1887

Abstract

Dendritic cell (DC) frequencies in the blood of patients with chronic hepatitis C virus (HCV) infection have been shown to be reduced significantly compared with those in healthy individuals. There is a further reduction of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in HCV patients receiving alpha interferon (IFN-)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their ‘loss’ in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN- treatment induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN- therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.83517-0
2008-05-01
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/5/1243.html?itemId=/content/journal/jgv/10.1099/vir.0.83517-0&mimeType=html&fmt=ahah

References

  1. Adams D. H., Hubscher S., Fear J., Johnston J., Shaw S., Afford S. 1996; Hepatic expression of macrophage inflammatory protein-1 α and macrophage inflammatory protein-1 β after liver transplantation. Transplantation 61:817–825 [CrossRef]
    [Google Scholar]
  2. Afford S. C., Fisher N. C., Neil D. A., Fear J., Brun P., Hubscher S. G., Adams D. H. 1998; Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. J Pathol 186:82–89 [CrossRef]
    [Google Scholar]
  3. Auffermann-Gretzinger S., Keeffe E. B., Levy S. 2001; Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood 97:3171–3176 [CrossRef]
    [Google Scholar]
  4. Averill L., Lee W. M., Karandikar N. J. 2007; Differential dysfunction in dendritic cell subsets during chronic HCV infection. Clin Immunol 123:40–49 [CrossRef]
    [Google Scholar]
  5. Bain C., Fatmi A., Zoulim F., Zarski J. P., Trepo C., Inchauspe G. 2001; Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology 120:512–524 [CrossRef]
    [Google Scholar]
  6. Banchereau J., Steinman R. M. 1998; Dendritic cells and the control of immunity. Nature 392:245–252 [CrossRef]
    [Google Scholar]
  7. Banchereau J., Briere F., Caux C., Davoust J., Lebecque S., Liu Y. J., Pulendran B., Palucka K. 2000; Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811 [CrossRef]
    [Google Scholar]
  8. Barnes E., Salio M., Cerundolo V., Medlin J., Murphy S., Dusheiko G., Klenerman P. 2004; Impact of alpha interferon and ribavirin on the function of maturing dendritic cells. Antimicrob Agents Chemother 48:3382–3389 [CrossRef]
    [Google Scholar]
  9. Bekisz J., Schmeisser H., Hernandez J., Goldman N. D., Zoon K. C. 2004; Human interferons alpha, beta and omega. Growth Factors 22:243–251 [CrossRef]
    [Google Scholar]
  10. Bonacchi A., Petrai I., DeFranco R. M., Lazzeri E., Annunziato F., Efsen E., Cosmi L., Romagnani P., Milani S. other authors 2003; The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 125:1060–1076 [CrossRef]
    [Google Scholar]
  11. Bowen D. G., Walker C. M. 2005; Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436:946–952 [CrossRef]
    [Google Scholar]
  12. Branca A. A. 1988; Interferon receptors. In Vitro Cell Dev Biol 24155–165 [CrossRef]
    [Google Scholar]
  13. Cella M., Jarrossay D., Facchetti F., Alebardi O., Nakajima H., Lanzavecchia A., Colonna M. 1999; Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5:919–923 [CrossRef]
    [Google Scholar]
  14. Decalf J., Fernandes S., Longman R., Ahloulay M., Audat F., Lefrerre F., Rice C. M., Pol S., Albert M. L. 2007; Plasmacytoid dendritic cells initiate a complex chemokine and cytokine network and are a viable drug target in chronic HCV patients. J Exp Med 204:2423–2437 [CrossRef]
    [Google Scholar]
  15. Della Bella S., Crosignani A., Riva A., Presicce P., Benetti A., Longhi R., Podda M., Villa M. L. 2007; Decrease and dysfunction of dendritic cells correlate with impaired hepatitis C virus-specific CD4+ T-cell proliferation in patients with hepatitis C virus infection. Immunology 121:283–292 [CrossRef]
    [Google Scholar]
  16. Dieu M. C., Vanbervliet B., Vicari A., Bridon J. M., Oldham E., Aït-yahia S., Brière F., Zlotnik A., Lebecque S., Caux C. 1998; Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 188:373–386 [CrossRef]
    [Google Scholar]
  17. Dolganiuc A., Chang S., Kodys K., Mandrekar P., Bakis G., Cormier M., Szabo G. 2006; Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol 177:6758–6768 [CrossRef]
    [Google Scholar]
  18. Dzionek A., Fuchs A., Schmidt P., Cremer S., Zysk M., Miltenyi S., Buck D. W., Schmitz J. 2000; BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 165:6037–6046 [CrossRef]
    [Google Scholar]
  19. Fanning S. L., George T. C., Feng D., Feldman S. B., Megjugorac N. J., Izaguirre A. G., Fitzgerald-Bocarsly P. 2006; Receptor cross-linking on human plasmacytoid dendritic cells leads to the regulation of IFN-alpha production. J Immunol 177:5829–5839 [CrossRef]
    [Google Scholar]
  20. Goddard S., Williams A., Morland C., Qin S., Gladue R., Hubscher S. G., Adams D. H. 2001; Differential expression of chemokines and chemokine receptors shapes the inflammatory response in rejecting human liver transplants. Transplantation 72:1957–1967 [CrossRef]
    [Google Scholar]
  21. Goutagny N., Vieux C., Decullier E., Ligeoix B., Epstein A., Trepo C., Couzigou P., Inchauspe G., Bain C. 2004; Quantification and functional analysis of plasmacytoid dendritic cells in patients with chronic hepatitis C virus infection. J Infect Dis 189:1646–1655 [CrossRef]
    [Google Scholar]
  22. Gunn M. D. 2003; Chemokine mediated control of dendritic cell migration and function. Semin Immunol 15:271–276 [CrossRef]
    [Google Scholar]
  23. Heydtmann M., Hardie D., Shields P. L., Faint J., Buckley C. D., Campbell J. J., Salmon M., Adams D. H. 2006; Detailed analysis of intrahepatic CD8 T cells in the normal and hepatitis C-infected liver reveals differences in specific populations of memory cells with distinct homing phenotypes. J Immunol 177:729–738 [CrossRef]
    [Google Scholar]
  24. Ho C. S., Munster D., Pyke C. M., Hart D. N., Lopez J. A. 2002; Spontaneous generation and survival of blood dendritic cells in mononuclear cell culture without exogenous cytokines. Blood 99:2897–2904 [CrossRef]
    [Google Scholar]
  25. Itose I., Kanto T., Inoue M., Miyazaki M., Miyatake H., Sakakibara M., Yakushijin T., Oze T., Hiramatsu N. other authors 2007; Involvement of dendritic cell frequency and function in virological relapse in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients. J Med Virol 79:511–521 [CrossRef]
    [Google Scholar]
  26. Kanto T., Hayashi N., Takehara T., Tatsumi T., Kuzushita N., Ito A., Sasaki Y., Kasahara A., Hori M. 1999; Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol 162:5584–5591
    [Google Scholar]
  27. Kanto T., Inoue M., Miyatake H., Sato A., Sakakibara M., Yakushijin T., Oki C., Itose I., Hiramatsu N. other authors 2004; Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J Infect Dis 190:1919–1926 [CrossRef]
    [Google Scholar]
  28. Krug A., Uppaluri R., Facchetti F., Dorner B. G., Sheehan K. C., Schreiber R. D., Cella M., Colonna M. 2002; IFN-producing cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation. J Immunol 169:6079–6083 [CrossRef]
    [Google Scholar]
  29. Kunitani H., Shimizu Y., Murata H., Higuchi K., Watanabe A. 2002; Phenotypic analysis of circulating and intrahepatic dendritic cell subsets in patients with chronic liver diseases. J Hepatol 36:734–741 [CrossRef]
    [Google Scholar]
  30. Kusano F., Tanaka Y., Marumo F., Sato C. 2000; Expression of C-C chemokines is associated with portal and periportal inflammation in the liver of patients with chronic hepatitis C. Lab Invest 80:415–422 [CrossRef]
    [Google Scholar]
  31. Lai W. K., Curbishley S. M., Goddard S., Alabrabra E., Shaw J., Youster J., McKeating J., Adams D. H. 2007; Hepatitis C is associated with perturbation of intrahepatic myeloid and plasmacytoid dendritic cell function. J Hepatol 47:338–347 [CrossRef]
    [Google Scholar]
  32. Larner A. C., Petricoin E. F., Nakagawa Y., Finbloom D. S. 1993; IL-4 attenuates the transcriptional activation of both IFN- α and IFN- γ -induced cellular gene expression in monocytes and monocytic cell lines. J Immunol 150:1944–1950
    [Google Scholar]
  33. Longman R. S., Talal A. H., Jacobson I. M., Rice C. M., Albert M. L. 2005; Normal functional capacity in circulating myeloid and plasmacytoid dendritic cells in patients with chronic hepatitis C. J Infect Dis 192:497–503 [CrossRef]
    [Google Scholar]
  34. Luft T., Pang K. C., Thomas E., Hertzog P., Hart D. N., Trapani J., Cebon J. 1998; Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol 161:1947–1953
    [Google Scholar]
  35. Mackay C. R. 2001; Chemokines: immunology's high impact factors. Nat Immunol 2:95–101 [CrossRef]
    [Google Scholar]
  36. Marra F., DeFranco R., Grappone C., Milani S., Pastacaldi S., Pinzani M., Romanelli R. G., Laffi G., Gentilini P. 1998; Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol 152:423–430
    [Google Scholar]
  37. Murakami H., Akbar S. M., Matsui H., Horiike N., Onji M. 2004; Decreased interferon-alpha production and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C. Clin Exp Immunol 137:559–565 [CrossRef]
    [Google Scholar]
  38. Nattermann J., Zimmermann H., Iwan A., von Lilienfeld-Toal M., Leifeld L., Nischalke H. D., Langhans B., Sauerbruch T., Spengler U. 2006; Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C. Hepatology 44:945–954 [CrossRef]
    [Google Scholar]
  39. Nischalke H. D., Nattermann J., Fischer H. P., Sauerbruch T., Spengler U., Dumoulin F. L. 2004; Semiquantitative analysis of intrahepatic CC-chemokine mRNAs in chronic hepatitis C. Mediators Inflamm 13:357–359 [CrossRef]
    [Google Scholar]
  40. Patel V. P., Kreider B. L., Li Y., Li H., Leung K., Salcedo T., Nardelli B., Pippalla V., Gentz S. other authors 1997; Molecular and functional characterization of two novel human C-C chemokines as inhibitors of two distinct classes of myeloid progenitors. J Exp Med 185:1163–1172 [CrossRef]
    [Google Scholar]
  41. Penna G., Sozzani S., Adorini L. 2001; Cutting edge: selective usage of chemokine receptors by plasmacytoid dendritic cells. J Immunol 167:1862–1866 [CrossRef]
    [Google Scholar]
  42. Piccioli D., Tavarini S., Nuti S., Colombatto P., Brunetto M., Bonino F., Ciccorossi P., Zorat F., Pozzato G. other authors 2005; Comparable functions of plasmacytoid and monocyte-derived dendritic cells in chronic hepatitis C patients and healthy donors. J Hepatol 42:61–67
    [Google Scholar]
  43. Platanias L. C. 2005; Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5:375–386 [CrossRef]
    [Google Scholar]
  44. Sallusto F., Schaerli P., Loetscher P., Schaniel C., Lenig D., Mackay C. R., Qin S., Lanzavecchia A. 1998; Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 28:2760–2769 [CrossRef]
    [Google Scholar]
  45. Schwabe R. F., Bataller R., Brenner D. A. 2003; Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 285:G949–G958 [CrossRef]
    [Google Scholar]
  46. Shields P. L., Morland C. M., Salmon M., Qin S., Hubscher S. G., Adams D. H. 1999; Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 163:6236–6243
    [Google Scholar]
  47. Shiina M., Kobayashi K., Kobayashi T., Kondo Y., Ueno Y., Shimosegawa T. 2006; Dynamics of immature subsets of dendritic cells during antiviral therapy in HLA-A24-positive chronic hepatitis C patients. J Gastroenterol 41:758–764 [CrossRef]
    [Google Scholar]
  48. Shiow L. R., Rosen D. B., Brdickova N., Xu Y., An J., Lanier L. L., Cyster J. G., Matloubian M. 2006; CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440:540–544 [CrossRef]
    [Google Scholar]
  49. Soo H. M., Garzino-Demo A., Hong W., Tan Y. H., Tan Y. J., Goh P. Y., Lim S. G., Lim S. P. 2002; Expression of a full-length hepatitis C virus cDNA up-regulates the expression of CC chemokines MCP-1 and RANTES. Virology 303:253–277 [CrossRef]
    [Google Scholar]
  50. Sozzani S., Allavena P., D'Amico G., Luini W., Bianchi G., Kataura M., Imai T., Yoshie O., Bonecchi R., Mantovani A. 1998; Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J Immunol 161:1083–1086
    [Google Scholar]
  51. Stark G. R., Kerr I. M., Williams B. R., Silverman R. H., Schreiber R. D. 1998; How cells respond to interferons. Annu Rev Biochem 67:227–264 [CrossRef]
    [Google Scholar]
  52. Ulsenheimer A., Gerlach J. T., Jung M. C., Gruener N., Wachtler M., Backmund M., Santantonio T., Schraut W., Heeg M. H. other authors 2005; Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection. Hepatology 41:643–651 [CrossRef]
    [Google Scholar]
  53. Valiante N. M., D'Andrea A., Crotta S., Lechner F., Klenerman P., Nuti S., Wack A., Abrignani S. 2000; Life, activation and death of intrahepatic lymphocytes in chronic hepatitis C. Immunol Rev 174:77–89 [CrossRef]
    [Google Scholar]
  54. Wertheimer A. M., Bakke A., Rosen H. R. 2004; Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology 40:335–345
    [Google Scholar]
  55. Willmann K., Dunne J. F. 2000; A flow cytometric immune function assay for human peripheral blood dendritic cells. J Leukoc Biol 67:536–544
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.83517-0
Loading
/content/journal/jgv/10.1099/vir.0.83517-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error