Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis

Background/Aims: Autoimmune hepatitis (AIH) and primary biliary cirrhosis ( PBC) are two autoimmune diseases with unknown etiologies that primarily tar get the liver. In both diseases, liver lesions are accompanied by large inf iltrates of mononuclear cells. The purpose of this study was to determine i f either the Fas-mediated or the granule-exocytosis pathways contribute to apoptosis in these diseases. Methods: To determine the involvement of apopt osis in tissue injury we examined liver tissue for DNA fragmentation and mo rphological characteristics of apoptosis. The major cytotoxic pathways of a ctivated lymphocytes were compared by quantitating the levels of transcript s for FasL and granzyme B, and expression was confirmed by immunoprecipitat ion of these molecules. Results: In both diseases, apoptosis was observed. However, the main cell types undergoing apoptosis were hepatocytes in AIH, and biliary epithelial cells in PBC. In AIH the levels of FasL and granzyme , B mRNA were increased over the levels detected in normal liver, while in PBC only the levels of granzyme B were elevated. Additionally, in AIH, the ratio of FasL transcripts to granzyme B transcripts was elevated, reflectin g a possible increase in the relative contribution of FasL to the progressi on of the disease. Immunoprecipitation studies further support an increase in FasL protein expression in AIH. Conclusions,: These data suggest that bo th FasL and granzyme, B contribute to the apoptosis observed in AIH and PBC . However, FasL appears to play a more prominent role in the induction of h epatocyte apoptosis and tissue destruction in AIH.