Journal of Hepatology
Volume 53, Issue 4 , Pages 608-615 , October 2010

The novel immunoregulatory molecule FGL2: A potential biomarker for severity of chronic hepatitis C virus infection

  • Katharina Foerster

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • Ahmed Helmy

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • Yi Zhu

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • Ramzi Khattar

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • Oyedele A. Adeyi

      Affiliations

    • Department of Pathology, University of Toronto, Toronto, Canada
  • ,
  • Kit Man Wong

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • Itay Shalev

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • David A. Clark

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
    • McMaster University, Hamilton, Canada
  • ,
  • Pui-Yuen Wong

      Affiliations

    • Department of Biochemistry, University of Toronto, Toronto, Canada
  • ,
  • Elizabeth J. Heathcote

      Affiliations

    • Department of Medicine, University of Toronto, Toronto, Canada
  • ,
  • Melville J. Phillips

      Affiliations

    • Department of Pathology, University of Toronto, Toronto, Canada
  • ,
  • David R. Grant

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • Eberhard L. Renner

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
  • ,
  • Gary A. Levy

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada
    • Corresponding Author InformationCorresponding author. Address: Multi Organ Transplant Program, University Health Network, Toronto General Hospital, NCSB 11-1236, 585 University Avenue, Toronto, ON, Canada M5G 2N2. Tel.: +1 (416) 340 5166; fax: +1 (416) 340 3378.
  • ,
  • Nazia Selzner

      Affiliations

    • Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada

Received 23 September 2009 ,Revised 8 April 2010 ,Accepted 12 April 2010.

References 

  1. Doolittle RF. The structure and evolution of vertebrate fibrinogen. Ann NY Acad Sci. 1983;408:13–27
  2. Levy GA, Leibowitz JL, Edgington TS. Induction of monocyte procoagulant activity by murine hepatitis virus type 3 parallels disease susceptibility in mice. J Exp Med. 1981;154:1150–1163
  3. Shalev I, Wong KM, Foerster K, et al. The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis. Hepatology. 2009;49:387–397
  4. Levy GA, Liu M, Ding J, et al. Molecular and functional analysis of the human prothrombinase gene (HFGL2) and its role in viral hepatitis. Am J Pathol. 2000;156:1217–1225
  5. Marsden PA, Ning Q, Fung LS, et al. The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis. J Clin Invest. 2003;112:58–66
  6. Herman AE, Freeman GJ, Mathis D, et al. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med. 2004;199:1479–1489
  7. Fontenot JD, Rasmussen JP, Gavin MA, et al. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142–1151
  8. Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8:277–284
  9. Marazzi S, Blum S, Hartmann R, et al. Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes. J Immunol. 1998;161:138–147
  10. Chan CW, Kay LS, Khadaroo RG, et al. Soluble fibrinogen-like protein 2/fibroleukin exhibits immunosuppressive properties: suppressing T cell proliferation and inhibiting maturation of bone marrow-derived dendritic cells. J Immunol. 2003;170:4036–4044
  11. Shalev I, Liu H, Koscik C, et al. Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis. J Immunol. 2008;180:249–260
  12. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30:636–645
  13. Stoop JN, van der Molen RG, Baan CC, et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005;41:771–778
  14. Xu D, Fu J, Jin L, et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol. 2006;177:739–747
  15. Boettler T, Spangenberg HC, Neumann-Haefelin C, et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol. 2005;79:7860–7867
  16. Rushbrook SM, Ward SM, Unitt E, et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol. 2005;79:7852–7859
  17. Cabrera R, Tu Z, Xu Y, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40:1062–1071
  18. Furuichi Y, Tokuyama H, Ueha S, et al. Depletion of CD25+CD4+ T cells (Tregs) enhances the HBV-specific CD8+ T cell response primed by DNA immunization. World J Gastroenterol. 2005;11:3772–3777
  19. Liu H, Shalev I, Manuel J, et al. The FGL2-FcgammaRIIB pathway: a novel mechanism leading to immunosuppression. Eur J Immunol. 2008;38:3114–3126
  20. Engvall E, Perlmann P. Enzyme-linked immunosorbent assay (ELISA). Quantitative assay of immunoglobulin G. Immunochemistry. 1971;8:871–874
  21. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24:289
  22. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6:345–352
  23. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6:353–360
  24. Allan SE, Song-Zhao GX, Abraham T, et al. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur J Immunol. 2008;38:3282–3289
  25. Denning TL, Granger SW, Mucida D, et al. Mouse TCRalphabeta+CD8alphaalpha intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses. J Immunol. 2007;178:4230–4239
  26. Zhou L, Wang H, Zhong X, et al. The IL-10 and IFN-gamma pathways are essential to the potent immunosuppressive activity of cultured CD8+ NKT-like cells. Genome Biol. 2008;9:R119.1–R119.18
  27. Valmori D, Merlo A, Souleimanian NE, et al. A peripheral circulating compartment of natural naive CD4 Tregs. J Clin Invest. 2005;115:1953–1962
  28. Ito T, Hanabuchi S, Wang YH, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity. 2008;27:870–880

PII: S0168-8278(10)00535-0

doi: 10.1016/j.jhep.2010.04.020

Journal of Hepatology
Volume 53, Issue 4 , Pages 608-615 , October 2010