Skip to main content
Log in

Phenotyping of Intrahepatic and Peripheral Blood Lymphocytes in Patients with Chronic Hepatitis C

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The host immune responses have been suggested toplay a role in liver injury occurring in patients withchronic hepatitis C. In order to explore therelationship between the relative proportions ofintrahepatic and peripheral blood lymphocytes (IHL, PBL),the levels of viremia, and the histological hepatitisactivity score, three-color fluorescence-activatedcytometric analysis was performed for 36 patients with chronic hepatitis C and six control subjectswithout chronic hepatitis. The liver biopsy wasperformed before any antiviral therapy. Each liverspecimen was divided into two parts: one forhistological examination and one for immunological analysis.Tricolor CD45 was used to improve“lymphogating.” Fluorescein isothiocyanate-or phycoerythrin-conjugated monoclonal antibodies withspecificity for CD3, CD4, CD8, and CD20 (lymphocyte subpopulations),for CD69 (activated lymphocytes), and for CD16/56(natural killer cells) were used. The livers of patientswith chronic hepatitis C contained a greater proportion of CD4+ lymphocytes that exhibitedmarked expression of CD69 than in control subjects (20.7± 7.3% vs 10.2 ± 4.6%, P = 0.027).Moreover, in patients with chronic hepatitis C, theproportion of CD4+ IHL correlated with the histological hepatitisactivity evaluated by the Knodell score (r = 0.48, P =0.004). No correlation was found between the percentageof CD4+ IHL and the level of viremia ortransaminase activities. Our findings clearly indicate thata cellular immune response does take place inHCV-infected livers and could thus contribute to theoutcome of hepatitis C virus infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. Ranger S, Martin P, Roussane MC, Denis F: Prevalence of hepatitis C virus antibodies in the general population and in selected groups of patients in Limoges, France. Gut 34(suppl):S50–S51, 1993

    Google Scholar 

  2. Resnick RH, Koff R: Hepatitis C-related hepatocellular carcinoma: Prevalence and significance. Arch Intern Med 153:1672–1677, 1993

    Google Scholar 

  3. Alterm MJ, Margolis HS, Karwczynski K, Judson FN, Mares A, Alexander WJ, Hu PY, Miller JK, Gerber M, Sampliner RE, Meeks EL, Beach MJ: The natural history of community-acquired hepatitis C in the United States. N Engl J Med 327:1899–1905, 1992

    Google Scholar 

  4. Koziel MJ, Dudley D, Afdhal N, Choo Q-L, Houghton M, Ralston R, Walker BD: Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV. J Virol 67:7522–7532, 1993

    Google Scholar 

  5. Botarelli P, Brunetto MR, Minutello MA, Calvo P, Unutmaz D, Weiner AJ, Choo QL, Shuster JR, Kuo G, Bonino F, Houghton M, Abrignani S: T-lymphocyte response to hepatitis C virus in different clinical courses of infection. Gastroenterology 104:580–587, 1993

    Google Scholar 

  6. Hoffmann RM, Diepolder HM, Zachoval R, Zwiebel F-M, Jung MC, Scholz S, Nitschko H, Riethmuller G, Pape GR: Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection. Hepatology 21:632–638, 1995

    Google Scholar 

  7. Liaw YF, Lee CS, Tsai SL, Liaw BW, Chen TC, Sheen IS, Chu CM: T-cell-mediated autologous hepatocytotoxicity in patients with chronic hepatitis C virus infection. Hepatology 22:1368–1373, 1995

    Google Scholar 

  8. Lunel F: Hepatitis C virus and autoimmunity: Fortuitous association or reality? Gastroenterology 107:1550–1555, 1994

    Google Scholar 

  9. Pham B-N, Mosnier JF, Walker F, Njapoum C, Bougy F, Degott C, Erlinger S, Cohen JHM, Degos F: Flow cytometry CD4+/CD8+ ratio of liver-derived lymphocytes correlates with viral replication in chronic hepatitis B. Clin Exp Immunol 97:403–410, 1994

    Google Scholar 

  10. Hata K, Zhang XR, Iwatsuki S, Van Thiel DH, Herberman RB, Whiteside TL: Isolation, phenotyping and functional analysis of lymphocytes from human liver. Clin Immunol Immunopathol 56:401–419, 1990

    Google Scholar 

  11. Knodell RG, Ishack KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1:431–435, 1981

    Google Scholar 

  12. Shirai M, Okada H, Nishioka M, Akatsuka T, Wychowski C, Houghton R, Pendleton CD, Feinstone S, Berzofsky JA: An epitope in hepatitis C core region recognized by cytotoxic T cells in mice and humans. J Virol 68:3334–3342, 1994

    Google Scholar 

  13. Battegay M, Fikes J, Di Bisceglie AM, Wentworth PA, Sette A, Celis E, Ching W, Grakoui A, Rice CM, Kurokohchi K, Berzofsky JA, Hoofnagle JA, Feinstone SM, Akatsuka T: Patients with chronic hepatitis C have circulating cytotoxic T cells which recognize hepatitis C virus-encoded peptides binding to HLA-A2.1 molecules. J Virol 69:2462–2470, 1995

    Google Scholar 

  14. Koziel MJ, Dudley D, Afdhal N, Grakoui A, Rice C, Choo Q-L, Houghton M, Walker BD: HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus: Identification of multiple epitopes and characterization of patterns of cytokine release. J Clin Invest 96:2311–2321, 1995

    Google Scholar 

  15. Gaweco AS, Van Thiel DH, Rustgi V, Hassanein T, El-Ashmawy L, Whiteside T, Hofmann WJ, Otto HF: Th1 cytokine pattern and defective IL-10 in chronic hepatitis C virus-infected livers. Hepatology 22:335A, 1995 (abstract)

    Google Scholar 

  16. Napoli J, Bishop A, McGuinness PH, Painter DM, McCaughan GW: Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of TH1-associated cytokines. Hepatology 24:759–765, 1996

    Google Scholar 

  17. Minutello MA, Pileri P, Unutmaz D, Censini S, Kuo G, Houghton M, Brunetto MR, Bonino F, Abrignani S: Compartimentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C. J Exp Med 178:17–25, 1993

    Google Scholar 

  18. Ferrari C, Valli A, Galati L, Penna A, Scaccaglia P, Giuberti T, Schianchi C, Missale G, Marin MG, Fiaccadori F: T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections. Hepatology 19:286–295, 1994

    Google Scholar 

  19. Schupper H, Hayashi P, Scheffel J, Aceituno S, Paglieroni T, Holland PV, Zeldis JB: Peripheral-blood mononuclear cell responses to recombinant hepatitis C virus antigens in patients with chronic hepatitis C. Hepatology 18:1055–1060, 1993

    Google Scholar 

  20. Leroux-Roels G, Esquivel CA, DeLeys R, Stuyver L, Elewaut A, Philippé J, Desombere I, Paradijs J, Maertens G: Lympho-proliferative responses to hepatitis C virus core, E1, E2, and NS3 in patients with chronic hepatitis C infection treated with interferon alfa. Hepatology 23:8–16, 1996

    Google Scholar 

  21. Lechmann M, Ihlenfeldt HG, Braunschweiger I, Giers G, Jung G, Matz B, Kaiser R, Sauerbruch T, Spengler U: T-and B-cell responses to different hepatitis C virus antigens in patients with chronic hepatitis C infection and healthy anti-hepatitis C virus-positive blood donors without viremia. Hepatology 24:790–795, 1996

    Google Scholar 

  22. Garcia-Monzon C, Sanchez-Madrid F, Garcia-Buey L, Garcia-Arroyo A, Garcia-Sanchez A, Moreno-Otero R: Vascular adhesion molecule expression in viral chronic hepatitis: evidence of neoangiogenesis in portal tracts. Gastroenterology 108:231–241, 1995

    Google Scholar 

  23. Garcia-Monzon C, Moreno-Otero R, Pajares JM, Garcia-Sanchez A, Lopez-Botet M, de Landazuri MO, Sanchez-Madrid F: Expression of a novel activation antigen on intrahepatic CD8+ T lymphocytes in viral chronic active hepatitis. Gastroenterology 98:1029–1035, 1990

    Google Scholar 

  24. Sanchez-Madrid F: Overview of CD69. In Leukocyte Typing V. White Cell. Differentiation Antigens. SF Schlossman et al (eds). 1995, pp 1123–1124

  25. Martell M, Esteban JI, Quer J, Genesca J, Weiner A, Esteban R, Guardia J, Gomez J: Hepatitis C virus circulates as a population of different but closely related genomes: Quasispecies nature of HCV genome distribution. J Virol 66:3225–3229, 1992

    Google Scholar 

  26. Weiner AJ, Geysen HM, Christopherson C, Hall JE, Mason TJ, Saracco G, Bonino F, Crawford K, Marion CD, Crawford KA: Evidence for immune selection of hepatitis C virus putative envelope glycoprotein variants: Potential role in chronic HCV infections. Proc Natl Acad Sci USA 89:3468–3472, 1992

    Google Scholar 

Download references

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernard, JL., Gugenheim, J., Saint-Paul, MC. et al. Phenotyping of Intrahepatic and Peripheral Blood Lymphocytes in Patients with Chronic Hepatitis C. Dig Dis Sci 42, 2495–2500 (1997). https://doi.org/10.1023/A:1018856410794

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018856410794

Navigation