Apoptosis of Peripheral Blood Cytotoxic T Lymphocytes in Chronic Hepatitis C Virus Infection: Relation to Disease Severity and Response to Therapy
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- Category: Vol. 77, March 2009
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Apoptosis of Peripheral Blood Cytotoxic T Lymphocytes in Chronic Hepatitis C Virus Infection: Relation to Disease Severity and Response to Therapy,
ERVAT ABO GABAL, DAHLIA ABD EL-MOHSEN, KHALID GAMIL, OLA I. AHMED and SOHA A. EL-HADY
Abstract
Background: More than 80% of HCV-infected individuals develop chronic disease, which can progress to liver cirrhosis and hepatocellular carcinoma. T cell-mediated protection against HCV depends on constantly activated effector CD8+ T cells that control emergence, spread and expansion of the virus. Why these cells fail to contain HCV replication in 70- 80% of the individuals who develop persistent viremia is not clear. Fas receptors (APO-1 or CD95) and the Fas ligand system (Fas/FasL) have been implicated in the induction of apoptosis which is related with the pathogenesis of hepatitis C.
Aim of the Study: Was to assess the expression of CD95 (Fas/ APO-1) (as an apoptotic marker) on peripheral blood cytotoxic T lymphocytes from patients with chronic HCV infection and to correlate this with disease severity in the liver, response to antiviral therapy and extrahepatic autoim-mune manifestations.
Subjects and Methods: Thirty patients with evidence of chronic HCV infection and 10 healthy age and sex matched volunteers with negative HCV antibodies sera serving as controls were enrolled into the present study. Our patients were classified into two main groups according to antiviral therapy, Group A: They were 17 patients not receiving treat-ment and Group B: They were 13 patients who received antiviral therapy for 24 weeks. Group A patients were further subdivided according to the presence or absence of extrahepatic manifestations into two groups: Group I: They were 11 patients not receiving therapy and had no extrahepatic manifestations. Group II: They were 6 patients not receiving therapy and had extrahepatic manifestations. Group I patients were also sub-divided according to the necroinflammatory score in liver biopsy into three groups with: Mild, moderate and severe disease activity. They were also subdivided as regard fibrosis stage in liver biopsy into groups with: Moderate and severe fibrosis. Group B patients were further subdivided according to their response to antiviral therapy into: Group III: 6 patients received therapy and were non responders and Group IV: 7 patients received therapy and showed good response. After detailed history taking and thorough clinical examination, the following investigations were done: CBC, AST and ALT, serum cryoglobulins (for patients with extrahepatic disease)
and flowcytometric estimation of the percentage of apoptotic peripheral blood cytotoxic T lymphocytes (CD8+CD95+) and non apoptotic cytotoxic T lymphocytes (CD8+ CD95-). Current liver biopsy was performed in patients of Group I and examined histopathologically.
Results: There was highly statistically significant differ-ence between HCV patients and controls as regard ALT, percentage of apoptotic cytotoxic T lymphocytes (CD8+ CD95+) and non apoptotic cytotoxic T lymphocytes (CD8+ CD95-) (p<0.001). There was statistically significant difference between patients of Group I, II, III, IV and controls in per-centage of CD8+CD95+ and CD8+CD95- cells. Comparison between Group I and II revealed non significant difference in percentage of CD8+CD95+ and CD8+CD95- cells or in percentage of CD8-CD95+ cells (apoptotic non cytotoxic T) (p>0.05). Comparison between Group III and IV revealed statistically significant difference in percentage of CD8+CD95+ and CD8+CD95- cells (p<0.05). In Group I the percentage of CD8+CD95+ tended to correlate with activity index of liver biopsy but significantly correlated with serum ALT in Group III. In Group II significant positive correlation between percentage of CD8+CD95+ and AST with tendency toward correlation with ALT was found. Also percentage of CD8+CD95+ correlated with purpura and arthritis but not with cryoglobulinemia. Percentage of CD8+CD95+ showed non statistically significant correlation except with serum prothrombin time in group IV. There was increase in the percentage of CD8+CD95+ cells in higher grade of necroin-flamatory activity and in higher stage of fibrosis in liver biopsy in group I.
Conclusion: Our findings support the suggestion of major role of peripheral blood CD8+ T cells in elimination of HCV and suggest that cellular immune response plays a key role not only in viral elimination, but also in liver pathology associated with HCV-infection. Monitoring apoptosis of CD8+ T cells by measuring FAS expression is useful in follow-up of antiviral response in these patients. Finally, Fas/FasL pathway is critical in persistent HCV infection in humans and represents a potential target for restoring function of exhausted HCV-specific CTLs.