Programmed death 1 and programmed death ligand 1 expressions in patients with chronic hepatitis B.
BACKGROUND
The role of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in persistent HBV infection is controversial. Increasing PD-1 and PD-L1 expression has been found in hepatitis B patients during immune clearance phase, but not in HBV-tolerant patients. We investigated PD-1 and PD-L1 expression and inflammation in chronic hepatitis B.


METHODS
Twenty patients with chronic hepatitis B participated in this study. Fifteen patients were in the immune clearance phase, and 5 were in the immune inactive phase. Circulating HBV-specific T cells were analyzed by flow cytometric detection of major histocompatibility complex (MHC) class I peptide complexes, known as pentamers. Intra-hepatic PD-1 and PD-L1 expressions were analyzed by immunostaining.


RESULTS
The frequency of pentamers, including core 18-27 (1.88%+/-0.36%), env 335-343 (1.85%+/-0.37%), and pol 575-583 (1.56%+/-0.29%) was 8.30-, 7.71- and 8.48-fold greater during immune clearance phase than those during the immune inactive phase. In addition, more than 70% of circulating pentamers were PD-1 positive. During immune clearance phase, the numbers of intra-hepatic PD-1 and PD-L1 positive cells were 108+/-23/HPF and 97+/-20/HPF respectively, in contrast, there was a paucity of PD-1 and PD-L1 positive cells in the immune inactive phase. The numbers of intra-hepatic PD-1 and PD-L1 positive cells were positively correlated with serum alanine aminotransferase and the number of intra-hepatic CD8+ T cells. Immunofluorescence showed that almost all of the intra-hepatic CD8+ T cells were PD-1 and CCR6 positive. These cells aggregated around macrophage inflammatory protein-3 alpha (MIP3alpha) positive cells and mixed with PD-L1 positive cells.


CONCLUSIONS
PD-1 and PD-L1 expressions were significantly correlated with inflammation. CCR6 and PD-1 co-expressed in the same cells; these cells were increased both in circulation and the inflamed liver and aggregated around MIP3alpha positive cells. The mixture of CCR6 and PD-1, MIP3alpha and PD-L1 positive cells created immune response compartments which played an important role in specific immune response in HBV immune clearance.
Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Wen-Jin
WJ
Zhang
Chuan-Hui
CH
Peng
Shu-Sen
SS
Zheng
D060890:B7-H1 Antigen / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002449:Cell Aggregation; D002465:Cell Movement; D019610:Cytoprotection; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000097:blood / Q000276:immunology*; D006801:Humans; D008099:Liver / Q000276:immunology*; D018655:Lymphocyte Count; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis*; D054399:Receptors, CCR6 / Q000032:analysis
D060890:B7-H1 Antigen; C106311:CCR6 protein, human; D061026:Programmed Cell Death 1 Receptor; D054399:Receptors, CCR6