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

Abstract

BackgroundControversy 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.MethodsFifteen 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.ConclusionThe 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.

Hepatitis B flares in chronic hepatitis B: Pathogenesis, natural course, and management

“…Longitudinal immunologic studies showed a decline of HBcAg-specific regulatory T cell (Treg) frequencies, associated with an increase in HBcAg-specific cytotoxic T lymphocyte (CTL) frequencies prior to the peak of the hepatitis flare [28][29][30], IL-10-producing regulatory B cell frequencies and serum IL-10 level peaked with the increase in viral load and decreased at the same time or shortly after the peak of ALT [31], large fluctuations in serum IFN-a and IL-8 concentrations with peak levels coinciding with a sharp increase in viral load preceding the onset of the hepatitis flare, and the increases in serum IFN-a and IL-8 promoted a pathway for the natural killer (NK)-cell mediated liver damage [32]. It was also shown that hepatitis flares were temporarily associated with high serum levels of INF-c inducible chemokines CXCL-9 and CXCL-10 [33], and that increase, peak and decline in the levels of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 went parallel with the ascend, peak and decline of HBV-specific T cells and serum ALT levels [34]. Integrated together (Table 1), these findings suggest that hepatitis B flares are the results of dynamic changes of the innate and adaptive immune responses with HLA-I restricted, CTL mediated immune cytolysis of HBV antigen(s) expressing hepatocytes and its downstream apoptotic mechanisms [3,7].…”

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

“…The fact that a PD-1 1 NK cell subset could be detected in only some of the subjects analyzed might be a result of latent chronic infections affecting these subjects (in this context it is of note that an increase in PD-1 1 lymphocyte numbers has been associated with hepatitis C virus, hepatitis B virus, and HIV infections). 6,7,[61][62][63] Although a correlation exists between the presence of PD-1 1 NK cells and HCMV infection, phenotypic analysis of PD-1 1 NK cells showed that NKG2C (the expression of which is associated to HCMV infection) is not preferentially expressed by PD-1 1 cells. However, similar to NKG2C 1 NK cells accumulating in response to HCMV infection, the PD-1 1 subset was almost exclusively composed of highly differentiated NKG2A 2 KIR 1 CD57 1 NK cells.…”

Serum soluble programmed death ligand-1 is correlated with HBsAg level and nucleos(t)ide analogue therapy in chronic hepatitis B

“…The second step of the increased serum sPD-L1 levels, from immunotolerance (CHB-IT) to immunoactivation (CHB-IA), is in concordance with the positive correlation of the intrahepatic expressions of PD-1 and PD-L1 with liver inflammation in CHB [29,30]. Thus, the PD-1/PD-L1 axis, after immunoactivation, is served as an adaption of the host defense to minimize immunopathology [31].…”

“…In CHB-IA, NUC treatment was correlated with significantly higher serum sPD-L1 levels, which was strong and independent on the status of ALT in HBeAg-positive CHB-IA. However, the correlation in HBeAg-negative CHB-IA was not obvious, probably because such NUC-treated patients with adequate response is more like CHB-IC, in which the long-term remission of liver inflammation is trend to decrease the intrahepatic PD-L1 expression [29,30]. Indeed, the serum sPD-L1 levels showed a downward trend in CHB-IC in this study.…”