Hepatic expression of programmed death-1 (PD-1) and its ligand, PD-L1, in children with autoimmune hepatitis: relation to treatment response

Abstract

Aim of the studyAutoimmune hepatitis (AIH) is characterized histologically by aggressive inflammation with interface hepatitis and prominent lymphoplasmacytic infiltration. Programmed death-1 (PD-1) is expressed on activated lymphocytes. Engagement of PD-1 by its ligand PD-L1 leads to cell apoptosis and death. We aimed to evaluate the immunohistochemical expression of PD-1 and PD-L1 in children with AIH, and its relation to treatment outcome.Material and methodsPre-treatment liver biopsies of 31 children with AIH were compared to 30 children with chronic hepatitis C virus (HCV) infection as a control group. PD-1 was evaluated in lymphocytes, while PD-L1 was evaluated in lymphocytes, hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells. All AIH patients received the standard treatment.ResultsThe mean PD-1 was significantly higher in AIH than HCV patients (29.19 ±18.5% vs. 15.2 ±10.1%; p = 0.002) while there was no statistically significant difference as regards PD-L1 on lymphocytes (p = 0.853). Neither PD-1 nor PD-L1 correlated with either liver fibrosis or the inflammatory activity (p > 0.05 for all). PD-1/PD-L1 ratio was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders (46.9 vs. 6.58). PD-1 expression was comparable in both responders and non-responders (p = 0.813), while PD-L1 was significantly upregulated in responders (4.17 ±3.15% vs. 0.63 ±1.3%; p = 0.046). PD-L1 expression on hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells was comparable in AIH and HCV groups.ConclusionsPD-1/PD-L1 ratio, which reflects immune aggression, was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders.

Increased Intrahepatic Expression of Immune Checkpoint Molecules in Autoimmune Liver Disease

“…Importantly, the accumulation of PD-1 + CD8 + T cells in the untreated derived liver tissue correlated positively with liver pathology (ALT and A possible involvement of PD-1/PD-L1 pathway in the pathogenesis of AIH w described in mice model of experimental AIH [20] and in human studies [ sults are in accordance with Oikawa et al, who previously demonstrated histochemistry that PD-1 ICM is expressed on more than half of the intrahe patients with AILD [21]. Similarly, a recent study showed a high frequency tive cells within liver tissue in children with AIH [22]. However, neither o determined the exact type of intrahepatic T cells that express the PD-1 mole ing levels of PD-1 are also increased in AILD, as recent studies have shown t levels of soluble PD-1 are elevated in AIH patients [23,24].…”

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression

“…Indeed, imbalanced expression of PD-1/PD-L1 has previously been reported in inflamed livers of PBC and AIH patients 41,42 . Moreover, recent case reports on the development of secondary sclerosing cholangitis in patients receiving checkpoint inhibitor treatment highlight the functional importance the PD-L1/PD-1 axis for biliary immune homeostasis 43,44 .…”

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

“…Binding of PD-L1 to PD-1 leads to T cell dysfunction by inhibiting T cell activation, causing T cell exhaustion, anergy, and T cell apoptosis, as well as by inducing Treg differentiation [7][8][9][10][11]. In addition, elevated PD-L1 levels in liver were observed in chronic necroinflammatory liver diseases and autoimmune hepatitis [12,13]. These indicate the immune regulatory function of the liver microenvironment that may lead to T cell exhaustion.…”