BMC Gastroenterology | |
Longitudinal fluctuations in PD1 and PD-L1 expression in association with changes in anti-viral immune response in chronic hepatitis B | |
Zheng Shusen2  Shaikh Abdul Lateef2  Wan Yunle1  Peng Chuanhui2  Zhang Wenjin2  | |
[1] Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong Province, China;Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China | |
关键词: Hepatitis B; PD-L1; PD1; | |
Others : 1121890 DOI : 10.1186/1471-230X-12-109 |
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received in 2012-03-11, accepted in 2012-08-08, 发布年份 2012 | |
【 摘 要 】
Background
Controversy exists regarding the role of PD1 and its ligand PD-L1 in chronic hepatitis B infection. In some studies, persistent HBV infection has been attributed to high levels of PD-1 and PD-L1 expression on HBV-specific T-cells and antigen-presenting cells (APCs) respectively. Other studies revealed that the up-regulation of PD-1 and PD-L1 during an acute inflammation phase is required to offset increasing positive co-stimulatory signals to avoid severe damage by an over-vigorous immune response.
Methods
Fifteen chronic hepatitis B patients, with inflammatory flare episode, were recruited prospectively. Based on serum HBV-DNA, HBsAg load, and ALT values, inflammatory flare episode were divided into initial, climax, decline and regression phase. Blood sample and liver biopsy tissues from each individual were taken in these 4 phases respectively. Circulating and intra-hepatic PD1 and PD-L1 expression levels were monitored throughout the inflammatory flare episode by flow cytometry and immunostaining and these expression levels were related to the HBV-specific T-cell changes, expression of pro-inflammatory cytokines, HBV-DNA replication and HBV antigen load.
Results
]The levels of PD-1 and PD-L1 expressions were significantly up-regulated in the inflammation ascending phase, initial and climax period and in parallel with HBV-specific colon expansion. It showed increasing the level of serum ALT and decreasing the HBV-DNA loads. As the level of inflammation reduced, the circulating and intra-hepatic PD1 and circulating PD-L1 decreased progressively in concordance with serum ALT, HBV-DNA and HBsAg loads decreased except intra-hepatic PD-1 expression. Intra-hepatic PD-L1 expression did not decrease significantly during the regression phase of inflammation compared to that in prior period. The intra-hepatic PD-L1 expression remained relatively on higher level when serum HBV-DNA load and ALT decreased to approximately normal range.
Conclusion
The relatively high level of intra-hepatic PD-L1 expression during the inflammatory regression period may contribute to constitute an immunosuppressive microenvironment, which facilitate persistent HBV infection via the inhibition of HBV-specific T cell clonal expansion.
【 授权许可】
2012 Wenjin et al.; licensee BioMed Central Ltd.
【 预 览 】
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【 参考文献 】
- [1]Peng G, Li S, Wu W, et al.: PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol 2008, 45:963-970.
- [2]Evans A, Riva A, Cooksley H, et al.: Programmed Death 1 Expression During Antiviral Treatment of Chronic Hepatitis B: Impact of Hepatitis B e-Antigen Seroconversion. Hepatology 2008, 48:759-769.
- [3]Rutebemberwa A, Ray SC, Astemborski J, et al.: High-Programmed Death-1 Levels on Hepatitis C Virus-Specific T Cells during Acute Infection Are Associated with Viral Persistence and Require Preservation of Cognate Antigen during Chronic Infection1. J Immunol 2008, 181:8215-8225.
- [4]Urbani S, Amadei B, Tola D, et al.: PD-1 Expression in Acute Hepatitis C Virus (HCV) Infection Is Associated with HCV-Specific CD8 Exhaustion. J Virol 2006, 80:11398-11403.
- [5]Jeong H-Y, Lee Y-J, Seo S-K, et al.: Blocking of monocyte-associated B7-H1 (CD274) enhances HCV-specific T cell immunity in chronic hepatitis C infection. J Leukoc Biol 2008, 83:755-764.
- [6]Carolina B, Paola F, Caterina V: Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection. J Virol 2007, 81:4215-4225.
- [7]Victoria K, Wiesch JSz, Thomas K, et al.: High Level of PD-1 Expression on Hepatitis C Virus (HCV)-Specifi CD8+ and CD4+ T Cells during Acute HCV Infection, Irrespective of Clinical Outcome. J Virol 2008, 82:3154-3160.
- [8]Lucy G-M, Brent P, Jared K, et al.: Upregulation of PD-1 Expression on Circulating and Intrahepatic Hepatitis C Virus-Specific CD8+ T Cells Associated with Reversible Immune Dysfunction. J Virol 2007, 81:9249-9258.
- [9]Selenko-Gebauer N, Majdic O, Szekeres A, et al.: B7-H1 (Programmed Death-1 Ligand) on Dendritic Cells Is Involved in the Induction and Maintenance of T Cell Anergy. J Immunol 2003, 170:3637-3644.
- [10]Iwai Y, Terawaki S, Ikegawa M, et al.: PD-1 Inhibits Antiviral Immunity at the Effector Phase in the Liver. J. Exp. Med 2003, 198:39-50.
- [11]Karrar A, Broome U, Uzunel M, et al.: Human liver sinusoidal endothelial cells induce apoptosis in activated T cells: a role in tolerance induction. Gut 2007, 56:243-252.
- [12]Chen L, Zhang Z, Chen W, et al.: B7–H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J Immunol 2007, 178:6634-6641.
- [13]Yu MC, Chen CH, Liang X, et al.: Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 2005, 40:1312-1321.
- [14]Kassel R, Cruise MW, Iezzoni JC, et al.: Chronically inflamed livers up-regulate expression of inhibitory B7 family members. Hepatology 2009, 50(5):1625-1637.
- [15]Poly M: Tolerance, danger, and the extended family. Annu. Rev.lmmunol 1994, 12:991-1045.
- [16]By Hiroyuki Y, Kenjiro M, Yanyun Z, et al.: Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract–associated lymphoid tissue, in a granulomatous liver disease. J. Exp. Med 2001, 193:35-49.
- [17]Hiroyuki Y, Kenjiro M, Yanyun Z, et al.: Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract–associated lymphoid tissue, in a granulomatous liver disease. J. Exp. Med 2001, 193:35-49.
- [18]Grant AJ, Goddard S, Ahmed-Choudhury J, et al.: Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am J Pathol 2002, 160:1445-1455.
- [19]Mazanet MM, Hughes CC, et al.: B7–H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J Immunol 2002, 169:3581-3588.
- [20]Rodig N, Ryan T, Allen J: A., Greenfield, E A, et al.: Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol 2003, 33:3117-3126.
- [21]Muhlbauer M, M Fleck C, Schutz T, et al.: PD-L1 is induced in hepatocytes by viral infection and by interferon-α andγand mediates T cell apoptosis. J Hepatol 2006, 45:520-528.
- [22]Abhishek D, Matthew H, Nathan D, et al.: Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J Exp Med 2008, 205(9):2111-2124.