Authors:B. Nemes, A. Doros, Á. Holczbauer, E. Sárváry, P. Nagy, G. Lengyel, A. Kiss and Zs. Schaff
Hepatitis C (HCV) is one of the main causes of liver transplantation (OLT). Previously we have reported that high serum C RNA level correlates with the severity of histopathological signs and poor clinical outcome. The core antigen of virus C is known to interfere with chaperones in the hepatocytes, results in an endoplasmic reticulum (ER) stress. In this study HCV positive liver transplanted patients were evaluated, whether there are correlations among chaperone expression, recurrence and viral titer. Patients were enrolled after surviving the first month following OLT. Sera were collected regularly, and biopsies were taken on demand following OLT. The diagnosis of recurrent HCV was proven by Knodell-Ishak scoring. In this case ribavirin+interferon were initiated, and maintained for one year. All chaperones were upregulated in the transplanted liver graft showing recurrent hepatitis C disease. ATF6, GP96, GRP78, CNX and CLR chaperones were upregulated significantly compared to their levels in normal livers. Except for one chaperone, the level of upregulation did not correlate with the serum's HCV-RNA titre: the only difference between Group1 and 2 (RNA titre above and below 8.78 106 respectively) was that the level of ATF6 was 1.6 times higher in Group1 compared to Group2. The expression of all chaperones was reduced, and some even became downregulated after the interferon treatment. In accordance with the literature our results suggest that hepatitis C might induce apoptosis through ER-stress. Those cells exposed to a high C viral load, had a lower chance to be eliminated.
Authors:Balázs Nemes, P. Sótonyi, G. Lotz, A. Heratizadeh, F. Gelley, C. Doege, M. Hubay, Zs. Schaff and B. Nashan
In chronic liver rejection lymphocyte mediated processes lead to chronic inflammation, necrosis and repair mechanisms. The aim of the present study was to investigate the expression of apoptosis related proteins (FAS/APO-1, FAS-L, Bcl-2, Bax, TNF-α, and INF-γ). ApopTag reaction and immunohistochemistry were performed on liver samples of chronically rejected allografts and compared with normal donor livers. In chronic rejection, apoptosis was detected in pericentral hepatocytes and in the biliary epithelium. Bcl-2 was strongly expressed on lymphocytes around the bile ducts, but not on the biliary epithelium itself. Bax, FAS, TNF-α and INF-γ were present in pericentral areas. T-cells showed up around bile ducts, whereas macrophages around pericentral areas. In pericentral areas apoptosis seems to be fostered through TNF-α and INF-γ and by the lack of Bcl-2. Based on these results both downregulation and upregulation of apoptotic proteins can be observed in chronic liver allograft rejection: FAS is upregulated in biliary epithelium and zone 2, protein levels of FASL remain unchanged, BAX is upregulated in zone 3, BCL2 is downregulated in both biliary epithelium and zone 1 and both TNFa and IFN are upregulated in zone 3. Our results suggest that the balance between pro- and antiapoptotic patterns was shifted to the proapoptotic side, mainly in the centrilobular area of the hepatic lobule, and in the bile ducts. According to these findings in chronic rejection the predictive sites of apoptosis are the biliary epithelium and the pericentral areas.