传染性单核细胞增多症患儿调节性T细胞/辅助性T细胞17免疫失衡与治疗后Epstein-Barr病毒-DNA仍阳性的相关性研究

doi:10.19871/j.cnki.xfcrbzz.2024.03.010

摘要/Abstract

摘要： 目的探讨传染性单核细胞增多症患儿调节性T细胞（regulatory T cell,Treg）/辅助性T细胞(helper T cell,Th）17免疫失衡与治疗后Epstein-Barr病毒（EBV）-DNA仍阳性的相关性,为传染性单核细胞增多症的治疗及预后评估提供重要标志物。方法以2021年1月至2023年6月就诊于秦皇岛市工人医院的88例传染性单核细胞增多症患儿作为研究对象。患儿接受基于阿昔洛韦或更昔洛韦的标准化治疗并持续随访,根据治疗14d时患儿EBV-DNA载量是否仍为阳性分为EBV-DNA阴性组（n=70）和EBV-DNA阳性组（n=18）。对比两组患儿一般临床资料、治疗相关特征、治疗前T细胞亚群、炎性细胞因子、免疫球蛋白等指标的差异。将单因素分析有意义的指标进行Spearman相关性分析及多因素Logistic回归分析,评价各差异性指标与传染性单核细胞增多症患儿治疗14d后EBV-DNA仍阳性的相关性和危险因素。结果 EBV-DNA阳性组患儿平均住院时间、平均体温恢复时间、淋巴结肿大恢复时间均显著长于EBV-DNA阴性组患儿（P<0.05）;EBV-DNA阳性组患儿平均CD4⁺T淋巴细胞比例、CD4⁺/CD8⁺比值、Treg细胞比例、Treg/Th17比值、血清IL-4水平均显著低于EBV-DNA阴性组患儿,平均Th17细胞比例及血清IFN-γ水平均显著高于EBV-DNA阴性组患儿（P<0.05）;多因素Logistic回归分析表明传染性单核细胞增多症患儿CD4⁺T淋巴细胞比例及Treg细胞比例较低、Th17细胞比例较高及Treg/Th17比值较低均是规范治疗14d后EBV-DNA仍阳性的危险因素（P<0.05）。结论传染性单核细胞增多症患儿治疗前T细胞亚群比例特征、Treg/Th17免疫失衡严重程度、Th1/Th2细胞因子水平及免疫球蛋白水平与治疗14d后EBV-DNA仍阳性具有显著相关性,密切监测并促进患儿免疫-炎症水平恢复平衡对于提高传染性单核细胞增多症治疗预后具有重要临床意义。

关键词: 传染性单核细胞增多症, 调节性T细胞/辅助性T细胞17, Epstein-Barr病毒, 儿童

Abstract: Objective To explore the relationship between Treg/Th17 immune imbalance and EBV-DNA positivity in children with infectious mononucleosis, and to provide important markers for treatment and prognosis evaluation of such children. Method 88 children with infectious mononucleosis who were treated in our hospital from January 2021 to June 2023 were studied. Children received standardized treatment based on acyclovir or ganciclovir and continued follow-up. According to whether the EBV-DNA load was positive or not at 14 days after treatment, they were divided into EBV-DNA negative group (n=70) and EBV-DNA positive group (n=18). The general clinical data, treatment-related characteristics, T cell subsets, inflammatory cytokines, immunoglobulin before treatment of the two groups were compared. Spearman correlation analysis and multiple Logistic regression analysis were used to evaluate the correlation between different indicators and EBV-DNA positive in children with infectious mononucleosis after 14 days of treatment, and screen for risk factors. Result The average hospitalization time, average temperature recovery time and lymph node enlargement recovery time in EBV-DNA positive group were significantly higher than those in EBV-DNA negative group (P<0.05). The average CD4⁺T cell ratio, CD4⁺/CD8⁺ ratio, Treg cell ratio, Treg/Th17 ratio and serum IL-4 level in the EBV-DNA positive group were significantly lower than those in the EBV-DNA negative group, while the average Th17 cell proportion and serum IFN-γ level in the EBV-DNA negative group were significantly higher (P<0.05). Spearman correlation analysis and multivariate Logistic regression analysis showed that lower proportion of CD4⁺T cells, lower proportion of Treg cells, higher proportion of Th17 cells and lower Treg/Th17 ratio were risk factors for EBV-DNA positive after 14 days of standardized treatment in children with infectious mononucleosis (P<0.05). Conclusion The proportion of T cell subsets, the severity of Treg/Th17 immune imbalance, Th1/Th2 cytokine levels and immunoglobulin levels in children with infectious mononucleosis before treatment were significantly correlated with EBV-DNA positive after 14 days of treatment. Close monitoring and promoting the recovery of immune-inflammatory balance in children with infectious mononucleosis has important clinical significance for improving the prognosis of infectious mononucleosis treatment.

Key words: Infectious mononucleosis, Treg/Th17, Epstein-Barr virus, Children

中图分类号:

R512.7

周桂娟, 贾月娥, 孙尤佳, 李海侠, 方雪. 传染性单核细胞增多症患儿调节性T细胞/辅助性T细胞17免疫失衡与治疗后Epstein-Barr病毒-DNA仍阳性的相关性研究[J]. 新发传染病电子杂志, 2024, 9(3): 45-50.

Zhou Guijuan, Jia Yuee, Sun Youjia, Li Haixia, Fang Xue. Correlation between Treg/Th17 immune imbalance and EBV-DNA positivity after treatment in children with infectious mononucleosis[J]. Electronic Journal of Emerging Infectious Diseases, 2024, 9(3): 45-50.

参考文献

[1] 吴洁. 传染性单核细胞增多症的研究进展[J].中国城乡企业卫生, 2021, 36(9):51-53.
[2] 张苡菲, 郭佳慧, 李玢. EB病毒感染相关血液病治疗的研究进展[J].沈阳医学院学报, 2021, 23(5):477-481.
[3] 杨智, 吴伟刚, 欧鹏程, 等. 成人EBV感染临床特点及发生噬血细胞综合征的预测因素[J/CD]. 新发传染病电子杂志, 2022, 7(2):35-40.
[4] LEUNG AKC, LAM JM, BARANKIN B.Infectious Mononucleosis: An Updated Review[J]. Curr Pediatr Rev, 2024, 20(3): 305-322.
[5] 苏继洲, 胡志东. EB病毒DNA检测对儿童传染性单核细胞增多症诊断的研究进展[J/CD]. 临床医药文献电子杂志, 2017, 4(72):14237+14240.
[6] CHEN L, CHEN X, YAO W, et al.Dynamic Distribution and Clinical Value of Peripheral Lymphocyte Subsets in Children with Infectious Mononucleosis[J]. Indian J Pediatr, 2021, 88(2):113-119.
[7] 沈燕, 陆建春, 冯妍, 等. 儿童传染性单核细胞增多症临床表现及外周血Th1/Th2型细胞标志物与EB病毒-DNA载量的关系[J].中国感染与化疗杂志, 2023, 23(3):318-322.
[8] 计晓兰, 胡春霞, 孔令军, 等.EBV-IM患儿外周血EBV-DNA载量与Th1/Th2相关细胞因子及临床特征的关系[J]. 中华医院感染学杂志, 2023, 33(16):2503-2507.
[9] 安晓刚, 孔雅俊, 张晓燕, 等. 传染性单核细胞增多症患儿淋巴细胞亚群、免疫球蛋白水平变化及与过敏性疾病的关系[J].中国国境卫生检疫杂志, 2023, 46(3):280-282.
[10] IKUTA K, SAIGA K, DEGUCHI M, et al.Epstein-Barr virus DNA is detected in peripheral blood mononuclear cells of EBV-seronegative infants with infectious mononucleosis-like symptoms[J]. Virus Genes, 2003, 26(2):165-173.
[11] 中华医学会儿科学分会感染学组, 全国儿童EB病毒感染协作组. 儿童EB病毒感染相关疾病的诊断和治疗原则专家共识[J]. 中华儿科杂志, 2021, 59(11):905-911.
[12] 栗春香, 史利欢, 郭明发, 等.儿童传染性单核细胞增多症EBV-DNA载量与异型淋巴细胞百分率及T淋巴细胞亚群的相关性分析[J]. 检验医学与临床, 2023, 20(8):1029-1032.
[13] 张伟, 徐国成.儿童传染性单核细胞增多症抗病毒治疗研究进展[J].齐齐哈尔医学院学报, 2022, 43(7):688-692.
[14] PÁEZ-GUILLÁN EM, CAMPOS-FRANCO J, ALENDE R, et al. Jaundice in relation to immune activation during Epstein-Barr virus-induced infectious mononucleosis[J]. Am J Med Sci, 2023, 365(3):270-278.
[15] 夏玉雪, 方峻. EB病毒与传染性单核细胞增多症的研究进展[J].临床内科杂志, 2019, 36(6):371-374.
[16] WANINGER KN, HARCKE HT.Determination of safe return to play for athletes recovering from infectious mononucleosis: a review of the literature[J]. Clin J Sport Med, 2005, 15(6):410-416.
[17] WATANABE H, SEKINE H, URUMA T, et al.Increase of atypical lymphocytes expressing CD4+/CD45RO+ in an infectious mononucleosis-like syndrome associated with hepatitis A virus infection[J]. J Infect Chemother, 2009,15(3):187-190.
[18] WANG Y, LUO Y, TANG G, et al.HLA-DR Expression Level in CD8+ T Cells Correlates With the Severity of Children With Acute Infectious Mononucleosis[J]. Front Immunol, 2021, 12:753290.
[19] SETSUDA J, TERUYA-FELDSTEIN J, HARRIS NL, et al.Interleukin-18, interferon-gamma, IP-10, and Mig expression in Epstein-Barr virus-induced infectious mononucleosis and posttransplant lymphoproliferative disease[J]. Am J Pathol, 1999, 155(1):257-265.
[20] ZHANG Y, HUANG C, ZHANG H, et al.Characteristics of immunological events in Epstein-Barr virus infection in children with infectious mononucleosis[J]. Front Pediatr, 2023, 11:1060053.
[21] BEKTAS A, SCHURMAN SH, GONZALEZ-FREIRE M, et al.Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy[J]. Aging (Albany NY), 2019, 11(21):9234-9263.
[22] HUO S, LUO Y, DENG R, et al.EBV-EBNA1 constructs an immunosuppressive microenvironment for nasopharyngeal carcinoma by promoting the chemoattraction of Treg cells[J]. J Immunother Cancer, 2020, 8(2):e001588.
[23] CHOW YH, CHANG HW, SIA R, et al.Tonsillar CD4+FOXP3+ T-regulatory cell dynamics in primary EBV infection[J]. Immunol Res, 2011, 50(1):97-101.
[24] AGHBASH PS, HEMMAT N, NAHAND JS, et al.The role of Th17 cells in viral infections[J]. Int Immunopharmacol, 2021, 91:107331.
[25] SHEHAB M, HUSSEIN H, FADLALLAH S, et al.An IL-17A-centric response to Epstein-Barr virus DNA mediated by dendritic Cell-T cell interactions[J]. Front Mol Biosci. 2024, 11:1243366.
[26] KIS LL, GERASIMCIK N, SALAMON D, et al.STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus-encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma[J]. Blood. 2011, 117(1):165-174.