儿童原发性免疫性血小板减少症Th17/Treg平衡及其临床意义

The Th17/Treg balance in primary immune thrombocytopenia in children and its clinical significance

摘要

目的 探讨儿童原发性免疫性血小板减少症(ITP)辅助性T细胞(Th17)/调节性T细胞(Treg)平衡及其临床意义。方法 回顾性选取2020年1月至2022年12月本院收治的96例ITP患儿(ITP组)和125例健康儿童(对照组)为研究对象.96例患儿有2例失访,根据预后将剩余94例患儿分为预后良好组(n=74)和预后不良组(n=20).使用流式细胞仪检测外周血Th17和Treg.收集ITP患儿临床资料,并采用多因素Logistic回归模型分析ITP患儿预后的影响因素;采用受试者工作特征(ROC)曲线分析外周血Th17、Treg和Th17/Treg对ITP患儿预后的预测效能。结果 与对照组比较,ITP组Th17、Th17/Treg和白细胞计数(WBC)明显较高(t=8.663、30.730、3.888,P<0.001),而Treg和淋巴细胞计数(ALC)明显较低(t=25.496、16.237,P<0.001).预后不良组Th17、Th17/Treg明显高于预后良好组(t=5.423、11.174,P<0.001),Treg、血小板计数(PLT)和ALC明显低于预后良好组(t=4.059、7.289、5.347,P<0.001),且两组患者年龄存在显著差异(χ²=8.520,P<0.05).多因素Logistic回归分析显示,Th17(OR=1.517,95%CI:1.139~2.020)、Th17/Treg(OR=1.765,95%CI:1.285~2.425)均为ITP患儿预后良好的危险因素(P<0.05),Treg(OR=0.932,95%CI:0.877~0.990)、PLT(OR=0.936,95%CI:0.889~0.985)及ALC(OR=0.819,95%CI:0.700~0.958)为其保护因素(P<0.05).ROC结果显示,Th17、Treg和Th17/Treg单独预测ITP患儿预后的曲线下面积(AUC)分别为0.682(95%CI:0.578~0.775)、0.778(95%CI:0.681~0.857)、0.721(95%CI:0.619~0.809),Th17、Treg和Th17/Treg联合预测ITP患儿预后的敏感度为85.00%、特异度为87.84%,AUC为0.913(95%CI:0.837~0.961),优于Th17(Z=2.481,P=0.013)、Treg(Z=2.549,P=0.011)和Th17/Treg(Z=2.042,P=0.041)单独预测的AUC。结论 儿童原发性免疫性血小板减少症的患儿Th17/Treg比例失衡,联合检测Th17、Treg及Th17/Treg可以提高对患儿预后的预测效能,为临床提供重要的参考依据.

Abstract

Objective To explore the balance of helper T cells (Th17)/regulatory T cells (Treg) in children with primary immune thrombocytopenia (ITP) and its clinical significance. Methods A retrospective study was conducted on 96 children with ITP (ITP group) and 125 healthy children (control group) admitted to our hospital from January 2020 to December 2022. Of the 96 children, 2 cases were lost to follow-up, and the remaining 94 children were divided into good prognosis group (n=74) and poor prognosis group (n=20) according to prognosis. Peripheral blood Th17 and Treg were detected using flow cytometry. Clinical data of ITP patients were collected, and multivariate logistic regression model was applied to analyze the factors affecting the prognosis of ITP patients. The predictive efficacy of peripheral blood Th17, Treg, and Th17/Treg for the prognosis of ITP patients was analyzed using receiver operating characteristic (ROC) curves. Results Compared with the control group, Th17, Th17/Treg and white blood cell count (WBC) in ITP group were significantly higher (t=8.663, 30.730, 3.888, P<0.001), while Treg and lymphocyte count (ALC) were significantly lower (t=25.496, 16.237, P<0.001). Th17 and Th17/Treg in the poor prognosis group were higher than those in the good prognosis group (t=5.423, 11.174, P<0.001), and the Treg, platelet count (PLT) and ALC in the poor prognosis group were significantly lower than those in the good prognosis group (t=4.059, 7.289, 5.347, P<0.001), and there was significant difference in age between the two groups (χ²=8.520, P<0.05). Multivariate Logistic regression analysis showed that Th17 (OR=1.517, 95%CI:1.139-2.020), Th17/Treg (OR=1.765, 95%CI:1.285-2.425) were all risk factors for good prognosis in ITP children (P<0.05), Treg (OR=0.932, 95%CI:0.877-0.990), PLT (OR=0.936, 95%CI:0.889-0.985) and ALC (OR=0.819, 95%CI:0.700-0.958) were protective factors (P<0.05). The results of ROC showed that the area under the curve (AUC) of Th17, Treg, and Th17/Treg in predicting the prognosis of ITP children was 0.682 (95%CI:0.578-0.775), 0.778 (95%CI:0.681-0.857), 0.721 (95%CI:0.619-0.809), respectively. The sensitivity and specificity of the combination of Th17, Treg, and Th17/Treg in predicting the prognosis of ITP children were 85.00%, 87.84%, and AUC was 0.913 (95%CI:0.837-0.961), which was better than the AUC of Th17 (Z=2.481, P=0.013), Treg (Z=2.549, P=0.011) and Th17/Treg (Z=2.042, P=0.041) alone. Conclusion The ratio of Th17/Treg in children with primary immune thrombocytopenia is unbalanced, and the combined detection of Th17, Treg and Th17/Treg can improve the predictive performance of children and provide an important reference for clinical practice.

关键词

儿童 / 原发性免疫性血小板减少症 / 辅助性T细胞 / 调节性T细胞 / 预测

Key words

children / primary immune thrombocytopenia / helper T cells / regulatory T cells / forecast

参考文献

[1] Cooper N, Kruse A, Kruse C, et al. Immune thrombocytopenia (ITP) World Impact Survey (I-WISh): impact of ITP on health-related quality of life[J]. Am J Hematol, 2021, 96(2): 199-207.

[2] 张晴, 李旭, 高长俊, 等. 血小板膜糖蛋白特异性抗体在ITP患儿中的表达及其与疗效、出血程度的关系分析[J]. 中国妇幼健康研究, 2023, 34(9): 13-18.

[3] Van Dijk W E M, Punt M C, van Galen K P M, et al. Menstrual problems in chronic immune thrombocytopenia: a monthly challenge-a cohort study and review[J]. Br J Haematol, 2022, 198(4): 753-764.

[4] Vianelli N, Auteri G, Buccisano F, et al. Refractory primary immune thrombocytopenia (ITP): current clinical challenges and therapeutic perspectives[J]. Ann Hematol, 2022, 101(5): 963-978.

[5] 胡晓燕, 贺锐, 米乐园, 等. MicroRNA-3162-3p在儿童原发性免疫性血小板减少症不同临床分期中的表达及其意义[J]. 中国实验血液学杂志, 2024, 32(1): 208-213.

[6] Liu X, Zhou M, Dai Z, et al. Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis-associated Th17/Treg imbalance[J]. Phytother Res, 2023, 37(2): 367-382.

[7] Ma M, Wang M, Xu F, et al. The imbalance in Th17 and Treg cells in polycystic ovarian syndrome patients with autoimmune thyroiditis[J]. Immunol Invest, 2022, 51(5): 1170-1181.

[8] Gu H, Chen Z, Shi X, et al. Increased proportion of Th17/Treg cells at the new diagnosed stage of chronic immune thrombocytopenia in pediatrics: the pilot study from a multi-center[J]. Eur J Pediatr, 2021, 180(11): 3411-3417.

[9] 中华医学会儿科学分会血液学组, 中华儿科杂志编辑委员会. 儿童原发性免疫性血小板减少症诊疗建议[J]. 中华儿科杂志, 2013, 51(5): 382-384.

[10] Al-Samkari H, Jiang D, Gernsheimer T, et al. Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: a multicentre US study[J]. Br J Haematol, 2022, 197(3): 359-366.

[11] 季丽莉, 程韵枫. 原发性免疫性血小板减少症中CD4+T细胞的免疫异常[J]. 血栓与止血学, 2023, 29(4): 178-182.

[12] Britto J, Holbrook A, Sun H, et al. Thrombopoietin receptor agonists and other second-line therapies for immune thrombocytopenia: a narrative review with a focus on drug access in Canada[J]. Clin Invest Med, 2024, 47(1): 13-22.

[13] Tu J, Zheng N, Mao C, et al. UC-BSCs exosomes regulate Th17/Treg balance in patients with systemic lupus erythematosus via miR-19b/KLF13[J]. Cells, 2022, 11(24): 4123.

[14] Chen J Y, Yang Y J, Ma X Q, et al. Neobaicalein inhibits Th17 cell differentiation resulting in recovery of Th17/Treg ratio through blocking STAT3 signaling activation[J]. Molecules, 2022, 28(1): 18.

[15] Wang T, Rui J, Shan W, et al. Imbalance of Th17, Treg, and helper innate lymphoid cell in the peripheral blood of patients with rheumatoid arthritis[J]. Clin Rheumatol, 2022, 41(12): 3837-3849.

[16] Shi Q Z, Yu H M, Chen H M, et al. Exosomes derived from mesenchymal stem cells regulate Treg/Th17 balance in aplastic anemia by transferring miR-23a-3p[J]. Clin Exp Med, 2021, 21(3): 429-437.

[17] 汪嘉佳, 李哲, 江继发, 等. 外周血Treg细胞、Th17细胞在成人原发性免疫性血小板减少症中的变化及意义[J]. 山东医药, 2021, 61(28): 74-77.

[18] 金娜, 王晟, 吕世琴, 等. 白藜芦醇纳米粒对原发性免疫性血小板减少性紫癜大鼠Treg/Th17免疫平衡的改善作用及其机制[J]. 免疫学杂志, 2022, 38(11): 990-998.

[19] 黄宝山, 徐佳丽, 姜帅, 等. ITP患儿免疫球蛋白、淋巴细胞亚群及Th17/Treg的表达分析[J]. 重庆医学, 2022, 51(17): 2961-2965.

[20] Yang X, Wan X, Huang C, et al. Re-evaluate the prognostic value of absolute lymphocyte count in pediatric immune thrombocytopenia[J]. J Pediatr Hematol Oncol, 2023, 45(2): e254-e258.

[21] Lee E, Kim M, Jeon K, et al. Mean platelet volume, platelet distribution width, and platelet count, in connection with immune thrombocytopenic purpura and essential thrombocytopenia[J]. Lab Med, 2019, 50(3): 279-285.

[22] 顾小海, 陈海华, 林小飞. 影响儿童初诊原发性免疫性血小板减少症预后的相关因素分析[J]. 临床医学研究与实践, 2023, 8(32): 13-16.

[23] 王峰, 娜斯曼·尼加提, 黎瞳, 等. 影响儿童原发性免疫性血小板减少症临床预后因素的研究[J]. 中国小儿血液与肿瘤杂志, 2021, 26(2): 93-97.

基金资助

河北省医学科学研究项目(20232096)