PD-1 immunobiology in autoimmune hepatitis and hepatocellular carcinoma

Abstract

Disruption of liver immune tolerance allows for the development of autoimmune hepatitis (AIH) and hepatocellular carcinoma (HCC). AIH rarely progresses to HCC but the diseases similarly induce the production of IL-18 and matrix metalloproteinases. These molecules have distinct effects on the immune response, including the programmed cell-death 1 (PD-1) axis. In this review, differences in PD-1 function and possible cell signals in AIH and HCC are highlighted.

Keywords: IL-18; autoimmune hepatitis; hepatocellular carcinoma; matrix metalloproteinases; programmed cell-death 1 (PD-1).

Figure 1. AIH versus HCC

AIH is an autoimmune disease depicted by the production of antibodies, the increased activation of DC, NK, B and Tfh cells and the production of cytokines (IL-12, IL-15, IL-18, IFN-γ) that promote the recruitment (CXCL9) and activation of Th1 CD4+ cells. In some cases of AIH, sPD-1 is produced which may be cleaved from the surface of lymphocytes by MMPs produced from Ito cells, NK cells or hepatocytes. Fibrosis and cirrhosis are precursors and risk factors in the development of HCC. IL-18 is a significant factor in AIH and HCC but in HCC the immune response is dampened by the immunosuppressive functions of DCs, B cells, and Tregs as well as the production of certain cytokines (IL-10, TGF-β). The release of sPD-L1 by MMPs in HCC may be a distinct biomarker of fibrotic disease and in identifying immune suppression in comparison to inflammation and sPD-1 release.