The immunologic characteristic of the stages of chronic hepatitis C and an assessment of immune system factors as prognostic criteria of a current disease

In the present study factors of immune system in peripheral blood (PB) of patients with chronic hepatitis C (CHС) with the different degree of fibrosis were determined. Patients with CHC have been divided into groups, according to the stages of disease: weak fibrosis F1 (n=32), moderate fibrosis F2 (n=22), heavy fibrosis F3 (n=19) and cirrhosis of liver F4 (n=13). The following subpopulations of T-lymphocytes have been investigated: CD3⁺CD4⁺, CD3⁺CD8⁺, CD3⁺CD16+56⁺, CD3⁺CD25⁺, CD3⁺HLA-DR⁺, CD3⁺CD4⁺CD25⁺, CD3⁺CD8⁺CD25⁺, CD3⁺CD4⁺HLA-DR+, CD3⁺CD8⁺HLA-DR⁺, CD3⁺CD95⁺. Besides, the subpopulations of В-cells (CD19⁺, CD3^CD25⁺, CD19⁺CD95⁺), Ig A, IgM, IgG, highly-, medial-, low-molecular circulating immune complexes (CIC), cytokines Th1 (IFN-γ),Th2 (IL-4, IL-10) types, as well as proinflammatory cytokines TNF-α, IL-1β were defined. This research showed that the patient with the high degree of fibrosis have the increased quantity NKT (CD3⁺CD16+56⁺) and total count of activated T-cells HLA-DR (CD3⁺HLA-DR⁺) and the tendency for growing percentages of activated cytotoxic T-cells (CD8⁺CD25⁺ and CD8⁺HLA-DR⁺), which reflects the evolution of autoimmune reactions as the disease continues.These results have shown that in the higher stages of fibrosis the patients with CHC increased activity of T-cells immunity and constant antigen-specific or non-specific stimulation of T-lymphocytes may play a significant role in pathogenesis of CHC.With the increase of the fibrosis degree in patient with CHС, levels of IgA, IgG, medium-, low-molecular CIC, cytokines IFN-γ, IL-10 were increasing and the quantity of activated B-cells (CD3^–CD25⁺) were decreasing. The research shows the domination of the B-cells response while the function of B-lymphocytes are injured and also are observed Th1/Th2 disbalance at all stages of disease. Besides, the direct correlation between CD95-antigen (Fas/APO-1) and activated CD3⁺CD4⁺CD25⁺, CD3⁺CD8⁺CD25⁺, CD3^CD25⁺ subsets of lymphocytes was found. The established changes of the factors of the immune system can be used as the prognostic criteria of CHC. 

1. Буеверов А.О. Клинические аспекты изучения апоптоза при хронических вирусных гепатитов / А.О. Буеверов, А.Е. Грязин // Рос. журн. гастроэнтерологии, гепатологии, колопроктологии. – 2006. – №2. – С.4-10.

2. Красавцев Е.Л. Уровень некоторых цитокинов и антител к вирусу гепатита С / Е.Л. Красавцев, В.М. Мицура, С.В. Жаворонок и др. // Журн. микробиол. – 2005. – №5. – С.103-105.

3. Логинов А.С. Интерлейкины при хроническом вирусном гепатите / А.С. Логинов, Т.Н. Царегородцева, М.М. Зотина // Терапевт. арх. – 2001. – Т.73, №2. – С.17-20.

4. Маммаев С.Н. Показатели клеточного и гуморального иммунитета больных хроническим гепатитом С при лечении интерфероном α. / С.Н. Mаммаев // Мед. иммунология. – 2001. – Т.3, №4. – С 557-562.

5. Наследникова И.О. Иммунорегуляторные цитокины и хронизация вирусного гепатита С: клинико-иммунологические параллели / И.О. Наследникова, Н.В. Рязанцева, Е.В. Белобородова и др. // Клин. мед. – 2005. – №9. – С.40-44.

6. Приймяги Л.С. Иммунорегуляторные Th1- и Th2-цитокины при хронических инфекциях, вызванных вирусами гепатитов В и С / Л.C. Приймяги, В.Т. Тефанова, Т.Г. Талло и др. // Вопр. вирусол. – 2003. – №4. – С. 37-40.

7. Рязанцева Н.В. Цитокины и противовирусный иммунитет / Н.В. Рязанцева, В.В. Новицкий, В.В. Белоконь и др. // Успехи физиологических наук. – 2006. – Т.37, №4. – С.34-44.

8. Сенников С.В. Экспрессия генов и продукция основных иммунорегуляторных цитокинов при вирусном гепатите С / С.В. Сенников, Д.Х. Курамшин, Н.П. Толоконская и др. // Цитокины и воспаление. – 2003. – Т.2, № 4. – С.10-13.

9. Скляр Л.Ф. Цитокиновый профиль при хроническом гепатите С / Л.Ф. Скляр, Н.Д. Никифоров, Е.В. Маркелова и др. // Клин. мед. − 2005. − №10. − С.40-44.

10. Собчак Д.М. Показатели иммунитета у больных хроническим гепатитом С при различной гистологической активности / Д.М. Собчак, Э.А. Монакова // Клин. мед. – 2004. – № 4. – С.49-52.

11. Фрейдлин И.С. Иммунные комплексы и цитокины / И.С. Фрейдлин, С.А. Кузнецова // Мед. иммунология. – 1999. – Т.1, №1-2. – С.27-36.

12. Царегородцева Т.М. Цитокины в гастроэнтерологии / Т.М. Царегородцева, Т.И. Серова. – М.: Анархасис, 2003. – 96 с.

13. Afdhal N.H. Evaluation of liver fibrosis: a concise review / N.H. Afdhal, D. Nunes // Am. J. Gastroenterol. – 2004. – Vol.99, N6. – P.1160-1174.

14. Ahmad A. Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis / A. Ahmad, F. Alvarez // J. Leukoc Biol. − 2004. − Vol.76, N4. − P.743-759.

15. Alter H.J. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome / H.J. Alter, L.B. Seeff // Semin. Liver Dis. – 2000. – Vol.20, N1. – P.17-35.

16. Cabrera R. An immunomodulatory role for CD4(+) CD25 (+) regulatory T lymphocytes in hepatitis C virus infection / R. Cabrera, Z. Tu, Y. Xu et al. // Hepatology. − 2004. − Vol.40, N5. − P.1062-1071.

17. Chang K.M. Immunopathogenesis of hepatitis virus infection / K.M. Chang // Clin. Liver Dis. – 2003. – Vol.7, N1. – P.89-105.

18. Cramp M. Hepatitis C virus (HCV) specific immune response in anti-HCV positive patients without hepatitis C viremia / M. Cramp, P. Catucci, S. Rossol et al. // Gut. – 1999. – Vol.44, N3. – P.424-429.

19. Day C.L. Broad specificity of virus-Specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection / C.L. Day, G.M. Lauer, G.K. Robbins et al. // J. Virol. – 2002. – Vol.76, N24. – P.12584-12595.

20. De Lalla C. Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis / C. De Lalla, G. Galli, L. Aldrighetti et al. // J. Immunol. – 2004. – Vol.173, N2. – P.1417-1425.

21. Kanto T. Immunopathogenesis of C Virus Infection: Multifaceted Strategies Subverting Innate and Adaptive Immunity / T. Kanto, N. Hayashi // Intern. Med. − 2006. − Vol.45, N4. − P.183-191.

22. Kawakami Y. Increased frequency of interferon-gamma-producing peripheral blood CD4+T cells in chronic hepatitis C virus infection / Y. Kawakami, S. Nabeshima, N. Farusyo et al. // Am. J.Gastroenterol. – 2000. – Vol.95, N1. – P.227-232.

23. Liu W.E. Lymphocyte subset and its apoptosis in chronic hepatitis C / W.E. Liu, D.M. Tan, Z. Zhang et al. // Zhonghua Gan Zang. Bing. Za Zhi. – 2000. – N8 – P.269-271.

24. Marcellin P. Fibrosis and disease progression in hepatitis C / P. Marcellin, T. Asselah, N. Boyer // J. Hepatol. – 2002. – Vol.36, Suppl.1. – P.47-56.

25. Morita K. Peripheral lymphocyte subsets vary with stage of hepatitis C virus-associated liver disease / K Morita, Y. Fukuda, I. Nakano et al. // Hepatogastroenterology. – 2005. – Vol.52, N66. – P.1803-1808.

26. Ni J. Accumulation of B lymphocytes with a naive, resting phenotype in a subset of hepatitis C patient / J. Ni, E. Hembrador, A.M.D. Bisceglie et al. // J. Immunol. – 2003. – Vol.170, N6. – C.3429-3439.

27. . Ogawa S. Increase in CD95 (Fas/APO-1) –positive CD4+ and CD8+ T cells in peripheral blood derived from patients with autoimmune hepatitis or chronic hepatitis C with autoimmune phenomena / S. Ogawa, K. Sakaguchi, A. Takaki et al. // J. Gastroenterol. Hepatol. – 2000. – Vol.15, N1. – P.69-75.

28. Panasiuk A. Peripheral blood T, B, and NK cells in relation to histological hepatitis activity and fibrosis stage in chronic hepatitis C / A. Panasiuk, D. Prokopowicz, J. Zak et al. // J. Hepatogastroenterol. – 2003. – Vol.50, N49. – P.178-82.

29. Racanelli V. Molecular Characterization of B Cell Clonal Expansions in the Liver of Chronically Hepatitis C Virus-Infected Patients / V. Racanelli, D. Sansonno , C. Piccoli et al. // J. Immunol. – 2001. – Vol.167, N1. – P.21-29.

30. Schirren C.A. Liver-Derived Hepatitis C Virus (HCV)-Specific CD4+ T Cells Recognize Multiple HCV Epitopes and Produce Interferon Gamma / C.A. Schirren, M.C. Jung, Gerlach J.T. et al. // Hepatology. – 2000. – Vol.32, N3. – P.597-603.

31. Shibolet O. NKT and CD8 lymphocytes mediate suppression of hepatocellular carcinoma growth via tumor antigen-pulsed dendritic cells / O. Shibolet, R. Alper, L. Zlotogarov et al. // Int J. Cancer. – 2003. – Vol.106, N2. – P.236-243.

32. Wedemeyer H. Impaired Effector Function of Hepatitis C Virus-Specific CD8+ T Cells in Chronic Hepatitis C Virus Infection / H. Wedemeyer, X.S. He, M. Nascimbeni et al. // J. Immunol. – 2002. – Vol.169, N6. – P.3447-3458.