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


CONCLUSIONS
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.
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.
Zhang
Z
Wenjin
Peng
P
Chuanhui
Wan
W
Yunle
Shaikh Abdul
SA
Lateef
Zheng
Z
Shusen
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D001706:Biopsy; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004279:DNA, Viral / Q000097:blood / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000096:biosynthesis / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000821:virology; D008137:Longitudinal Studies; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D004279:DNA, Viral; D015789:HLA-A2 Antigen; D006514:Hepatitis B Surface Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000410:Alanine Transaminase