Clinical Significance of Serum Soluble Fas, Fas Ligand and Fas in Hepatitis C

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Slide 1 : Clinical Significance of SerumSoluble Fas, Fas Ligand and Fasin Hepatitis CPresented byMaysaa El Sayed Zaki,et al.,Professor of Clinical Pathology-Mansoura faculty of Medicine
Slide 2 : Hepatitis C Virus (HCV) is a major etiological agent of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Fas-mediated apoptosis is the major cause of hepatocyte damage during liver disease. Interaction between Fas receptor on hepatocytes and Fas ligand on cytotoxic T cell induces apoptosis, a major mechanism of hepatitis C- induced hepatocyte injury (Abe et al., 2001).
Slide 3 : There is accumulating evidence showing that Fas is important in the regulation of apoptosis in hepatocytes and plays a role in the pathogenesis of hepatic diseases including liver injury, hepatitis, cirrhosis and hepatocellular carcinoma (Jiang et al., 1999). When HCV-specific T cell migrate into hepatocytes, and recognize the viral antigen via the T-cell receptor, they become activated and express Fas ligand that transduce the apoptotic death signal to Fas-bearing hepatocytes resulting in their destruction (Nasir, 2000).
Slide 4 : Aim of the Work The present work was performed to study the fas system (Fas-FasL and soluble Fas) in chronic hepatitis C infection. Also, to correlate the degree of liver cell damage with the Fas system.
Slide 5 : Material and Methods The study was carried out on 45 patients positive for HCV RNA by nested RT-PCR in addition to 13 HCV negative control subjects. Wedge liver biopsies samples were obtained from patients and controls during abdominal operations for determination of cellular expression of Fas and Fas-L on hepatocytes and infiltrating lymphocytes respectively by flow cytometry.
Slide 6 : Histological activity index (HAI) was determined in chronic HCV patients. Also blood samples were taken from patients and controls for determination of sFas by ELISA technique.
Slide 7 : Results and Discussion There was statistically insignificant difference in Fas expression in hepatocytes of patients (P = 0.34) in comparison to control. Meanwhile, there was a statistically significant decrease in FasL expression in patients compared to control (P<0.001). Feng and Kaplowitz (2000) observed that high density of Fas receptors on the plasma membrane would predispose the cell to Fas ligand-mediated injury and clearance of virally infected hepatocytes.
Slide 8 : There was statistically significant increase in soluble Fas in patients compared to control (P<0.001). In agreement with our findings, Kamihara et al. (1999) found that sFs isoform competing with the mFas isoform for ligand and thereby, decreasing receptor-mediated transduction and can protect cells from apoptosis. This leads to persistence of viral infection, predispose to liver cirrhosis and coat FasL.
Slide 9 : The HAI of liver fibrosis for all patients were within mild score with mean ± SD 4 ± 0.5. Kiyici et al. (2003)(8) found that apoptosis and Fas antigen expression in hepatocytes were correlated closely with histological activity (grade) of chronic viral hepatitis, but there were no correlations with histological stage, patient age or serum transaminase levels.
Slide 10 : In our study there was no correlation between liver enzymes ALT and AST and components of Fas system. On contrary to our results Raghuraman et al. (2005) reported that plasma levels of sFas in patients with chronic HCV infection showed significant positive correlations to ALT. The difference in finding could be attributed to difference in severity of hepatitis C infections between our patients and their patients.
Slide 11 : Conclusion From this study, we could conclude that Fas system is one of the important pathways regulating the response to HCV infection. Increased serum sFas in HCV patients is accompanied by down- regulation of Fas/Fas-L expression, resulting in inhibition of apoptosis in liver cells as a process for elimination of virus- infected cells This ultimately leads to chronicity of the disease.
Slide 12 : References Abe, S., Kotoh, K., Arao, S, et al. (2001). Fas antigen expression on hepatocytes predicts the short and long term response to interferon therapy in patients with chronic hepatitis C. Scand J. Gastroenterol. 36:326. Jiang, S., Song, M.J., Shin, E.C., et al. (1999). Apoptosis in human hepatoma cell lines chemotherapeutic drugs via fas-dependent and fas-independent pathways. Hepatology 29:101–104. Nasir, A., Arora, H.S., Kaiser, H.E. (2000). Apoptosis and pathogenesis of viral hepatits. An update. In vitro 14:297–300.
Slide 13 : Feng, G., Kaplowitz, N. (2000). Dying in fast traffic. J. Clin. Invest. 105:329–334. Kamihara, S., Yamada, Y., Tomonage, M., et al. (1999). Discrepant expression of membrane and soluble isoforms of Fas (CD95/Apo-1) in adult T- cell leukemia: soluble fas isoform is an independent factor for prognosis. Br. J. Haematol. 107:851–856. Kiyici, M., Gurel, S., Budak, F., Dolar, E., Gulten, M., Nak, S.G., Memik, F. (2003). Fas antigen (CD95) expression and apoptosis in hepatocytes of patients with chronic viral hepatitis. Eur. J. Gastroenterol. Hepatol. 15(10):1079–1084.
Slide 14 : Raghuraman, S., Abraham, P., Daniel, H.D., Ramakrishna, B.S., Sridharan, G. (2005). Characterization of soluble FAS, FAS ligand and tumor necrosis factor-alpha in patients with chronic HCV infection. J. Clin. Virol. 34(1):63–70.
Slide 15 : Thanks

 


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