目的 分析幼年特发性关节炎（juvenile idiopathic arthritis，JIA）活动期及稳定期CD4+NKG2D+ T细胞及NKG2D可溶性配体，即可溶性MHC-Ⅰ类链相关分子A和B（soluble MHC class I chain-related molecules A/B，sMICA/sMICB）表达水平，探讨其在JIA疾病活动中的作用。 方法 前瞻性纳入2019年11月—2021年12月重庆医科大学附属儿童医院确诊的全身型JIA 19例和关节型JIA 20例，6例健康儿童为对照组。收集外周血标本，采用酶联免疫吸附法测定sMICA和sMICB水平，采用流式细胞术检测CD4+NKG2D+ T细胞比例，采用全身型幼年关节炎疾病活动评分-27（systemic Juvenile Arthritis Disease Activity Score，sJADAS-27）/幼年关节炎疾病活动评分-27（Juvenile Arthritis Disease Activity Score-27，JADAS-27）评估JIA患儿的疾病活动性。采用Pearson相关分析法、受试者工作特征曲线分析CD4+NKG2D+ T细胞及sMICA、sMICB在JIA疾病活动中的作用。 结果 全身型JIA活动期组及关节型JIA活动期组CD4+NKG2D+ T细胞比例较对照组及各自稳定期组升高（P<0.05）。JIA各组sMICA和sMICB水平均高于对照组（P<0.05）。关节型JIA活动期组sMICB水平高于关节型JIA稳定期组（P<0.05）。JIA患儿CD4+NKG2D+ T细胞比例及sMICA、sMICB水平与sJADAS-27/JADAS-27评分呈正相关（P<0.05）。sMICB对JIA疾病活动性评估的曲线下面积为0.755，特异度为0.90，灵敏度为0.64。 结论 JIA患儿CD4+NKG2D+ T细胞比例及sMICA、sMICB水平较健康儿童升高，且与疾病活动性呈正相关，提示CD4+NKG2D+ T细胞及NKG2D配体可作为JIA疾病活动性评估的新指标。
Abstract
Objective To study the expression levels of CD4+NKG2D+ T cells and NKG2D soluble ligands, the soluble MHC class I chain-related molecules A and B (sMICA/sMICB) in the active stage and stable stage of juvenile idiopathic arthritis (JIA) and their role in the disease activity of JIA. Methods Nineteen children with systemic JIA and 20 children with articular JIA who were diagnosed in Children's Hospital of Chongqing Medical University from November 2019 to December 2021 were enrolled in this prospective study. Six healthy children were enrolled as the control group. After peripheral blood samples were collected, ELISA was used to measure the levels of sMICA and sMICB, and flow cytometry was used to measure the percentage of CD4+NKG2D+ T cells. Systemic Juvenile Arthritis Disease Activity Score-27 (sJADAS-27)/Juvenile Arthritis Disease Activity Score-27 (JADAS-27) was used to evaluate the disease activity in children with JIA. The Pearson correlation analysis and the receiver operating characteristic (ROC) curve were used to assess the role of CD4+NKG2D+ T cells, sMICA and sMICB in the disease activity of JIA. Results The active systemic JIA and active articular JIA groups had a significant increase in the percentage of CD4+NKG2D+ T cells compared with the control group and their corresponding inactive JIA group (P<0.05). The JIA groups had significantly higher levels of sMICA and sMICB than the control group (P<0.05), and the active articular JIA group had a significantly higher level of sMICB than the stable articular JIA group (P<0.05). In the children with JIA, the percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB were positively correlated with sJADAS-27/JADAS-27 disease activity scores (P<0.05). The ROC curve analysis showed that sMICB had an area under the curve of 0.755 in evaluating the disease activity of JIA, with a specificity of 0.90 and a sensitivity of 0.64. Conclusions The percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB increase in children with JIA compared with healthy children and are positively correlated with the disease activity of JIA, suggesting that CD4+NKG2D+ T cells and NKG2D ligands can be used as potential biomarkers for evaluating the disease activity of JIA.
关键词
幼年特发性关节炎 /
自然杀伤细胞活化性受体2D /
疾病活动性 /
儿童
Key words
Juvenile idiopathic arthritis /
Natural-killer group 2 member D /
Disease activity /
Child
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
1 刘大玮, 梁芳芳, 唐雪梅. 儿童风湿病国际相关诊治指南系列解读之二——幼年特发性关节炎分类标准解读[J]. 中国实用儿科杂志, 2020, 35(4): 252-255. DOI: 10.19538/j.ek2020040602.
2 张利平, 李志刚, 王天有. MICB/NKG2D信号通路在免疫逃逸和癌症治疗中的研究进展[J]. 中国小儿血液与肿瘤杂志, 2020, 25(1): 37-40. DOI: 10.3969/j.issn.1673-5323.2020.01.010.
3 Wensveen FM, Jelen?i? V, Poli? B. NKG2D: a master regulator of immune cell responsiveness[J]. Front Immunol, 2018, 9: 441. PMID: 29568297. PMCID: PMC5852076. DOI: 10.3389/fimmu.2018.00441.
4 曹伟娅, 李存娣, 王健. NKG2D的结构与功能[J]. 中国免疫学杂志, 2019, 35(6): 760-766. DOI: 10.3969/j.issn.1000-484X.2019.06.024.
5 王亚曙, 陶琳琳. 免疫受体NKG2D及其配体介导的细胞免疫与疾病的关系[J]. 国际儿科学杂志, 2019, 46(2): 127-130. DOI: 10.3760/cma.j.issn.1673-4408.2019.02.014.
6 Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001[J]. J Rheumatol, 2004, 31(2): 390-392. PMID: 14760812.
7 Tibaldi J, Pistorio A, Aldera E, et al. Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis[J]. Rheumatology (Oxford), 2020, 59(11): 3505-3514. PMID: 32829413. DOI: 10.1093/rheumatology/keaa240.
8 Hervier B, Ribon M, Tarantino N, et al. Increased concentrations of circulating soluble MHC class I-related chain A (sMICA) and sMICB and modulation of plasma membrane MICA expression: potential mechanisms and correlation with natural killer cell activity in systemic lupus erythematosus[J]. Front Immunol, 2021, 12: 633658. PMID: 34012432. PMCID: PMC8126610. DOI: 10.3389/fimmu.2021.633658.
9 Mariotte A, Bernardi L, Macquin C, et al. NKG2D ligands in inflammatory joint diseases: analysis in human samples and mouse models[J]. Clin Exp Rheumatol, 2021, 39(5): 982-987. PMID: 33427619. DOI: 10.55563/clinexprheumatol/klc3h6.
10 Stojanovic A, Correia MP, Cerwenka A. The NKG2D/NKG2DL axis in the crosstalk between lymphoid and myeloid cells in health and disease[J]. Front Immunol, 2018, 9: 827. PMID: 29740438. PMCID: PMC5924773. DOI: 10.3389/fimmu.2018.00827.
11 Babic M, Romagnani C. The role of natural killer group 2, member D in chronic inflammation and autoimmunity[J]. Front Immunol, 2018, 9: 1219. PMID: 29910814. PMCID: PMC5992374. DOI: 10.3389/fimmu.2018.01219.
12 Yang D, Tian Z, Zhang M, et al. NKG2D+CD4+ T cells kill regulatory T cells in a NKG2D-NKG2D ligand-dependent manner in systemic lupus erythematosus[J]. Sci Rep, 2017, 7(1): 1288. PMID: 28455530. PMCID: PMC5430709. DOI: 10.1038/s41598-017-01379-y.
13 赵文君, 崔爽爽, 邢国胜, 等. 类风湿关节炎滑膜成纤维细胞MICA及其受体NKG2D表达的初步研究[J]. 中国免疫学杂志, 2013, 29(5): 514-517. DOI: 10.3969/j.issn.1000-484X.2013.05.014.
14 Pedicino D, Liuzzo G, Trotta F, et al. Adaptive immunity, inflammation, and cardiovascular complications in type 1 and type 2 diabetes mellitus[J]. J Diabetes Res, 2013, 2013: 184258. PMID: 23762872. PMCID: PMC3676957. DOI: 10.1155/2013/184258.
15 Giubilato S, Liuzzo G, Brugaletta S, et al. Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus[J]. Eur Heart J, 2011, 32(10): 1214-1226. PMID: 21217142. DOI: 10.1093/eurheartj/ehq499.
16 Pariente B, Mocan I, Camus M, et al. Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn's disease[J]. Gastroenterology, 2011, 141(1): 217-226. PMID: 21600899. DOI: 10.1053/j.gastro.2011.03.061.
17 Fasth AE, Bj?rkstr?m NK, Anthoni M, et al. Activating NK-cell receptors co-stimulate CD4+CD28- T cells in patients with rheumatoid arthritis[J]. Eur J Immunol, 2010, 40(2): 378-387. PMID: 19904767. DOI: 10.1002/eji.200939399.
18 Groh V, Bruhl A, El-Gabalawy H, et al. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis[J]. Proc Natl Acad Sci U S A, 2003, 100(16): 9452-9457. PMID: 12878725. PMCID: PMC170939. DOI: 10.1073/pnas.1632807100.
19 Hamada S, Caballero-Benitez A, Duran KL, et al. Soluble MICB in plasma and urine explains population expansions of NKG2D+CD4 T cells inpatients with juvenile-onset systemic lupus erythematosus[J]. Open J Immunol, 2017, 7(1): 1-17. PMID: 28944101. PMCID: PMC5604888. DOI: 10.4236/oji.2017.71001.
20 Dai Z, Turtle CJ, Booth GC, et al. Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus[J]. J Exp Med, 2009, 206(4): 793-805. PMID: 19289577. PMCID: PMC2715116. DOI: 10.1084/jem.20081648.
基金
国家重点研发计划项目（2021YFC2702003）；重庆医科大学未来医学青年创新团队支持计划（W0114）；重庆渝中区科技局科研项目（20210136）。
PDF(581 KB)
