与对照组比较，JIA外周血中MDSC的表达量升高[（6.2±4.2）%与（1.2±1.6）%，Z=-5.258，P〈0.01]，血浆中细胞因子IL-1β[（175±306）pg/ml与（66±29）pg/ml，Z=-2.246，P=0.034]、IL-6[（86.6±257.2）pg/ml与（14.0±2.6）pg/ml，Z=-3.123，P=0.002]、IL-10[（44±36）pg/ml与（24±6）pg/ml，Z=-2.166，P=0.03]，IL-17A[（9.1±17.6）pg/ml与（2.7±0.4）pg/ml，Z=-3.965，P〈0.01）]水平升高，差异具有统计学意义；然而STAT3 mRNA的水平变化差异无统计学意义（P〉0.05）。经Spearman相关性分析显示，JIA中MDSC的数量与疾病活动（DAS28评分、ESR）指标呈正相关（r=0.447，P=0.037；r=0.456，P=0.033）；与STAT3 mRNA的表达水平呈负相关（r=-0.522，P=0.041）；与细胞因子IL-1β、IL-10表达水平呈正相关（r=0.496，P=0.044；r=0.498，P=0.035）；然而与T/B/NK绝对计数和炎症因子IL-6、IL-17A的表达水平无相关性（P〉0.05）。结论JIA中MDSC的数量升高且与疾病严重程度有关，其表达量可作为JIA炎症反应活动的临床指标之一，然而关于其在JIA中的功能需要进一步的研究。

Objective Myeloid-derived suppressor cell （MDSC） have the potential to suppress autoimmune T cell response, while the levels and function of it had not been studied in juvenile idiopathic arthritis （JIA）. Therefore, we used flow cytometry to detect MDSC in peripheral blood of JIA and analyzed its correlation with cytokines, providing clinical basis for the generation and function of MDSCs in JIA.MethodsA total of 34 patients with JIA were included. The disease activity was evaluated by calculating the 28-joint Disease Activity Score （DAS28） based on clinical information. JIA patients were divided into the active disease group and inactive disease group according to the DAS28 score. Twenty healthy controls were recruited from the Health Care Section of our hospital.The frequency of MDSC in peripheral blood from JIA patients and healthy controls were determinedby flow cytometry; enzyme-linked immunosorbent assay （ELISA） was used to detect plasma Interleukin （IL）-1β, IL-6, IL-10 and IL-17A of JIA patients and healthy controls; RT-quantitative polymerase chain reaction （qPCR） was performed to detect the expression levels of signal transducer and activator of transcription 3（STAT3）, IL-17A gene in patients with JIA and control subjects, and Spearman correlation was used to investigate the association between MDSC and DAS28 score, cytokines; non-parametric test and Spearman test were used for two group comparisons and correlation analysis, respectively.ResultsThe frequency of MDSC [（6.2±4.2）% vs （1.2±1.6）%, Z=-5.258, P〈0.01], and the levels of plasma cytokines IL-1β [（175±306） pg/ml vs （66±29） pg/ml, Z=-2.246, P=0.034], IL-6 [（86.6±257.2） pg/ml vs （14.0±2.6） pg/ml, Z=-3.123, P=0.002）, IL-10 [（44±36） pg/ml vs （24±6） pg/ml, Z=-2.166, P=0.03], IL-17A [（9.1±17.6） pg/ml vs （2.7±0.4） pg/ml, Z=-3.965, P〈0.01] incre-ased significantly in JIA patients compared with healthy control group, while STAT3 had no differences （P〉0.05）. The frequency of MDSC correlated positively with DAS28 and erythrocyte sedimentation rate（ESR） disease activity （r=0.447, P=0.037; r=0.456, P=0.033）, IL-1β（r=0.496, P=0.044）, IL-10 （r=0.498, P=0.035）; negatively cor-related with the STAT3 mRNA （r=-0.522, P=0.041）; but not correlated with the IL-6, IL-17A by Spearman＇s test.ConclusionWe have found that the frequency of MDSC in JIA increases and is associated disease activity, closely associated with inflammatory cytokines. The frequency of MDSC can be used as a clinical indicator to reflect inflammatory activity in JIA, However, the current knowledge of MDSC is incomplete and further experiment is required.