Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis.
OBJECTIVE
Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are two autoimmune diseases with unknown etiologies that primarily target the liver. In both diseases, liver lesions are accompanied by large infiltrates of mononuclear cells. The purpose of this study was to determine if either the Fas-mediated or the granule-exocytosis pathways contribute to apoptosis in these diseases.


METHODS
To determine the involvement of apoptosis in tissue injury we examined liver tissue for DNA fragmentation and morphological characteristics of apoptosis. The major cytotoxic pathways of activated lymphocytes were compared by quantitating the levels of transcripts for FasL and granzyme B, and expression was confirmed by immunoprecipitation 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, reflecting a possible increase in the relative contribution of FasL to the progression of the disease. Immunoprecipitation studies further support an increase in FasL protein expression in AIH.


CONCLUSIONS
These data suggest that both 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 hepatocyte apoptosis and tissue destruction in AIH.
Fox
C K
CK
Stanford University School of Medicine, Department of Surgery, Division of Transplantation, Stanford, CA 94305-5492, USA.
Furtwaengler
A
A
Nepomuceno
R R
RR
Martinez
O M
OM
Krams
S M
SM
D017209:Apoptosis; D053222:Fas Ligand Protein; D019693:Hepatitis, Autoimmune / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000473:pathology* / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000502:physiology; D015398:Signal Transduction
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins