T淋巴细胞亚群、B淋巴细胞及NK细胞水平与高危型HPV感染预后的相关性

Correlation of T lymphocyte subsets, B lymphocytes and NK cell levels with the prognosis of high-risk HPV infection

摘要

目的 探究T淋巴细胞亚群（CD3⁺T淋巴细胞、CD4⁺T淋巴细胞、CD8⁺T淋巴细胞）、CD19⁺B淋巴细胞及自然杀伤（NK）细胞水平与高危型人乳头状瘤病毒（HR-HPV）感染患者预后的相关性。方法 回顾性选取2021年1月至2022年2月广州市红十字会医院收治的子宫颈HR-HPV患者210例。根据随访2年内，患者HR-HPV感染的转归情况，分为阴性组（ n = 94）与阳性组（ n = 116）。另选取2022年3月至2023年1月间收治的子宫颈HR-HPV患者90例为验证集。通过单因素及多因素Logistic逐步回归分析各因素对HR-HPV转归的影响，基于随访24个月转归构建的子宫颈HR-HPV患者转阴概率绘制列线图。采用受试者操作特征（ROC）曲线评估免疫细胞联合预测、临床指标和Logistic模型对HR-HPV转归的相关价值。采用校准曲线和临床决策曲线分析评估Logistic模型的预测效能及临床应用价值，并在验证集中进行验证。结果 年龄、既往阴道微生态异常史、HPV感染型别、宫颈细胞学检查结果、CD3⁺T淋巴细胞、CD4⁺T淋巴细胞、CD8⁺T淋巴细胞、CD19⁺B淋巴细胞及NK细胞为HR-HPV患者随访24个月预后的相关因素（均 P ＜ 0.05）。Logistic模型的AUC值高于仅含临床特征的模型，表明免疫学指标能提升对HR-HPV感染转归的预测效能。Logistic模型在训练集及验证集中均表现出良好的校准度和临床获益。结论 CD3⁺T淋巴细胞、CD4⁺T淋巴细胞、CD8⁺T淋巴细胞、CD19⁺B淋巴细胞、NK细胞为子宫颈HR-HPV转归的相关因素。

Abstract

Objective To investigate the correlation of T lymphocyte subsets, including CD3 ⁺T lymphocytes, CD4 ⁺T lymphocytes and CD8 ⁺T lymphocytes, CD19 ⁺B lymphocytes, and natural killer (NK) cell levels with the prognosis of patients with high-risk human papillomavirus (HR-HPV) infection. Methods A total of 210 patients with cervical HR-HPV infection admitted to Guangzhou Red Cross Hospital from January 2021 to February 2022 were retrospectively selected. According to the outcome of HR-HPV infection during two years of follow-up, the patients were divided into a negative group ( n = 94) and a positive group ( n = 116). Another 90 patients with cervical HR-HPV infection admitted between March 2022 and January 2023 were selected as the validation set. Univariate and multivariate stepwise Logistic regression analyses were used to analyze the effects of various factors on HR-HPV outcomes. A nomogram for the probability of HR-HPV clearance in patients with cervical HR-HPV infection was constructed based on the outcomes after 24 months of follow-up. Receiver operating characteristic (ROC) curves were used to evaluate the value of combined immune cell prediction, clinical indicators, and the Logistic model in relation to HR-HPV outcomes. Calibration curves and decision curve analysis (DCA) were used to evaluate the predictive performance and clinical application value of the Logistic model, which was further validated in the validation set. Results Age, history of vaginal microecological abnormality, HPV infection type, cervical cytology results, CD3 ⁺ T lymphocytes, CD4 ⁺ T lymphocytes, CD8 ⁺ T lymphocytes, CD19 ⁺ B lymphocytes, and NK cells were factors associated with the 24-month prognosis of patients with HR-HPV infection (all P ＜ 0.05). The area under the curve (AUC) of the Logistic model was higher than that of the model containing only clinical features, indicating that immunological indicators could improve the predictive performance for the outcome of HR-HPV infection. The Logistic model showed good calibration and clinical benefit in both the training set and the validation set. Conclusions CD3 ⁺ T lymphocytes, CD4 ⁺ T lymphocytes, CD8 ⁺ T lymphocytes, CD19 ⁺ B lymphocytes, and NK cells are factors associated with the outcome of cervical HR-HPV infection.

关键词

T淋巴细胞亚群 / B细胞 / NK细胞 / 子宫颈 / 高危型人乳头状瘤病毒

Key words

T-lymphocyte subsets / B lymphocytes / NK cells / Cervix / High-risk human papillomavirus

参考文献

[1] 米建锋， 朱玲. 宫颈高危型人乳头状瘤病毒感染的治疗现状及进展[J]. 实用妇科内分泌电子杂志， 2022， 9（36）： 20-22. DOI: 10.3969/j.issn.2095-8803.2022.36.007.

[2] MI J F, ZHU L. Treatment status and progress of cervical high-risk HPV infection[J]. Electron J Pract Gynecol Endocrinol, 2022, 9(36): 20-22. DOI: 10.3969/j.issn.2095-8803.2022.36.007.

[3] 吴荣莉， 吴冬梅， 林兰. 易黄汤调节cGAS/STING信号通路对宫颈癌小鼠移植瘤HPV及免疫功能的影响[J]. 广西中医药大学学报， 2025， 28（1）： 58-63. DOI: 10.3969/j.issn.2095-4441.2025.01.016.

[4] WU R L, WU D M, LIN L. Effect of Yihuang decoction on regulating the cGAS/STING signaling pathway and its impact on the immune function and transplanted tumor HPV in mice with cervical cancer [J]. J Guangxi Univ Chin Med, 2025, 28(1): 58-63. DOI: 10.3969/j.issn.2095-4441.2025.01.016.

[5] 张潇潇， 王俊， 马苗苗， 等 . HR-HPV阳性宫颈癌患者免疫细胞与炎症因子特征分析[J]. 检验医学与临床， 2023， 20（16）： 2391-2394，2399. DOI: 10.3969/j.issn.1672-9455.2023.16.020.

[6] ZHANG X X, WANG J, MA M M, et al. Analysis of characteristics of immune cells and inflammatory factors in HR-HPV positive cervical cancer patients[J]. Lab Med Clin, 2023, 20(16): 2391-2394, 2399. DOI: 10.3969/j.issn.1672-9455.2023.16.020.

[7] 刘丹， 张洁， 郭正阳， 等 . 流式细胞术检测细胞周期影响因素及不同免疫细胞亚群周期分析[J]. 中国生物化学与分子生物学报， 2024， 40（9）： 1308-1316. DOI: 10.13865/j.cnki.cjbmb.2024.09.1302.

[8] LIU D, ZHANG J, GUO Z Y, et al. Factors influencing flow cytometry-based cell cycle detection and analysis of various immune cell subpopulations[J]. Chin J Biochem Mol Biol, 2024, 40(9): 1308-1316. DOI: 10.13865/j.cnki.cjbmb.2024.09.1302.

[9] 张诗蒙， 谭志容， 孙宇飞， 等 . 宫颈癌生物标志物鉴定及其生物信息学[J]. 中国老年学杂志， 2024， 44（18）： 4368-4374. DOI: 10.3969/j.issn.1005-9202.2024.18.005.

[10] ZHANG S M, TAN Z R, SUN Y F, et al. Identification of biomarkers of cervical cancer and its bioinformatics[J]. Chin J Gerontol, 2024, 44(18): 4368-4374. DOI: 10.3969/j.issn.1005-9202.2024.18.005.

[11] 王家良. 临床流行病学：临床科研设计，测量与评价[M]. 上海： 上海科学技术出版社， 2014.

[12] WANG J L. Clinical epidemiology: clinical research design, measurement and evaluation[M]. Shanghai: Shanghai Scientific Technical Publishers, 2014.

[13] 杨雅婷， 钟斐， 黄维， 等 . 广州地区人乳头瘤病毒感染情况及其与TCT的关系[J]. 暨南大学学报（自然科学与医学版）， 2025， 46（3）： 375-386. DOI: 10.11778/j.jdxb.20240289.

[14] YANG Y T, ZHONG F, HUANG W, et al. Human papillomavirus infection and its relationship with TCT in Guangzhou[J]. J Jinan Univ (Nat Sci Med Ed), 2025, 46(3): 375-386. DOI: 10.11778/j.jdxb.20240289.

[15] 阿斯木古丽·克力木， 玛伊热·安外尔， 杨秀玮， 等 . 喀什地区妇女高危型HPV感染高危因素分析及三联教育干预效果评价[J]. 中山大学学报（医学科学版）， 2025， 46（1）： 98-106. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2025.0111.

[16] ASIMUGULI K, MAYIRE A, YANG X W, et al. Investigation of high-risk HPV infection in Kashgar and evaluation of health awareness education intervention[J]. J Sun Yat-sen Univ (Med Sci), 2025, 46(1): 98-106. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2025.0111.

[17] 崔光娥， 文帅， 刘英杰， 等 . 宫颈癌组织Survivin、HPV16E7水平与患者临床病理特征、预后及化疗敏感性的关系研究[J]. 黑龙江医学， 2024， 48（24）： 2960-2963. DOI: 10.3969/j.issn.1004-5775.2024.24.005.

[18] CUI G E, WEN S, LIU Y J, et al. Relationship between survivin and HPV16E7 levels in cervical cancer tissues and patient clinicopathological characteristics, prognosis and chemotherapy sensitivity[J]. Heilongjiang Med J, 2024, 48(24): 2960-2963. DOI: 10.3969/j.issn.1004-5775.2024.24.005.

[19] 曹丹丹， 曹悦， 张建玲. 南京江北新区26 604例免费宫颈癌筛查女性高危型HPV流行病学调查[J]. 中国临床研究， 2025， 38（3）： 424-428. DOI: 10.13429/j.cnki.cjcr.2025.03.021.

[20] CAO D D, CAO Y, ZHANG J L. Epidemiological survey of high-risk HPV in 26 604 free cervical cancer-screened women in Jiangbei New District, Nanjing[J]. Chin J Clin Res, 2025, 38(3): 424-428. DOI: 10.13429/j.cnki.cjcr.2025.03.021.

[21] 周平平， 杜珍武， 秦续元， 等 . 长春地区女性人乳头瘤病毒感染基因类型分布及特征分析[J]. 国际老年医学杂志， 2025， 46（1）： 25-30. DOI: 10.3969/j.issn.1674-7593.2025.01.006.

[22] ZHOU P P, DU Z W, QIN X Y, et al. Distribution and characteristics of human papilloma virus infection genotyping in women in Changchun area[J]. Int J Geriatr, 2025, 46(1): 25-30. DOI: 10.3969/j.issn.1674-7593.2025.01.006.

[23] JU Y, ZHOU Q . The impact of photodynamic therapy on cellular immune function in patients with cervical HPV infection[J]. Clinics, 2025, 80: 100537. DOI: 10.1016/j.clinsp.2024.100537.

[24] 何婷婷. 乳酸菌阴道胶囊联合干扰素及激光治疗对子宫颈炎伴HPV感染患者阴道微生态和外周免疫功能的影响[J]. 中国医学创新， 2024， 21（28）： 48-52. DOI: 10.3969/j.issn.1674-4985.2024.28.011.

[25] HE T T. Effects of interferon combined with lacidophilin vaginal capsules and laser therapy on vaginal microecosystem and peripheral immune function in patients with cervicitis and HPV infection[J]. Med Innov China, 2024, 21(28): 48-52. DOI: 10.3969/j.issn.1674-4985.2024.28.011.

[26] DA FONSECA D O, PUGA M A M, GUBERT V T, et al. Cellular immune response to high-risk human papillomavirus infection: a systematic review[J]. Crit Rev Immunol, 2025, 45(3): 33-49. DOI: 10.1615/critrevimmunol.2025057517.

[27] TORTELLINI E, GUARDIANI M, CARRARO A, et al. Role of prior HPV infection and CD4 T-cell count in modulating cellular immune responses to a three-dose nonavalent HPV vaccine schedule in PWH receiving ART[J]. BMC Med, 2025, 23(1): 689. DOI: 10.1186/s12916-025-04504-1.

[28] VAN BOCKEL D, KELLEHER A . The crossroads: divergent roles of virus-specific CD4⁺ T lymphocytes in determining the outcome for human papillomavirus infection [J]. Immunol Cell Biol, 2023, 101(6): 525-534. DOI: 10.1111/imcb.12650.

[29] WUI S, HEWAVISENTI R V, RABIEI M, et al. HPV status shapes T-cell immunoprofiles in oesophageal adenocarcinoma: high regulatory T cell infiltration predicts poor prognosis[J]. J Transl Med, 2025, 24(1): 12. DOI: 10.1186/s12967-025-07482-3.

[30] 刘质斌， 申鑫鑫， 豆贝贝， 等 . T淋巴细胞在HPV感染小鼠生殖道黏膜上皮细胞免疫反应中的作用[J]. 中华医院感染学杂志， 2024， 34（6）： 897-902. DOI: 10.11816/cn.ni.2024-231122.

[31] LIU Z B, SHEN X X, DOU B B, et al. Effect of T lymphocyte on immune response of epithelial cells of genital tract mucosa of rats with HPV infection[J]. Chin J Nosocomiology, 2024, 34(6): 897-902. DOI: 10.11816/cn.ni.2024-231122.

[32] YOUNG R J, ANGEL C, BRESSEL M, et al. Characterising B cell expression and prognostic significance in human papillomavirus positive oropharyngeal cancer[J]. Oral Oncol, 2024, 150: 106687. DOI: 10.1016/j.oraloncology.2024.106687.

[33] GUBERMAN BRACHA M, BIBER G, ZELIKSON N, et al. Mouse B cells engineered to express an anti-HPV antibody elicit anti-tumor T cell responses[J]. Front Immunol, 2025, 16: 1613879. DOI: 10.3389/fimmu.2025.1613879.

[34] O’HARA M P, YANAMANDRA A V, SASTRY K J . Immunity from NK cell subsets is important for vaccine-mediated protection in HPV+ cancers[J]. Vaccines, 2024, 12(2): 206. DOI: 10.3390/vaccines12020206.

[35] 蔡礼仲， 姚锐. 高级别宫颈上皮内病变患者环形电切术后HPV持续感染及病变残留复发的危险因素[J]. 中国妇幼保健， 2024， 39（19）： 3775-3780. DOI: 10.19829/j.zgfybj.issn.1001-4411.2024.19.024.

[36] CAI L Z, YAO R. Risk factors for persistent HPV infection and residual recurrence in patients with high-grade cervical intraepithelial neoplasia after LEEP surgery[J]. Matern Child Health Care China, 2024, 39(19): 3775-3780. DOI: 10.19829/j.zgfybj.issn.1001-4411.2024.19.024.

[37] 白雁飞， 徐丽娟. 高危型人乳头瘤病毒和宫颈病变与阴道微生态的相关性分析[J]. 中国医药科学， 2025， 15（8）： 85-88. DOI: 10.20116/j.issn2095-0616.2025.08.18.

[38] BAI Y F, XU L J. Correlation analysis between high-risk human papillomavirus, cervical lesions and vaginal microbiota[J]. China Med Pharm, 2025, 15(8): 85-88. DOI: 10.20116/j.issn2095-0616.2025.08.18.

[39] TAO H, ZENG D, CHEN W, et al. Focused ultrasound: a novel therapy for improving vaginal microecology in patients with high-risk HPV infection[J]. Int J Hyperthermia, 2023, 40(1): 2211276. DOI: 10.1080/02656736.2023.2211276.

[40] LV Z, HE X, LI Z, et al. Outcomes and associated factors of cervical human papillomavirus infection among 608 women in Shenzhen, China, 2018-2023[J]. Front Public Health, 2025, 12: 1523839. DOI: 10.3389/fpubh.2024.1523839.

[41] LIU Y, LI R, DU H, et al. HPV negative conversion following Hiporfin PDT for HPV associated HSIL in the female lower reproductive tract[J]. Sci Rep, 2025, 15: 31973. DOI: 10.1038/s41598-025-17292-8.

[42] WU M, MA X, LI H, et al. Which is the best management for women with normal cervical cytologic findings despite positivity for non-16/18 high risk human papillomaviruses[J]. Front Public Health, 2022, 10: 950610. DOI: 10.3389/fpubh.2022.950610.

基金资助

广东省中医药局科研项目(20261292)