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Open Access Research article

Longitudinal fluctuations in PD1 and PD-L1 expression in association with changes in anti-viral immune response in chronic hepatitis B

Zhang Wenjin1, Peng Chuanhui1, Wan Yunle2, Shaikh Abdul Lateef1 and Zheng Shusen1*

Author Affiliations

1 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

2 Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong Province, China

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BMC Gastroenterology 2012, 12:109  doi:10.1186/1471-230X-12-109

Published: 16 August 2012

Abstract

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.

Keywords:
PD1; PD-L1; Hepatitis B