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慢性乙型肝炎患者血清细胞因子IL-17A、IL-2、IL-21、IL-4表达水平及意义
董旭¹,刘亚允¹,蒋蒙²,朱彤¹,徐爱静¹,梁雪松^1*
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(1. 海军军医大学(第二军医大学)第一附属医院感染科, 上海 200433; 2. 中国人民解放军东部战区海军医院感染科, 舟山 316000 ^*通信作者)

摘要:

目的探索初治慢性乙型肝炎（CHB）患者血清中细胞因子表达水平及其与病毒载量和肝脏炎症程度的关系，以期为临床动态评估CHB的病情和预后提供新思路。方法选择2018年10月至2019年11月就诊于海军军医大学（第二军医大学）第一附属医院感染科的初治慢性乙型肝炎病毒（HBV）感染者68例，健康对照者12名，通过ELISA检测血清中细胞因子IL-17A、IL-2、IL-21和IL-4表达水平，化学发光法检测HBV血清学标志物，qPCR法检测血清HBV DNA定量，全自动生化分析仪检测肝功能指标。采用Spearman相关分析评估血清细胞因子与病毒载量及肝脏炎症程度的相关性，绘制ROC曲线评价血清细胞因子水平对肝脏炎症程度的判断效能。结果相较于健康对照者，初治CHB患者血清IL-17A[17.50（11.99，25.36）pg/mL vs 13.74（9.07，16.94）pg/mL，Z=-2.001，P=0.045]、IL-21[37.12（23.85，77.66）pg/mL vs 20.30（17.90，24.19）pg/mL，Z=-3.485，P＜0.01]水平升高，IL-2[57.19（31.10，79.92）pg/mL vs 73.06（62.41，105.84）pg/mL，Z=-2.509，P=0.012]水平降低，IL-4[11.40（5.79，18.62）pg/mL vs 10.84（8.05，25.20）pg/mL，Z=-0.681，P=0.496]水平差异无统计学意义。不同病程CHB患者的IL-17A表达水平差异有统计意义（H=8.870，P=0.031）。与非活动状态患者相比，炎症活动状态CHB患者血清中IL-17A[17.71（12.25，27.92）pg/mL vs 16.51（6.29，20.22）pg/mL]和IL-21[39.29（24.71，83.19）pg/mL vs 25.06（19.37，49.43）pg/mL]水平升高、IL-2[57.19（31.10，77.68）pg/mL vs 71.24（48.07，117.39）pg/mL]水平下降（均P＜0.05），IL-4[11.40（5.94，18.12）pg/mL vs 14.57（3.12，24.49）pg/mL]水平差异无统计学意义（P＞0.05）。HBeAg阳性CHB患者、HBeAg阴性CHB患者血清IL-17A[15.34（10.65，25.04）、19.98（15.55，34.14）pg/mL vs 13.74（9.07，16.94）pg/mL，H=10.061，P=0.007]和IL-21[37.74（25.06，82.87）、51.74（23.32，83.82）pg/mL vs 20.30（17.90，24.19）pg/mL，H=12.444，P=0.002]水平高于健康对照者，IL-2[57.19（37.45，79.92）、37.45（18.32，73.06）pg/mL vs 73.06（62.41，105.84）pg/mL，H=6.576，P=0.037]水平低于健康对照者。初治CHB患者血清IL-17A、IL-21、IL-4水平与HBV DNA定量无相关性（r=0.02、0.23、0.07，均P＞0.05），IL-2水平与HBV DNA定量存在弱相关性（r=0.32，P=0.01）。初治CHB患者血清IL-17A、IL-21水平与丙氨酸转氨酶（ALT）水平（r=0.59、0.49，均P＜0.01）和天冬氨酸转氨酶（AST）水平（r=0.47、0.36，均P＜0.01）均存在相关性，而IL-2、IL-4水平与ALT、AST水平均无相关性（均P＞0.05）。ALT≥300 U/L初治CHB组、ALT＜300 U/L初治CHB组及健康对照组间血清IL-17A、IL-2、IL-21水平差异有统计学意义（均P＜0.05），其中ALT≥300 U/L初治CHB组IL-17A、IL-21水平均高于ALT＜300 U/L初治CHB组及健康对照组（均P＜0.01），ALT＜300 U/L初治CHB组IL-2水平低于健康对照组、IL-21水平高于健康对照组（均P＜0.01）。ROC曲线分析结果显示，IL-17A判断肝脏炎症程度的AUC值为0.893 3（95% CI 0.793 0～0.993 6），IL-21判断肝脏炎症程度的AUC值为0.760 0（95% CI 0.622 7～0.897 3）。结论 I L-17A、IL-2和IL-21参与慢性HBV感染进程。初治CHB患者无论HBeAg阳性与否或炎症程度高低，血清IL-17A和IL-21水平均升高，IL-2水平均下降；IL-2与HBV DNA定量有一定相关性；IL-17A和IL-21与ALT及AST均存在正相关；检测IL-17A和IL-2有助于病情评估与预后判断。

关键词: 慢性乙型肝炎细胞因子白细胞介素17A 白细胞介素2 白细胞介素21 白细胞介素4

DOI：10.16781/j.CN31-2187/R.20230252

投稿时间：2023-05-06修订日期：2023-11-09

基金项目:上海市自然科学基金（16ZR1400400，20ZR1456900）．

Expression of serum cytokines IL-17A, IL-2, IL-21, and IL-4 in patients with chronic hepatitis B and its significance

DONG Xu¹,LIU Yayun¹,JIANG Meng²,ZHU Tong¹,XU Aijing¹,LIANG Xuesong^1*

(1. Department of Infectious Diseases, The First Hospital Affiliated of Naval Medical University (Second Military Medical University), Shanghai 200433, China;
2. Department of Infectious Diseases, Naval Hospital of PLA Eastern Theater Command, Zhoushan 316000, Zhejiang, China
^*Corresponding author)

Abstract:

Objective To explore the expression levels of cytokines in serum of treatment-naive chronic hepatitis B (CHB) patients and its relationships with viral load and liver inflammation, so as to provide new ideas for dynamic assessment of disease and prognosis of CHB.Methods A total of 68 treatment-naive patients with chronic hepatitis B virus (HBV) infection, who were admitted to Department of Infectious Diseases of The First Hospital Affiliated to Naval Medical University (Second Military Medical University) from Oct. 2018 to Nov. 2019, and 12 healthy controls were enrolled. The expression levels of cytokines interleukin (IL)-17A, IL-2, IL-21, and IL-4 in serum were tested by enzyme-linked immunosorbent assay (ELISA). Chemiluminescence method was used to detect HBV serological markers, quantitative polymerase chain reaction (qPCR) was used to detect serum HBV DNA quantification, and automatic biochemical analyzer was used to detect liver function indexes. Spearman correlation analysis was used to evaluate the correlations of serum cytokines with viral load and degree of liver inflammation. Receiver operating characteristic (ROC) curves were drawn to evaluate the efficacy of serum cytokines in judging liver inflammation. Results Compared with the healthy controls, the serum IL-17A and IL-21 levels in the treatment-naive CHB patients were significantly higher (17.50 ［11.99, 25.36］ pg/mL vs 13.74 ［9.07, 16.94］ pg/mL, Z=-2.001, P=0.045; 37.12 (23.85, 77.66) pg/mL vs 20.30［17.9, 24.19］ pg/mL, Z=-3.485, P＜0.01), the IL-2 level was significantly lower (57.19 ［31.10, 79.92］ pg/mL vs 73.06 ［62.41, 105.84］ pg/mL, Z=-2.509, P=0.012), and there was no significant difference in IL-4 level (11.40 ［5.79, 18.62］ pg/mL vs 10.84 ［8.05, 25.20］ pg/mL;Z=-0.681, P=0.496). The expression levels of IL-17A in CHB patients with different disease courses were significantly different (H=8.870, P=0.031). Compared to the patients with inflammatory inactive CHB, the serum IL-17A and IL-21 levels were significantly higher (17.71 ［12.25, 27.92］ pg/mL vs 16.51 ［6.29, 20.22］ pg/mL and 39.29 ［24.71, 83.19］ pg/mL vs 25.06 ［19.37, 49.43］ pg/mL), the IL-2 level was significantly lower (57.19 ［31.10, 77.68］ pg/mL vs 71.24 ［48.07, 117.39］ pg/mL) (allP＜0.05), and there was no significant difference in IL-4 level (11.40 ［5.94, 18.12］ pg/mL vs 14.57 ［3.12, 24.49］ pg/mL,P＞0.05) in the patients with inflammatory active CHB. The levels of serum IL-17A (15.34 ［10.65, 25.04］, 19.98 ［15.55, 34.14］ pg/mL vs 13.74 ［9.07, 16.94］ pg/mL, H=10.061, P=0.007) and IL-21 (37.74 ［25.06, 82.87］, 51.74 ［23.32, 83.82］ pg/mL vs 20.30 ［17.90, 24.19］ pg/mL, H=12.444, P=0.002) in hepatitis B e antigen (HBeAg)-positive CHB patients and HBeAg-negative CHB patients were significantly higher than those in healthy controls, while the level of IL-2 (57.19 ［37.45, 79.92］, 37.45 ［18.32, 73.06］ pg/mL vs 73.06 ［62.41, 105.84］ pg/mL, H=6.576, P=0.037) was significantly lower than that in healthy controls. There were no correlations between serum IL-17A, IL-21, IL-4 levels and HBV DNA quantification in treatment-naive CHB patients (r=0.02, 0.23, 0.07, all P＞0.05), while the level of IL-2 was weakly correlated with HBV DNA quantification (r=0.32, P=0.01). There were correlations between serum IL-17A, IL-21 and alanine transaminase (ALT) (r=0.59, 0.49, both P＜0.01), aspartate transaminase (AST) (r=0.47, 0.36, both P＜0.01) in treatment-naive CHB patients, while IL-2 and IL-4 had no significant correlations with ALT or AST (all P＞0.05). There were statistically significant differences in serum levels of IL-17A, IL-2, and IL-21 among the treatment-naive CHB group with ALT≥300 U/L, the treatment-naive CHB group with ALT＜300 U/L, and healthy control group (all P＜0.05). Specifically, the levels of IL-17A and IL-21 in the treatment-naive CHB group with ALT≥300 U/L were significantly higher than those in the treatment-naive CHB group with ALT＜300 U/L and healthy control group (all P＜0.01). The level of IL-2 in the treatment-naive CHB group with ALT＜300 U/L was significantly lower than that in healthy control group, while the level of IL-21 was significantly higher than that in healthy control group (all P＜0.01). ROC curve analysis results showed that the area under curve (AUC) values of IL-17A and IL-21 to judge the degree of liver inflammation were 0.893 3 (95% confidence interval ［CI］ 0.793 0-0.993 6) and 0.760 0 (95% CI 0.622 7-0.897 3), respectively. Conclusion IL-17A, IL-2, and IL-21 are involved in the progression of chronic HBV infection. Regardless of whether HBeAg is positive or not or the degree of inflammation, the serum levels of IL-17A and IL-21 in the treatment-naive CHB patients are increased, while the level of IL-2 is decreased. IL-2 has a certain correlation with HBV DNA quantification. IL-17A and IL-21 are positively correlated with ALT and AST. Detection of IL-17A and IL-2 is helpful for disease assessment and prognosis.

Key words: chronic hepatitis B cytokines interleukin 17A interleukin 2 interleukin 21 interleukin 4