脐带来源间充质干细胞对脊柱关节炎患者受累关节局部白介素-23/Th17轴的抑制作用
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摘要
第一部分白介素-23/Th17轴在脊柱关节炎患者受累关节局部的异常表达
背景及目的：白介素-23（IL-23）是IL-12细胞因子家族的一个新的成员，主要由天然免疫细胞分泌。目前有研究报道HLA-B27诱发未折叠蛋白反应，上调IL-23的表达。IL-23与IL-23R结合，促进Th17细胞的产生。IL-23/Th17轴参与多种慢性炎性疾病的发生，如银屑病、炎性肠病等。本研究通过评估IL-23/Th17轴在脊柱关节炎（SpA）患者受累关节局部的表达，验证IL-23/Th17轴在SpA中的致病作用。
方法：（1）选取2012年9月至2013年1月中国人民解放军总医院风湿科门诊接受关节腔穿刺抽液及注射药物治疗的SpA及膝骨关节炎（OA）患者；（2）无菌条件下抽取关节液，以密度梯度离心法分离关节液单个核细胞（SFMCs）；（3）利用流式分选技术分选出CD14~~+单核细胞，在LPS（100ng/ml）刺激下体外培养24h；（4）SFMCs在PHA（1μg/ml）刺激下体外培养72h；（5）细胞内染色及流式细胞仪检测CD14~~+IL-23~~+及CD3~~+CD4~~+IL-17~~+(Th17)细胞比例，采用FlowJo软件分析流式数据；（6）应用SPSS16.0软件进行统计分析。两个样本之间的比较采用Mann-Whitneyu检验或t检验；计数资料的比较采用Fisher确切概率法；相关分析采用Spearman秩相关分析法，以P<0.05为差异有统计学意义。结果：（1）共纳入22例SpA患者，男性19例，女性3例，HLA-B27阳性16例，
阴性6例，年龄20~45（32.4±8.4）岁；病程5~96月，中位数病程27.0（6.8，60.0）月；6例OA患者，男性2例，女性4例，HLA-B27均为阴性，年龄46~67（58.3±7.9）岁；病程18~120月，中位数病程43.0（22.5，75.0）月；（2）SpA患者关节液CD14~~+IL-23~~+细胞比例为1.49%(1.18，1.87)，Th17细胞比例为4.15%(3.15，5.63)，均分别高于OA患者关节液中CD14~~+IL-23~~+细胞比例[0.68%(0.48，1.11)]及Th17细胞比例[1.11%
(0.81，1.69)]，两组比较差异具有统计学意义（P<0.05）；（3）HLA-B27阳性SpA
患者关节液CD14+IL-23+细胞比例为1.60%(1.24，2.11)，HLA-B27阴性SpA患者关
节液中CD14+IL-23+细胞比例为1.26%(0.88，1.59)，两组比较差异无统计学意义（P>0.05）；（4）SpA患者关节液CD14+IL-23+细胞比例与Th17细胞比例呈正相关关系（r=0.67,P<0.01）；但二者与患者的病程、ESR、CRP、BASDAI、BASFI、BASMI及VAS均无相关性。
结论：SpA患者关节液中表达IL-23的单核细胞及Th17细胞较OA患者明显增多，且二者之间存在正相关关系，提示IL-23/Th17轴在SpA中具有致病作用。
第二部分脐带来源间充质干细胞对脊柱关节炎患者受累关节局部白介素-23/Th17轴的体外抑制作用
背景及目的：间充质干细胞（MSCs）是存在于正常人体多种组织中具有多向分化潜力的非造血干细胞，同时具有强大的抗炎及免疫调节作用。近年MSCs已在多种慢性炎性及自身免疫性疾病的治疗中显示了一定的疗效及安全性。SpA是一组以天然免疫反应为驱动的慢性炎性疾病，近年研究显示IL-23/Th17轴在SpA的发病中发挥重要作用。本研究通过观察脐带来源MSCs（UCMSCs）对SpA患者受累关节局部IL-23/Th17轴的抑制作用，为UCMSCs应用于SpA的临床治疗提供理论依据。
方法：（1）选取2012年9月至2013年1月中国人民解放军总医院风湿科门诊接受关节腔穿刺抽液及注射药物治疗的SpA患者；（2）无菌条件下抽取关节液，以密度梯度离心法分离SFMCs；（3）利用流式分选技术将SFMCs分为CD14~+单核细胞和去CD14~+-SFMCs两部分；（4）SFMCs贴壁分选出单核细胞，与UCMSCs在LPS（100ng/ml）刺激下共培养4h，利用流式分选技术分选出CD14~+单核细胞，即CD14~+单核细胞（UCMSCs预处理）；（5）CD14~+单核细胞在LPS（100ng/ml）
刺激下单独培养或与UCMSCs共培养24h，细胞内染色和流式细胞仪检测CD14~+IL-23~+细胞比例，ELISA检测细胞培养上清IL-23的浓度；（6）去CD14~+-SFMCs在PHA（1μg/ml）刺激下单独培养，或分别与CD14~+单核细胞（未处理）或CD14~+单核细胞（UCMSCs预处理）共培养72h，细胞内染色和流式细胞仪检测Th17细胞比例；（7）在CD14~+单核细胞存在或缺席下，去CD14~+-SFMCs单独培养或与UCMSCs共培养72h，细胞内染色和流式细胞仪检测Th17细胞比例；（8）应用SPSS16.0软件进行统计分析；采用Wilcoxonsignedrank检验进行两个配对样本之间的比较，采用Friedman检验进行多个相关样本比较；以P<0.05为差异有统计学意义。
结果：（1）共纳入9例SpA患者，男性7例，女性2例，HLA-B27阳性8例，阴性1例，年龄21~44（31.1±8.3）岁；病程6~96（39.7±31.9）月；（2）SpA患者关节液CD14~+单核细胞体外培养（LPS,100ng/ml）24h，CD14~+IL-23~+细胞比例为1.55%(1.32,2.61)；UCMSCs与CD14~+单核细胞直接接触共培养，CD14~+IL-23~+细胞比例下降至1.06%(0.80,1.81)，两组比较差异具有统计学意义（P<0.05）；CD14~+单核细胞单独培养，上清中IL-23浓度为205.6pg/ml(182.8,256.7)，与UCMSCs共培养，上清中IL-23浓度为121.1pg/ml(111.1,195.0)，两组比较差异具有统计学意义（P<0.01）；（3）去CD14~+-SFMCs在PHA（1μg/ml）刺激下体外培养72h，Th17细胞比例为0.86%(0.22,0.94)；培养体系中加入CD14~+单核细胞（未处理），Th17细胞比例升至2.71%(0.65,3.31)；加入CD14~+单核细胞（UCMSCs预处理），Th17细胞比例2.26%(0.40,2.66)，三组比较差异具有统计学意义（P<0.01）；（4）去CD14~+-SFMCs在PHA（1μg/ml）刺激下单独培养72h，Th17细胞比例为2.71%（1.80,3.05），UCMSCs共培养使Th17细胞比例降至1.59%（1.20,2.67），两组比较差异具有统计学意义（P<0.01）；CD14~+单核细胞（未处理）与去CD14~+-SFMCs混合后培养72h，Th17细胞比例为3.10%（2.81,5.49），UCMSCs共培养使Th17细胞比例降至2.20%(1.52,2.95），两组比较差异具有统计学意义（P<0.01）；在CD14~+单核细胞（未处理）存在下，UCMSCs对Th17的抑制率由18.0%（11.6,32.5）升至40.3%（25.8,51.6），两组比较差异具有统计学意义（P<0.05）。
结论：UCMSCs对SpA患者受累关节局部IL-23/Th17轴具有抑制作用，显示其对SpA患者体内天然免疫应答及获得性免疫应答反应具有平衡及协调作用，在SpA患者的临床治疗中具有一定的应用前景。
PART I Local activation of the interleukin-23/Th17axis in patients with spondyloarthritis
Background and Objective. Interleukin-23(IL-23), a new member of IL-12family, is mainly produced by innate immune cells. It has been shown that HLA-B27misfolding leads to activation of the unfolded protein response, which significantly enhances the expression of IL-23in macrophages. Binding to IL-23receptor, IL-23favors the generation of Th17cells. Growing evidence shows that the IL-23/Th17axis may play an important role in the pathogenesis of several chronic immune-mediated inflammatory diseases, such as psoriasis, inflammatory bowel disease. In order to evaluate the pathogenic role of the IL-23/Th17axis in spondyloarthritis (SpA), we investigated the expression of the IL-23/Th17axis in involved joints of patients with SpA.
Methods. SpA patients and osteoarthritis (OA) patients with knee effusion seen at outpatient clinic of Department of Rheumatology, Chinese PLA General Hospital between September2012and January2013, were recruited in the study. Synovial fluid mononuclear cells (SFMCs) were isolated from all subjects by density gradient centrifugation on Ficoll-paqueTM-Plus. CD14+monocytes were separated from SFMCs by fluorescence activated cell sorting. The frequencies of CD14+IL-23+cells and Th17cells were analyzed by intracellular staining and flow cytometry.
Results.(1) Twenty-two SpA patients (19men and3women) and6knee OA patients (2men and4women) were enrolled in the study. All SpA patients had a mean (SD) age of32.4(8.4) years. The median disease duration of the SpA patients was27.0months ((interquartile range, IQR),6.8to60.0) and all patients'Bath Ankylosing Spondylitis Disease Activity Indices were≥4. OA patients with knee involvement had a mean (SD) age of58.3(7.9) years. Their median disease durations were43.0months (IQR,22.5to75.0). Sixteen out of22SpA patients were positive for HLA-B27, while none of6OA patients was HLA-B27positive.(2) SpA patients had a higher frequency of CD14+IL-23+cells in SF compared with OA patients (median1.49%in SpA patients vs0.68%in OA patients, P<0.05). Frequency of Th17cells from SF of patients with SpA was greater than that from OA patients (median4.15%in SpA patients vs1.11%in OA patients, P<0.05).(3) HLA-B27-positive SpA patients had a higher frequency of CD14+IL-23+cells (1.60%(IQR,1.24to2.11)) compared with HLA-B27-negative SpA patients (1.26%(IQR,0.88to1.59)), although the difference did not reach statistical significance (P>0.05).(4) There was a strong positive association between the frequency of CD14+IL-23+cells and Th17cells in SF of SpA patients.
Conclusions. Our findings indicate that local activation of IL-23/Th17axis exists in SpA, suggesting that IL-23/Th17axis may contribute to the pathogenesis of SpA.
PART Ⅱ Inhibitory effect of umbilical cord-derived mesenchymal stem cells on local interleukin-23/Th17axis in spondyloarthritis patients
Background and Objective. Mesenchymal stem cells (MSCs) are adult multipotent non-hematopoietic stem cells which are now shown to reside in various tissues of normal human body. These cells possess not only multiple differentiation potential, but also potent immunoregulatory and anti-inflammatory properties. Recent studies have shown that MSCs have therapeutic potential in several autoimmune diseases and chronic inflammatory disease. SpA belong to a group of chronic immune-mediated inflammatory diseases. In order to explore the fesibility of MSCs transplantation applied to the treatment for SpA, we evaluated the effect of human umbilical cord-derived MSCs (UCMSCs) on local IL-23/Th17axis, which may play an important role in the pathogenesis of SpA.
Methods. SpA patients with knee effusion seen at outpatient clinic of Department of Rheumatology, Chinese PL A General Hospital between September2012and January2013, were recruited in the study. After isolated from all subjects by density gradient centrifugation on Ficoll-paqueTM-Plus, SFMCs were divided into two subsets:CD14+monocytes and CD14+-depleted SFMCs by fluorescence activated cell sorting. CD14+monocytes or CD14+-depleted SFMCs were cultured in the absence or presence of UCMSCs. Celluar interactions between CD14+monocytes and CD14+-depleted SFMCs were investigated simultaneously. The frequencies of CD14+IL-23+cells and Th17cells were analyzed by intracellular staining and flow cytometry.
Results.(1) Nine SpA patients (7men and2women) were enrolled in the study. All SpA patients had a mean (SD) age of31.1(8.3) years. The mean (SD) disease duration of the SpA patients was39.7(31.9) months and all patients' Bath Ankylosing Spondylitis Disease Activity Indices were≥4.(2) UCMSCs significantly diminished the frequency of CD14+IL-23+cells (absence of UCMSC,1.55%(IQR,1.32,2.61) vs presence of UCMSC,1.06%(IQR,0.80,1.81), P<0.05). Moreover, the concentration of IL-23in cell supernatant of coculture of CD14+monocytes and UCMSCs were significantly lower than that of CD14+monocytes cultured alone (coculture of CD14+monocytes and UCMSCs,121.1pg/ml (IQR,111.1,195.0) vs CD14+monocytes cultured alone,205.6pg/ml (IQR,182.8,256.7), P<0.05).(3) The presence of untreated monocytes significantly increased the frequency of Th17cells in CD14+-depleted SFMCs (absence of monocytes,0.86%(IQR,0.22,0.94) vs presence of untreated monocytes,2.71%(IQR,0.65,3.31), P<0.05). The ability of monocytes to drive Th17cells generation was downregulated by UCMSCs treatment (untreated monocytes, 2.71%(IQR,0.65,3.31) vs UCMSCs-treated monocytes,2.26%(IQR,0.40,2.66), P<0.05).(4) In the absence of monocytes, the frequency of Thl7cells was diminished from2.71%(IQR,1.80,3.05) to1.59%(IQR,1.20,2.67) by the coculture of UCMSCs. In the presence of monocytes, UCMSCs diminished the frequency of Th17cells from3.10%(IQR,2.81,5.49) to2.20%(IQR,1.52,2.95). The inhibitory rate of UCMSCs on Th17cells generation was enhanced from18.0%(IQR,11.6,32.5) to40.3%(IQR,25.8,51.6) by the addition of monocytes (P<0.05).
Conclusion. These results show that monocytes from SF of SpA patients have a enhanced ability to produce IL-23, which may contribute to excessive generation of Th17cells. IL-23/Th17axis that may play an important role in the pathogenesis of SpA, could be inhibited by UCMSCs, which may be applied to the treatment for SpA.
背景及目的：白介素-23（IL-23）是IL-12细胞因子家族的一个新的成员，主要由天然免疫细胞分泌。目前有研究报道HLA-B27诱发未折叠蛋白反应，上调IL-23的表达。IL-23与IL-23R结合，促进Th17细胞的产生。IL-23/Th17轴参与多种慢性炎性疾病的发生，如银屑病、炎性肠病等。本研究通过评估IL-23/Th17轴在脊柱关节炎（SpA）患者受累关节局部的表达，验证IL-23/Th17轴在SpA中的致病作用。
方法：（1）选取2012年9月至2013年1月中国人民解放军总医院风湿科门诊接受关节腔穿刺抽液及注射药物治疗的SpA及膝骨关节炎（OA）患者；（2）无菌条件下抽取关节液，以密度梯度离心法分离关节液单个核细胞（SFMCs）；（3）利用流式分选技术分选出CD14~~+单核细胞，在LPS（100ng/ml）刺激下体外培养24h；（4）SFMCs在PHA（1μg/ml）刺激下体外培养72h；（5）细胞内染色及流式细胞仪检测CD14~~+IL-23~~+及CD3~~+CD4~~+IL-17~~+(Th17)细胞比例，采用FlowJo软件分析流式数据；（6）应用SPSS16.0软件进行统计分析。两个样本之间的比较采用Mann-Whitneyu检验或t检验；计数资料的比较采用Fisher确切概率法；相关分析采用Spearman秩相关分析法，以P<0.05为差异有统计学意义。结果：（1）共纳入22例SpA患者，男性19例，女性3例，HLA-B27阳性16例，
阴性6例，年龄20~45（32.4±8.4）岁；病程5~96月，中位数病程27.0（6.8，60.0）月；6例OA患者，男性2例，女性4例，HLA-B27均为阴性，年龄46~67（58.3±7.9）岁；病程18~120月，中位数病程43.0（22.5，75.0）月；（2）SpA患者关节液CD14~~+IL-23~~+细胞比例为1.49%(1.18，1.87)，Th17细胞比例为4.15%(3.15，5.63)，均分别高于OA患者关节液中CD14~~+IL-23~~+细胞比例[0.68%(0.48，1.11)]及Th17细胞比例[1.11%
(0.81，1.69)]，两组比较差异具有统计学意义（P<0.05）；（3）HLA-B27阳性SpA
患者关节液CD14+IL-23+细胞比例为1.60%(1.24，2.11)，HLA-B27阴性SpA患者关
节液中CD14+IL-23+细胞比例为1.26%(0.88，1.59)，两组比较差异无统计学意义（P>0.05）；（4）SpA患者关节液CD14+IL-23+细胞比例与Th17细胞比例呈正相关关系（r=0.67,P<0.01）；但二者与患者的病程、ESR、CRP、BASDAI、BASFI、BASMI及VAS均无相关性。
结论：SpA患者关节液中表达IL-23的单核细胞及Th17细胞较OA患者明显增多，且二者之间存在正相关关系，提示IL-23/Th17轴在SpA中具有致病作用。
第二部分脐带来源间充质干细胞对脊柱关节炎患者受累关节局部白介素-23/Th17轴的体外抑制作用
背景及目的：间充质干细胞（MSCs）是存在于正常人体多种组织中具有多向分化潜力的非造血干细胞，同时具有强大的抗炎及免疫调节作用。近年MSCs已在多种慢性炎性及自身免疫性疾病的治疗中显示了一定的疗效及安全性。SpA是一组以天然免疫反应为驱动的慢性炎性疾病，近年研究显示IL-23/Th17轴在SpA的发病中发挥重要作用。本研究通过观察脐带来源MSCs（UCMSCs）对SpA患者受累关节局部IL-23/Th17轴的抑制作用，为UCMSCs应用于SpA的临床治疗提供理论依据。
方法：（1）选取2012年9月至2013年1月中国人民解放军总医院风湿科门诊接受关节腔穿刺抽液及注射药物治疗的SpA患者；（2）无菌条件下抽取关节液，以密度梯度离心法分离SFMCs；（3）利用流式分选技术将SFMCs分为CD14~+单核细胞和去CD14~+-SFMCs两部分；（4）SFMCs贴壁分选出单核细胞，与UCMSCs在LPS（100ng/ml）刺激下共培养4h，利用流式分选技术分选出CD14~+单核细胞，即CD14~+单核细胞（UCMSCs预处理）；（5）CD14~+单核细胞在LPS（100ng/ml）
刺激下单独培养或与UCMSCs共培养24h，细胞内染色和流式细胞仪检测CD14~+IL-23~+细胞比例，ELISA检测细胞培养上清IL-23的浓度；（6）去CD14~+-SFMCs在PHA（1μg/ml）刺激下单独培养，或分别与CD14~+单核细胞（未处理）或CD14~+单核细胞（UCMSCs预处理）共培养72h，细胞内染色和流式细胞仪检测Th17细胞比例；（7）在CD14~+单核细胞存在或缺席下，去CD14~+-SFMCs单独培养或与UCMSCs共培养72h，细胞内染色和流式细胞仪检测Th17细胞比例；（8）应用SPSS16.0软件进行统计分析；采用Wilcoxonsignedrank检验进行两个配对样本之间的比较，采用Friedman检验进行多个相关样本比较；以P<0.05为差异有统计学意义。
结果：（1）共纳入9例SpA患者，男性7例，女性2例，HLA-B27阳性8例，阴性1例，年龄21~44（31.1±8.3）岁；病程6~96（39.7±31.9）月；（2）SpA患者关节液CD14~+单核细胞体外培养（LPS,100ng/ml）24h，CD14~+IL-23~+细胞比例为1.55%(1.32,2.61)；UCMSCs与CD14~+单核细胞直接接触共培养，CD14~+IL-23~+细胞比例下降至1.06%(0.80,1.81)，两组比较差异具有统计学意义（P<0.05）；CD14~+单核细胞单独培养，上清中IL-23浓度为205.6pg/ml(182.8,256.7)，与UCMSCs共培养，上清中IL-23浓度为121.1pg/ml(111.1,195.0)，两组比较差异具有统计学意义（P<0.01）；（3）去CD14~+-SFMCs在PHA（1μg/ml）刺激下体外培养72h，Th17细胞比例为0.86%(0.22,0.94)；培养体系中加入CD14~+单核细胞（未处理），Th17细胞比例升至2.71%(0.65,3.31)；加入CD14~+单核细胞（UCMSCs预处理），Th17细胞比例2.26%(0.40,2.66)，三组比较差异具有统计学意义（P<0.01）；（4）去CD14~+-SFMCs在PHA（1μg/ml）刺激下单独培养72h，Th17细胞比例为2.71%（1.80,3.05），UCMSCs共培养使Th17细胞比例降至1.59%（1.20,2.67），两组比较差异具有统计学意义（P<0.01）；CD14~+单核细胞（未处理）与去CD14~+-SFMCs混合后培养72h，Th17细胞比例为3.10%（2.81,5.49），UCMSCs共培养使Th17细胞比例降至2.20%(1.52,2.95），两组比较差异具有统计学意义（P<0.01）；在CD14~+单核细胞（未处理）存在下，UCMSCs对Th17的抑制率由18.0%（11.6,32.5）升至40.3%（25.8,51.6），两组比较差异具有统计学意义（P<0.05）。
结论：UCMSCs对SpA患者受累关节局部IL-23/Th17轴具有抑制作用，显示其对SpA患者体内天然免疫应答及获得性免疫应答反应具有平衡及协调作用，在SpA患者的临床治疗中具有一定的应用前景。
PART I Local activation of the interleukin-23/Th17axis in patients with spondyloarthritis
Background and Objective. Interleukin-23(IL-23), a new member of IL-12family, is mainly produced by innate immune cells. It has been shown that HLA-B27misfolding leads to activation of the unfolded protein response, which significantly enhances the expression of IL-23in macrophages. Binding to IL-23receptor, IL-23favors the generation of Th17cells. Growing evidence shows that the IL-23/Th17axis may play an important role in the pathogenesis of several chronic immune-mediated inflammatory diseases, such as psoriasis, inflammatory bowel disease. In order to evaluate the pathogenic role of the IL-23/Th17axis in spondyloarthritis (SpA), we investigated the expression of the IL-23/Th17axis in involved joints of patients with SpA.
Methods. SpA patients and osteoarthritis (OA) patients with knee effusion seen at outpatient clinic of Department of Rheumatology, Chinese PLA General Hospital between September2012and January2013, were recruited in the study. Synovial fluid mononuclear cells (SFMCs) were isolated from all subjects by density gradient centrifugation on Ficoll-paqueTM-Plus. CD14+monocytes were separated from SFMCs by fluorescence activated cell sorting. The frequencies of CD14+IL-23+cells and Th17cells were analyzed by intracellular staining and flow cytometry.
Results.(1) Twenty-two SpA patients (19men and3women) and6knee OA patients (2men and4women) were enrolled in the study. All SpA patients had a mean (SD) age of32.4(8.4) years. The median disease duration of the SpA patients was27.0months ((interquartile range, IQR),6.8to60.0) and all patients'Bath Ankylosing Spondylitis Disease Activity Indices were≥4. OA patients with knee involvement had a mean (SD) age of58.3(7.9) years. Their median disease durations were43.0months (IQR,22.5to75.0). Sixteen out of22SpA patients were positive for HLA-B27, while none of6OA patients was HLA-B27positive.(2) SpA patients had a higher frequency of CD14+IL-23+cells in SF compared with OA patients (median1.49%in SpA patients vs0.68%in OA patients, P<0.05). Frequency of Th17cells from SF of patients with SpA was greater than that from OA patients (median4.15%in SpA patients vs1.11%in OA patients, P<0.05).(3) HLA-B27-positive SpA patients had a higher frequency of CD14+IL-23+cells (1.60%(IQR,1.24to2.11)) compared with HLA-B27-negative SpA patients (1.26%(IQR,0.88to1.59)), although the difference did not reach statistical significance (P>0.05).(4) There was a strong positive association between the frequency of CD14+IL-23+cells and Th17cells in SF of SpA patients.
Conclusions. Our findings indicate that local activation of IL-23/Th17axis exists in SpA, suggesting that IL-23/Th17axis may contribute to the pathogenesis of SpA.
PART Ⅱ Inhibitory effect of umbilical cord-derived mesenchymal stem cells on local interleukin-23/Th17axis in spondyloarthritis patients
Background and Objective. Mesenchymal stem cells (MSCs) are adult multipotent non-hematopoietic stem cells which are now shown to reside in various tissues of normal human body. These cells possess not only multiple differentiation potential, but also potent immunoregulatory and anti-inflammatory properties. Recent studies have shown that MSCs have therapeutic potential in several autoimmune diseases and chronic inflammatory disease. SpA belong to a group of chronic immune-mediated inflammatory diseases. In order to explore the fesibility of MSCs transplantation applied to the treatment for SpA, we evaluated the effect of human umbilical cord-derived MSCs (UCMSCs) on local IL-23/Th17axis, which may play an important role in the pathogenesis of SpA.
Methods. SpA patients with knee effusion seen at outpatient clinic of Department of Rheumatology, Chinese PL A General Hospital between September2012and January2013, were recruited in the study. After isolated from all subjects by density gradient centrifugation on Ficoll-paqueTM-Plus, SFMCs were divided into two subsets:CD14+monocytes and CD14+-depleted SFMCs by fluorescence activated cell sorting. CD14+monocytes or CD14+-depleted SFMCs were cultured in the absence or presence of UCMSCs. Celluar interactions between CD14+monocytes and CD14+-depleted SFMCs were investigated simultaneously. The frequencies of CD14+IL-23+cells and Th17cells were analyzed by intracellular staining and flow cytometry.
Results.(1) Nine SpA patients (7men and2women) were enrolled in the study. All SpA patients had a mean (SD) age of31.1(8.3) years. The mean (SD) disease duration of the SpA patients was39.7(31.9) months and all patients' Bath Ankylosing Spondylitis Disease Activity Indices were≥4.(2) UCMSCs significantly diminished the frequency of CD14+IL-23+cells (absence of UCMSC,1.55%(IQR,1.32,2.61) vs presence of UCMSC,1.06%(IQR,0.80,1.81), P<0.05). Moreover, the concentration of IL-23in cell supernatant of coculture of CD14+monocytes and UCMSCs were significantly lower than that of CD14+monocytes cultured alone (coculture of CD14+monocytes and UCMSCs,121.1pg/ml (IQR,111.1,195.0) vs CD14+monocytes cultured alone,205.6pg/ml (IQR,182.8,256.7), P<0.05).(3) The presence of untreated monocytes significantly increased the frequency of Th17cells in CD14+-depleted SFMCs (absence of monocytes,0.86%(IQR,0.22,0.94) vs presence of untreated monocytes,2.71%(IQR,0.65,3.31), P<0.05). The ability of monocytes to drive Th17cells generation was downregulated by UCMSCs treatment (untreated monocytes, 2.71%(IQR,0.65,3.31) vs UCMSCs-treated monocytes,2.26%(IQR,0.40,2.66), P<0.05).(4) In the absence of monocytes, the frequency of Thl7cells was diminished from2.71%(IQR,1.80,3.05) to1.59%(IQR,1.20,2.67) by the coculture of UCMSCs. In the presence of monocytes, UCMSCs diminished the frequency of Th17cells from3.10%(IQR,2.81,5.49) to2.20%(IQR,1.52,2.95). The inhibitory rate of UCMSCs on Th17cells generation was enhanced from18.0%(IQR,11.6,32.5) to40.3%(IQR,25.8,51.6) by the addition of monocytes (P<0.05).
Conclusion. These results show that monocytes from SF of SpA patients have a enhanced ability to produce IL-23, which may contribute to excessive generation of Th17cells. IL-23/Th17axis that may play an important role in the pathogenesis of SpA, could be inhibited by UCMSCs, which may be applied to the treatment for SpA.
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