高迁移率族蛋白1在肠道病毒71型手足口病患者中的表达及临床价值

doi:10.3877/cma.j.issn.1674-1358.2022.01.002

中华实验和临床感染病杂志(电子版) ›› 2022, Vol. 16 ›› Issue (01) : 9 -15. doi: 10.3877/cma.j.issn.1674-1358.2022.01.002

论著

高迁移率族蛋白1在肠道病毒71型手足口病患者中的表达及临床价值

张玉凤¹, 万涵², 樊华峰¹, 袁娟¹, 刘瑞清¹, 徐鹏飞¹, 王军¹, 邓慧玲³^,^†(

)

^1. 710003　西安市，西安市儿童医院感染二科
^2. 710065　西安市，西安市兵器工业521医院肝胆科
^3. 710003　西安市，西安市中心医院儿科

收稿日期:2021-04-27 出版日期:2022-02-15
通信作者: 邓慧玲
基金资助:
陕西省科技统筹重点产业创新链工程计划资助项目(No. 2016KTZD SF02-04); 西安市科技计划项目(No. 201805098YX6SF32（7）)

Expression and clinical value of high mobility group protein 1 in patients with enterovirus 71 related hand, foot and mouth disease

Yufeng Zhang¹, Han Wan², Huafeng Fan¹, Juan Yuan¹, Ruiqing Liu¹, Pengfei Xu¹, Jun Wang¹, Huiling Deng³^,^†()

^1. Department of Infectious Diseases, Xi’an Children’s Hospital, Xi’an 710003, China
^2. Department of Hepatology, 521 Hospital of Xi’an Ordnance Industry, Xi’an 710065, China
^3. Department of Pediatrics, Xi’an Central Hospital, Xi’an 710003, China

Received:2021-04-27 Published:2022-02-15
Corresponding author: Huiling Deng

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引用本文：

张玉凤, 万涵, 樊华峰, 袁娟, 刘瑞清, 徐鹏飞, 王军, 邓慧玲. 高迁移率族蛋白1在肠道病毒71型手足口病患者中的表达及临床价值[J/OL]. 中华实验和临床感染病杂志(电子版), 2022, 16(01): 9-15.

Yufeng Zhang, Han Wan, Huafeng Fan, Juan Yuan, Ruiqing Liu, Pengfei Xu, Jun Wang, Huiling Deng. Expression and clinical value of high mobility group protein 1 in patients with enterovirus 71 related hand, foot and mouth disease[J/OL]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2022, 16(01): 9-15.

目的

分析不同分期肠道病毒71型（EV71）手足口病（HFMD）患儿高迁移率族蛋白1（HMGB1）水平的表达变化，研究HMGB1在HFMD重症化中的临床价值及其相关作用机制。

方法

将2018年5月至2019年12月西安市儿童医院感染科收治住院的EV71型HFMD患儿共130例纳入研究（研究组），其中普通型90例（轻症组）、重症40例（重症组）。以儿保科同期体检的50例健康儿童纳入对照组，采用Real time-PCR检测各组儿童外周血单核细胞HMGB1 mRNA表达水平，同时用ELISA方法检测血浆HMGB1和肿瘤坏死因子-α（TNF-α）、转化生长因子-β（TGF-β）及白细胞介素-6（IL-6）水平，比较血浆高水平HMGB1和低水平HMGB1患儿重症发生率并分析HMGB1与细胞因子肿瘤坏死因子-α（TNF-α）、转化生长因子-β（TGF-β）、白细胞介素-6（IL-6）间的相关性。

结果

HFMD轻症组和重症组患儿和对照组HMGB1 mRNA表达水平和血浆HMGB1含量差异有统计学意义（F = 54.629、P < 0.001，F = 127.924、P < 0.001）。受试者工作特征曲线提示，当HMGB1为13 090 pg/ml时约登指数最大，对应的敏感度和特异度分别为80.9%和73.5%。高HMGB1患儿重症发生率（44.6%、33/74）显著高于低HMGB1患儿（12.5%、7/56），差异有统计学意义（χ² = 26.986、P < 0.001）。三组研究对象TNF-α（F = 11.284、P < 0.001）、TGF-β（F = 57.346、P < 0.001）及IL-6（F = 45.362、P < 0.001）差异均有统计学意义，重症组较轻症组患儿升高更为显著（TNF-α：t = 7.503、P = 0.035；TGF-β：t = 9.307、P = 0.017；IL-6：t = 25.618、P < 0.001）。入组HFMD患儿血浆中HMGB1含量与TNF-α、TGF-β及IL-6水平均呈正相关（r = 0.642、0.775、0.825，P均< 0.001）。

结论

HFMD患儿HMGB1水平升高，以重症患儿HMGB1水平升高更显著；HMGB1可能通过调控IL-6、TGF-β和TNF-α等细胞因子参与手足口病重症的发生、发展过程。

关键词: 手足口病, 高迁移率族蛋白1, 细胞因子, 临床价值

Objective

To investigate the expression changes of high mobility group protein 1 (HMGB1) in children with different stages of enterovirus 71 (EV71) related hand, foot and mouth disease (HFMD), and to analyze the clinical value and mechanism of HMGB1 in the severity of HFMD.

Methods

Total of 130 cases of EV71 HFMD admitted to the Department of infection of Xi’an Children’s Hospital from May 2018 to December 2019 were enrolled in study group, including 90 mild cases (mild group) and 40 severe cases (severe group). While a total of 50 healthy children who had medical check-up in Child Health Unit in the same period were selected as the control group. Real time PCR was used to detect the expression of HMGB1 mRNA in peripheral blood mononuclear cells in each group. ELISA was used to detect the plasma levels of HMGB1, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and interleukin-6 (IL-6). The incidence of severity in children with high plasma level of HMGB1 and low level of HMGB1 was compared, and the correlation between HMGB1 and cytokines TNF-α, TGF-β and IL-? were analyzed, respectively.

Results

The expression of HMGB1 mRNA and the content of plasma HMGB1 were significantly different among cases in mild group, severe group and control group (F = 54.629, P < 0.001; F = 127.924, P < 0.001). The receiver operating characteristic curve (ROC) showed that when HMGB1 was 13 090 pg/ml, the Youden index was the highest, the sensitivity was 80.9%, and the specificity was 73.5%. The incidence of severe cases in children with high HMGB1 (44.6%, 33/74) was significantly lower than that of children with low HMGB1 (12.5%, 7/56), with significant difference (χ² = 26.986, P < 0.001). The levels of TNF-α (F = 11.284, P < 0.001), TGF-β (F = 57.346, P < 0.001) and IL-? (F = 45.362, P < 0.001) among the three groups were all significantly different, especially in severe group (TNF-α: severe group vs. mild group: t = 7.503, P = 0.035; TGF-β: severe group vs. mild group: t = 9.307, P = 0.017; IL-6: severe group vs. mild group: t = 25.618, P < 0.001). The level of plasma HMGB1 of children with HFMD was positively correlated with the levels of TNF-α, TGF-β and IL-? (r = 0.642, 0.775, 0.825; all P < 0.001).

Conclusions

HMGB1 level were increased in children with EV71 HFMD, especially in severe cases; HMGB1 may participate in the occurrence and development of severe HFMD by regulating cytokines such as IL-6, TGF-β and TNF-α.

Key words: Hand, foot and mouth disease, High mobility group protein 1, Cytokines, Clinical value

表1 三组儿童HMGB1 mRNA表达和血浆HMGB1水平（\d ± s）

组别	例数	HMGB1 mRNA	HMGB1（pg/ml）
重症组	40	28.53 ± 2.46	15 759.39 ± 2 419.28
轻症组	90	16.89 ± 2.53	11 598.89 ± 2 199.37
对照组	50	5.76 ± 1.27	10 116.41 ± 2 435.59
F值		54.629	127.924
P值		< 0.001	< 0.001

表1 三组儿童HMGB1 mRNA表达和血浆HMGB1水平（\d ± s）

组别	例数	HMGB1 mRNA	HMGB1（pg/ml）
重症组	40	28.53 ± 2.46	15 759.39 ± 2 419.28
轻症组	90	16.89 ± 2.53	11 598.89 ± 2 199.37
对照组	50	5.76 ± 1.27	10 116.41 ± 2 435.59
F值		54.629	127.924
P值		< 0.001	< 0.001

图1 血浆HMGB1水平预测EV71 HFMD重症化的ROC曲线

表2 三组儿童血浆TNF-α、TGF-β及IL-6水平（\d ± s，pg/ml）

组别	例数	TNF-α	TGF-β	IL-6
重症组	50	29.56 ± 9.58	259.41 ± 31.58	65.27 ± 11.57
轻症组	100	25.69 ± 10.97	229.48 ± 21.64	28.26 ± 10.74
对照组	50	21.30 ± 8.69	44.36 ± 16.32	14.32 ± 2.97
F值		11.284	57.346	45.362
P值		< 0.001	< 0.001	< 0.001

表2 三组儿童血浆TNF-α、TGF-β及IL-6水平（\d ± s，pg/ml）

组别	例数	TNF-α	TGF-β	IL-6
重症组	50	29.56 ± 9.58	259.41 ± 31.58	65.27 ± 11.57
轻症组	100	25.69 ± 10.97	229.48 ± 21.64	28.26 ± 10.74
对照组	50	21.30 ± 8.69	44.36 ± 16.32	14.32 ± 2.97
F值		11.284	57.346	45.362
P值		< 0.001	< 0.001	< 0.001

图2 EV71 HFMD患儿血浆HMGB1与TNF-α水平的相关性

图3 EV71型HFMD患儿血浆HMGB1与TGF-β水平的相关性

图4 EV71型HFMD患儿血浆HMGB1与IL-6水平的相关性

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Expression and clinical value of high mobility group protein 1 in patients with enterovirus 71 related hand, foot and mouth disease

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Expression and clinical value of high mobility group protein 1 in patients with enterovirus 71 related hand, foot and mouth disease