Liver FOXP3 and PD1/PDL1 Expression is Down-Regulated in Chronic HBV Hepatitis on Maintained Remission Related to the Degree of Inflammation

Abstract

Background and Aim: T cell expression of PD1 and inhibition of T effector cells by Foxp3+-T regulatory cells are among the most powerful mechanisms for achieving a balanced immune response. Our aim was to investigate, how liver FOXP3 and PD1/PDL1 expression is regulated in chronic HBV hepatitis (CHB) on maintained long-term remission in comparison with active disease, and whether they are correlated to the expression of pro- and anti-inflammatory cytokines and apoptosis mediators, along with the degree of histological inflammation and markers of T cell effector restoration.Methods: Fifty-three HBeAg-negative CHB patients with both active (30) and completely remitted disease on long-term antiviral treatment (23) and four controls (submitted to liver biopsy due to a mild increase of aminotransferases but without liver necroinflammatory and architecture changes) were enrolled in the study. Liver mRNA levels of immunoregulatory genes (FOXP3, IL10, TGFB1, and those of PD1/PDL1/PDL2 pathway), major apoptosis mediators (FAS, FASL, TNFA, TRAIL), cytokines of effector T cell restoration (IL2, IFNG), and those of IL1B, CD4, and CD8, were evaluated by quantitative real-time reverse-transcriptase PCR and were correlated with each other, along with the intensity of liver inflammation and fibrosis staging. The expression and localization of FOXP3, PD1, PDL1, CD4, and CD8 were also assessed by immunohistochemistry.Results: The expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly down-regulated in the remission state. In contrast, liver expression of IL2 and IFNG, along with CD4, IL1B, TNFA, and FAS did not change significantly. Moreover, FOXP3, PD1, PDL1, and CD8 transcripts were positively correlated to the intensity of liver inflammation.Conclusion: Our data indicate that in the CHB disease model, the immunosuppressive liver environment is down-regulated in the maintained on-treatment long-term remission state and correlates with the intensity of liver inflammation, but not liver T cell restoration.

Varicella-Zoster Virus Downregulates Programmed Death Ligand 1 and Major Histocompatibility Complex Class I in Human Brain Vascular Adventitial Fibroblasts, Perineurial Cells, and Lung Fibroblasts

“…First-strand cDNA synthesis was carried out using the Transcriptor first-strand cDNA synthesis kit (Roche, San Francisco, CA). Primers specific for PD-L1 (15) and RPL13a (16) were used for amplification, and results were analyzed using the ⌬⌬C T method. Gene expression is represented as fold change in virusinfected versus mock-infected cells or cytokine-treated versus mock-infected cells.…”

Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis

“…It remains unclear, however, whether this decrease in PD-1 expression is a direct effect of the drugs on this molecule, or it is secondary to the decrease of the in-vivo inflammatory milieu under laboratory conditions. The former hypothesis is supported by the finding of a direct association between increase in PD-1 mRNA levels and intensity of liver inflammation in chronic hepatitis B [40].…”

Checkpoint modulation in chronic hepatitis B: From hypothesis to approval

“…In this most common clinical case scenario, we have found that the expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly downregulated in the remission state. (4) Moreover, FOXP3, PD1, PDL1, and CD8 transcripts were positively correlated with the intensity of liver inflammation. However, it is still uncertain whether the expression of PDL1 on hepatocytes truly contributes to the development of T-cell exhaustion or whether it is a homoeostatic mechanism that dampens the inflammatory reaction.…”

“…However, it is still uncertain whether the expression of PDL1 on hepatocytes truly contributes to the development of T-cell exhaustion or whether it is a homoeostatic mechanism that dampens the inflammatory reaction. (4) Therefore, the targeting of Tregs and/or PD1/ PDL1 pathway in the acute, or the early chronic HBV infection setting, may trigger autoimmune phenomena or increase immune-mediated liver damage.…”