HBV相关慢加急性肝衰竭患者外周血CD3+CD56+自然杀伤T淋巴细胞中TIM-3的表达及意义

高梦丹; 覃岭; 孙坚萍; 李康; 李昂; 娄金丽; 张永宏; 赵艳

doi:10.3969/j.issn.1001-5256.2019.09.024

HBV相关慢加急性肝衰竭患者外周血CD3+CD56+自然杀伤T淋巴细胞中TIM-3的表达及意义

DOI: 10.3969/j.issn.1001-5256.2019.09.024

首都医科大学附属北京佑安医院临床检验中心

基金项目:

北京市医管局“扬帆计划”重点专业(ZYLX201711)；十三五国家传染病重大专项(2017ZX10202102-003-003)；北京市医院管理局“登峰”计划专项经费资助(DFL20181701)；十二五(旷博)基于传染病发生、发展临床分期的血清microRNA表达谱系列诊断试剂盒研发(2015ZX10004801-001)；

详细信息

中图分类号: R512.62;R575.3
计量
- 文章访问数: 1356
- HTML全文浏览量: 61
- PDF下载量: 260
- 被引次数: 0
出版历程
- 收稿日期: 2019-03-20
- 出版日期: 2019-09-20

Expression and significance of T-cell immunoglobulin and mucin domain-containing molecule 3 in peripheral blood CD3+CD56+ natural killer T cells in patients with hepatitis B virus-related acute-on-chronic liver failure

Clinical Laboratory Center, Beijing YouAn Hospital, Capital Medical University

Research funding:

摘要

摘要:
目的探讨HBV相关慢加急性肝衰竭（HBV-ACLF）患者外周血自然杀伤T淋巴细胞（NKT细胞）数量及T淋巴细胞免疫球蛋白和黏蛋白结构域3（TIM-3）表达水平与患者肝损伤及预后的相关性。方法收集2016年9月-2018年6月在首都医科大学附属北京佑安医院接受治疗的43例HBV-ACLF患者和28例慢性乙型肝炎（CHB）患者的外周血单个核细胞,采用流式细胞技术检测患者外周血CD3+CD56+NKT细胞数量及其TIM-3表达水平。呈正态分布的计量资料2组间比较采用t检验;非正态分布的计量资料多组间比较采用Kruskal-Wallis H检验,2组间比较采用Mann-Whitney U检验;计数资料2组间比较采用χ2检验,相关性分析采用Pearson相关系数。结果 HBV-ACLF组ALT、AST、TBil、Cr、INR、HBV DNA、TBil/ALT比值及MELD评分等指标明显高于CHB组,Alb、PTA指标明显低于CHB组（P值均<0. 05）。HBV-ACLF患者外周血CD3+CD56+NKT细胞数量为明显低于CHB组[（19. 13±13. 82）%vs （26. 75±11...
- 乙型肝炎 /
- 慢加急性肝功能衰竭 /
- 杀伤细胞,天然 /
- 预后
Abstract:
Objective To investigate the expression of T-cell immunoglobulin and mucin domain-containing molecule 3 ( TIM-3) in natural killer T ( NKT) cells and its association with liver injury and prognosis in patients with hepatitis B virus-related acute-on-chronic liver failure ( HBV-ACLF) . Methods Peripheral blood mononuclear cells were isolated from 43 patients with HBV-ACLF and 28 patients with chronic hepatitis B ( CHB) who were treated in Beijing YouAn Hospital, Capital Medical University, from September 2016 to June 2018, and flow cytometry was used to measure the number of peripheral blood CD3+CD56+NKT cells and the expression of TIM-3.The t-test was used for comparison of normally distributed continuous data between two groups. The Kruskal-Wallis H test was used for comparision of non-normally distributed continuous data between multiple groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between groups, and the Pearson correlation coefficient was used to investigate correlation. Results Compared with the CHB group, the HBV-ACLF group had significantly higher alanine aminotransferase ( ALT) , aspartate aminotransferase ( AST) , total bilirubin ( TBil) , creatinine, international normalized ratio ( INR) , HBV DNA, TBil/ALT ratio, and Model for End-Stage Liver Disease ( MELD) score, as well as significantly lower albumin and prothrombin time activity ( PTA) ( all P < 0. 05) . Compared with the CHB group, the HBV-ACLF grouphad a significantly higher number of CD3+CD56+NKT cells ( 19. 13% ± 13. 82% vs 26. 75% ± 11. 84%, t = 2. 401, P = 0. 019) and significantly higher expression of TIM-3 in CD3+CD56+NKT cells [5. 53% ( 2. 95%-10. 2%) vs 1. 59% ( 0. 91%-2. 7%) , Z =-5. 260, P < 0. 001]. The expression of TIM-3 in CD3+CD56+NKT cells was positively correlated with ALT ( r = 0. 637, P < 0. 000 1) , AST ( r = 0. 414, P = 0. 006) , INR ( r = 0. 335, P = 0. 031) , and MELD score ( r = 0. 355, P = 0. 021) and was negatively correlated with PTA% ( r =-0. 313, P = 0. 043) . Among the 43 patients with HBV-ACLF, 12 had early-stage HBV-ACLF, 21 had middle-stage HBV-ACLF, and 10 had advanced HBV-ACLF, and there was no significant difference in the number of CD3+CD56+NKT cells between the three groups ( all P > 0. 05) , but with a tendency of increase; the patients with middle-stage or advanced HBV-ACLF had significantly higher expression of TIM-3 in CD3+CD56+NKT cells than those with early-stage HBV-ACLF [6. 5% ( 3. 16%-11. 45%) /8. 56% ( 4%-10. 93%) vs 2. 58% ( 1. 92%-6. 02%) , Z =-2. 284, -2. 641, both P < 0. 05]. Among the 43 patients with HBV-ACLF, the28-day survival group had significantly lower expression of TIM-3 in CD3+CD56+NKT cells than the 28-day liver transplantation/death group [2. 98% ( 1. 94%-6. 88%) vs 8. 56% ( 4. 27%-11. 43%) , Z =-2. 831, P = 0. 005]. Conclusion There is an increase in the expression of TIM-3 in peripheral blood CD3+CD56+NKT cells in patients with HBV-ACLF, which is associated with the degree of liver injury and prognosis.
- hepatitis B /
- acute-on-chronic liver failure /
- killer cells, natural /
- prognosis

HTML全文

参考文献(25)

[1] Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, CMA; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, CMA. Guideline for diagnosis and treatment of liver failure[J]. Chin J Clin Infect Dis, 2012, 5 (6) :321-327. (in Chinese) 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组.肝衰竭诊治指南 (2012年版) [J].中华临床感染病杂志, 2012, 5 (6) :321-327.

[2] ALAM A, CHUN SUEN K, MA D. Acute-on-chronic liver failure:Recent update[J]. J Biomed Res, 2017, 31 (3) :1-18.

[3] SMYK DS, MAVROPOULOS A, MIELI-VERGANI G, et al. The role of invariant NKT in autoi-mmune liver disease:Can vitamin D act as an immunomodulator?[J]. Can J Gastroenterol Hepatol, 2018:8197937.

[4] SIDDIQUI S, VISVABHARATHY L, WANG CR. Role of group 1CD1-restricted T cells in infectious disease[J]. Front Immunol, 2015, 6:337.

[5] BAE EA, SEO H, KIM IK, et al. Roles of NKT cells in cancer immunotherapy[J]. Arch Pharm Res, 2019, 42 (7) :543-548.

[6] SASIDHARAN NAIR V, TOOR SM, TAHA RZ, et al. DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer[J]. Clin Epigenetics, 2018, 10 (1) :104.

[7] WANG L, ZHAO CN, PENG QX, et al. Expression levels of CD28, CTLA-4, PD-1 and Tim-3 as novel indicators of Tcell immune function in patients with chronic hepatitis B virus infection[J]. Biomed Rep, 2014, 2 (2) :270-274.

[8] Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J]. J Clin Hepatol, 2015, 31 (12) :1941-1960. (in Chinese) 中华医学会肝病学分会, 中华医学会感染病学分会.慢性乙型肝炎防治指南 (2015年更新版) [J].临床肝胆病杂志, 2015, 31 (12) :1941-1960.

[9] BERNSMEIER C, TRIANTAFYLLOU E, BRENIG R, et al. CD14+CD15-HLA-DR-myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure[J]. Gut, 2018, 67 (6) :1155-1167.

[10] KAMATH PS, WIESNER RH, MALINCHOC M, et al. A model to predict survival in patients with end-stage liver disease[J]. Hepatology, 2001, 33 (2) :464-470.

[11] LIU J, HILL BJ, DARKO S, et al. The peripheral differentiation of human natural killer T cells[J]. Immunol Cell Biol, 2019, 97 (6) :586-596.

[12] ZHANG CP, ZHANG D. Mechanism of intrahepatic T lymphocytes in acute liver injury[J〗]. J Clin Exp Med, 2017, 16 (22) :2278-2281. (in Chinese) 张春盼, 张栋.肝内T淋巴细胞在急性肝损伤中的作用机制[J].临床和实验医学杂志, 2017, 16 (22) :2278-2281.

[13] HASHEMI V, DOLATI S, HOSSEINI A, et al. Natural killer T cells in Preeclampsia:An updated review[J]. Biomed Pharmacother, 2017, 95:412-418.

[14] PENG LS, MAO FY, ZHAO YL, et al. Altered phenotypic and functional characteristics of CD3+CD56+NKT-like cells in human gastric cancer[J]. Oncotarget, 2016, 7 (34) :55222-55230.

[15] WERNER JM, LANG C, SCHERER MN, et al. Distribution of intrahepatic T, NK and CD3 (+) CD56 (+) NKT cells alters after liver transplantation:Shift from innate to adaptive immunity?[J]. Transpl Immunol, 2011, 25 (1) :27-33.

[16] FABIANI S. Hepatitis B virus infection and interferon-inducible protein-10[J]. Clin Ter, 2015, 166 (3) :e188-e196.

[17] KARLMARK KR, WASMUTH HE, TRAUTWEIN C, et al. Chemokine-directed immune cell infiltration in acute and chronic liver disease[J]. Expert Rev Gastroenterol Hepatol, 2008, 2 (2) :233-242.

[18] S’ANCHEZ-FUEYO A, TIAN J, PICARELLA D, et al. Tim-3inhibits T helper type 1-mediated auto-and alloimmune responses and promotes immunological tolerance[J]. Nat Immunol, 2003, 4 (11) :1093-10101.

[19] ELAHI S, NIKI T, HIRASHIMA M, et al. Galectin-9 binding to Tim-3 renders activated human CD4+T cells less susceptible to HIV-1 infection[J]. Blood, 2012, 119 (18) :4192-4204.

[20] MOORMAN JP, WANG JM, ZHANG Y, et al. Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection[J]. J Immunol, 2012, 189 (2) :755-766.

[21] XU Y, WANG ZH, DU XH, et al. Tim-3 blockade promotes i NKT cell function to inhibit HBV replication[J]. J Cell Mol Med, 2018, 22 (6) :3192-3201.

[22] RONG YH, WAN ZH, SONG H, et al. Tim-3 expression on peripheral monocytes and CD3+CD16/CD56+natural killerlike T cells in patients with chronic hepatitis B[J]. Tissue Antigens, 2014, 83 (2) :76-81.

[23] XU Q, HIGGINS T, CEMBROWSKI GS. Limiting the testing of AST a diagnostically nonspecific enzyme[J]. Am J Clin Pathol, 2015, 144 (3) :423-426.

[24] YU JW, SUN LJ, ZHAO YH, et al. Prediction value of model for end-stage liver disease scoring system on prognosis in patients with acute-on-chronic hepatitis B liver failure after plasma exchange and lamivudine treatment[J]. J Gastroenterol Hepatol, 2008, 23 (8 Pt 1) :1242-1249.

[25] BAO S, ZHENG J, LI N, et al. Role of interleukin-23 in monocyte-derived dendritic cells of HBV-related acute-onchronic liver failure and its correlation with the severity of liver damage[J]. Clin Res Hepatol Gastroenterol, 2017, 41 (2) :147-155.

施引文献

资源附件(0)

访问统计