title: The Role of FGL2 in the Pathogenesis and Treatment of Hepatitis C Virus Infection.
abstract: Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide and remains the most common indication for liver transplantation. The current standard of care leads to a sustained viral response of roughly 50% of treated patients at best. Furthermore, anti-viral therapy is expensive, prolonged, and associated with serious side-effects. Evidence suggests that a poor response to treatment may be the result of a suppressed anti-viral immunity due to the presence of increased numbers and activity of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells). We and others have recently identified fibrinogen-like protein 2 (FGL2) as a putative effector of Treg cells, which accounts for their suppressive function through binding to Fc gamma receptors (FcγR). In an experimental model of fulminant viral hepatitis, our laboratory showed that increased plasma levels of FGL2 pre- and post-viral infection were predictive of susceptibility and severity of disease. Moreover, treatment with antibody to FGL2 fully protected susceptible animals from the lethality of the virus, and adoptive transfer of wild-type Treg cells into resistant fgl2-deficient animals accelerated their mortality post-infection. In patients with HCV infection, plasma levels of FGL2 and expression of FGL2 in the liver correlated with the course and severity of the disease. Collectively, these studies suggest that FGL2 may be used as a biomarker to predict disease progression in HCV patients and be a logical target for the development of novel therapeutic approaches for the treatment of patients with HCV infection.
authors.affiliation: Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada.
authors.forename: Itay
authors.initials: I
authors.lastname: Shalev
authors.forename: Nazia
authors.initials: N
authors.lastname: Selzner
authors.forename: Ahmed
authors.initials: A
authors.lastname: Helmy
authors.forename: Katharina
authors.initials: K
authors.lastname: Foerster
authors.forename: Oyedele A
authors.initials: OA
authors.lastname: Adeyi
authors.forename: David R
authors.initials: DR
authors.lastname: Grant
authors.forename: Gary
authors.initials: G
authors.lastname: Levy
keywords: FGL2; HCV; MHV-3; Treg; immunity; regulation
references.citation: J Immunol. 2002 Sep 15;169(6):3447-58
references.pmid: 12218168
references.citation: Nature. 2007 Feb 22;445(7130):936-40
references.pmid: 17237761
references.citation: J Immunol. 2004 May 1;172(9):5693-701
references.pmid: 15100314
references.citation: Adv Exp Med Biol. 1984;173:397-9
references.pmid: 6331127
references.citation: J Antimicrob Chemother. 2004 Jul;54(1):17-20
references.pmid: 15190032
references.citation: Curr Top Microbiol Immunol. 2006;305:51-66
references.pmid: 16724800
references.citation: J Exp Med. 1981 Oct 1;154(4):1150-63
references.pmid: 6270227
references.citation: Liver Int. 2009 Jan;29 Suppl 1:74-81
references.pmid: 19207969
references.citation: J Immunol. 2007 Apr 1;178(7):4230-9
references.pmid: 17371979
references.citation: Hepatology. 1999 Sep;30(3):787-93
references.pmid: 10462387
references.citation: J Virol. 1995 Sep;69(9):5252-60
references.pmid: 7636967
references.citation: Hepatology. 2002 Nov;36(5 Suppl 1):S237-44
references.pmid: 12407599
references.citation: Zhonghua Yi Xue Za Zhi. 2003 Apr 25;83(8):678-83
references.pmid: 12887828
references.citation: Hepatology. 2009 Feb;49(2):387-97
references.pmid: 19085958
references.citation: Circulation. 2005 Jul 12;112(2):248-56
references.pmid: 15998670
references.citation: Gastroenterology. 1999 Oct;117(4):926-32
references.pmid: 10500076
references.citation: J Virol. 1998 Sep;72(9):7084-90
references.pmid: 9696801
references.citation: J Med Virol. 2003 Mar;69(3):306-12
references.pmid: 12526039
references.citation: Am J Pathol. 2000 Apr;156(4):1217-25
references.pmid: 10751347
references.citation: J Mol Med (Berl). 1996 Oct;74(10):583-8
references.pmid: 8912179
references.citation: J Clin Invest. 2003 Jul;112(1):58-66
references.pmid: 12840059
references.citation: Hepatology. 2004 Apr;39(4):1147-71
references.pmid: 15057920
references.citation: Adv Exp Med Biol. 1995;380:151-7
references.pmid: 8830472
references.citation: J Immunol. 2003 Apr 15;170(8):4036-44
references.pmid: 12682232
references.citation: Clin Exp Immunol. 2006 May;144(2):188-96
references.pmid: 16634790
references.citation: J Biol Chem. 2003 May 2;278(18):15541-9
references.pmid: 12594208
references.citation: Gastroenterology. 2008 May;134(6):1699-714
references.pmid: 18471548
references.citation: Jpn J Cancer Res. 2000 Nov;91(11):1103-10
references.pmid: 11092974
references.citation: Nat Rev Immunol. 2002 Jun;2(6):389-400
references.pmid: 12093005
references.citation: Liver Transpl. 2009 Apr;15(4):390-9
references.pmid: 19326408
references.citation: Liver Transpl. 2006 Feb;12(2):277-84
references.pmid: 16447185
references.citation: J Exp Med. 1998 Dec 21;188(12):2205-13
references.pmid: 9858507
references.citation: J Autoimmun. 2001 Dec;17(4):347-54
references.pmid: 11771960
references.citation: Odontology. 2004 Sep;92(1):43-7
references.pmid: 15490304
references.citation: Annu Rev Microbiol. 2004;58:391-424
references.pmid: 15487943
references.citation: J Viral Hepat. 2001 Jul;8(4):264-9
references.pmid: 11454177
references.citation: J Proteome Res. 2008 Oct;7(10):4289-98
references.pmid: 18715028
references.citation: J Immunol. 1998 Jul 1;161(1):138-47
references.pmid: 9647217
references.citation: Nat Immunol. 2003 Jan;4(1):10-1
references.pmid: 12496970
references.citation: Hepatology. 2004 Nov;40(5):1062-71
references.pmid: 15486925
references.citation: J Exp Med. 2004 Jun 7;199(11):1479-89
references.pmid: 15184501
references.citation: Eur J Immunol. 2008 Nov;38(11):3114-26
references.pmid: 18991288
references.citation: J Virol. 2005 Jun;79(12):7860-7
references.pmid: 15919940
references.citation: Science. 2003 Oct 24;302(5645):659-62
references.pmid: 14576438
references.citation: Ann Intern Med. 2004 Mar 2;140(5):346-55
references.pmid: 14996676
references.citation: Lancet. 2001 Sep 22;358(9286):958-65
references.pmid: 11583749
references.citation: Hepatogastroenterology. 2002 May-Jun;49(45):788-92
references.pmid: 12063991
references.citation: J Virol. 2004 Jan;78(1):187-96
references.pmid: 14671100
references.citation: Proc Natl Acad Sci U S A. 1987 Mar;84(6):1609-13
references.pmid: 3550794
references.citation: Immunity. 2009 May;30(5):636-45
references.pmid: 19464986
references.citation: Hepatology. 1983 Nov-Dec;3(6):964-73
references.pmid: 6313508
references.citation: Genomics. 2001 Feb 1;71(3):330-8
references.pmid: 11170750
references.citation: J Biol Chem. 1999 Apr 9;274(15):9930-6
references.pmid: 10187767
references.citation: Mol Hum Reprod. 2004 Feb;10(2):99-108
references.pmid: 14742694
references.citation: J Hepatol. 2008 May;48(5):708-13
references.pmid: 18329749
references.citation: J Immunol. 2009 Aug 1;183(3):1975-82
references.pmid: 19596987
references.citation: J Immunol. 2008 Jan 1;180(1):249-60
references.pmid: 18097026
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15661-8
references.pmid: 12441397
references.citation: N Engl J Med. 2002 Sep 26;347(13):975-82
references.pmid: 12324553
references.citation: Gastroenterology. 2001 Sep;121(3):646-56
references.pmid: 11522749
references.citation: Nat Immunol. 2005 Nov;6(11):1142-51
references.pmid: 16227984
references.citation: Nat Rev Immunol. 2005 Mar;5(3):215-29
references.pmid: 15738952
references.citation: Clin Infect Dis. 2006 Jun 1;42(11):1561-9
references.pmid: 16652313
references.citation: J Immunol. 2002 May 15;168(10):5170-7
references.pmid: 11994472