Abstract
The liver is well known as an organ with important functions in the metabolism of lipids, proteins, and carbohydrates. Besides these functions, it is getting increasingly clear that the liver has also a central role in initiating and modulating immune responses. Special attention is linked to the fact that 75% of the liver’s blood supply comes as venous blood from the gut, not only rich in nutrients but also rich in microbial degradation products. To protect the organ and the body from these immunostimulatory microbial products, the liver has an extraordinary scavenger function clearing all these molecules. At the same time, the liver itself is protected by establishing a tolerogenic state by modulating immune responses. Adaptive and innate immune reactions are suppressed to avoid unnecessary immune activation. Here we describe the parenchymal and non-parenchymal cell populations contributing to the tolerogenic status. An organ that represses immune reactions is a well-suited target for pathogens. Here we describe the viral pathogens targeting the liver, their infection behavior, and potential therapeutic options.
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References
Abe M et al (2006) Endotoxin modulates the capacity of CpG-activated liver myeloid DC to direct Th1-type responses. Eur J Immunol 36(9):2483–2493
Aggarwal R, Jameel S (2011) Hepatitis E. Hepatology 54:2218–2226
Benseler V et al (2011) Hepatocyte entry leads to degradation of autoreactive CD8 T cells. Proc Natl Acad Sci USA 108:16735–40
Bertolino P et al (1995) Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver. Eur J Immunol 25(7):1932–1942
Bertolino P et al (2005) Early intrahepatic antigen-specific retention of naive CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice. Hepatology 42(5):1063–1071
Bissell DM et al (1995) Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest 96(1):447–455
Biswas SK, Lopez-Collazo E (2009) Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 30(10):475–487
Bosma BM et al (2006) Characterization of human liver dendritic cells in liver grafts and perfusates. Liver Transpl 12(3):384–393, Official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation SocietY
Bowen DG, Walker CM (2005) Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436(7053):946–952
Bowen DG et al (2004) The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest 114(5):701–712
Braet F, Wisse E (2002) Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol 1(1):1
Breiner KM, Schaller H, Knolle PA (2001) Endothelial cell-mediated uptake of a hepatitis B virus: a new concept of liver targeting of hepatotropic microorganisms. Hepatology 34(4 Pt 1):803–808
Breous E et al (2009) Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology 50(2):612–621
Bumgardner GL et al (1990) Comparison of in vivo and in vitro immune response to purified hepatocytes. Transplantation 49(2):429–436
Calne RY et al (1969) Induction of immunological tolerance by porcine liver allografts. Nature 223(5205):472–476
Castellaneta A et al (2009) NOD2 ligation subverts IFN-alpha production by liver plasmacytoid dendritic cells and inhibits their T cell allostimulatory activity via B7-H1 up-regulation. J Immunol 183(11):6922–6932
Chen M et al (2005) Hepatocytes express abundant surface class I MHC and efficiently use transporter associated with antigen processing, tapasin, and low molecular weight polypeptide proteasome subunit components of antigen processing and presentation pathway. J Immunol 175(2):1047–1055
Chen Y et al (2009) Distinct response of liver myeloid dendritic cells to endotoxin is mediated by IL-27. J Hepatol 51(3):510–519
Chisari FV, Isogawa M, Wieland SF (2010) Pathogenesis of hepatitis B virus infection. Pathol Biol 58(4):258–266
Diehl L et al (2008) Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 47(1):296–305
Dong H et al (2004) B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 20(3):327–336
Evans MJ et al (2007) Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446(7137):801–805
Foy E et al (2003) Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300(5622):1145–1148
Gale M Jr, Foy EM (2005) Evasion of intracellular host defence by hepatitis C virus. Nature 436(7053):939–945
Gallegos-Orozco JF, Rakela-Brodner J (2010) Hepatitis viruses: not always what it seems to be. Rev Med Chil 138(10):1302–1311
Gao B, Jeong WI, Tian Z (2008) Liver: an organ with predominant innate immunity. Hepatology 47(2):729–736
Gardner JP et al (2003) L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci USA 100(8):4498–4503
Guidotti LG, Chisari FV (2006) Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 1:23–61
Hosel M et al (2009) Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 50(6):1773–1782
Iwai Y et al (2003) PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med 198(1):39–50
Jacob AI et al (1977) Endotoxin and bacteria in portal blood. Gastroenterology 72(6):1268–1270
Jomantaite I et al (2004) Hepatic dendritic cell subsets in the mouse. Eur J Immunol 34(2):355–365
Ju C et al (2003) Tolerogenic role of Kupffer cells in allergic reactions. Chem Res Toxicol 16(12):1514–1519
Kassel R et al (2009) Chronically inflamed livers up-regulate expression of inhibitory B7 family members. Hepatology 50(5):1625–1637
Kern M et al (2010) Virally infected mouse liver endothelial cells trigger CD8(+) T-cell immunity. Gastroenterology 138:336–346
Knolle P et al (1995) Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 22(2):226–229
Knolle PA et al (1998) IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clin Exp Immunol 114(3):427–433
Knolle PA et al (1999) Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. J Immunol 162(3):1401–1407
Kruse N et al (2009) Priming of CD4+ T cells by liver sinusoidal endothelial cells induces CD25low forkhead box protein 3- regulatory T cells suppressing autoimmune hepatitis. Hepatology 50(6):1904–1913
Lanford RE et al (2011) Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA. Proc Natl Acad Sci USA 108(27):11223–11228
Lang PA et al (2010) Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice. Hepatology 52(1):25–32
Lee WY et al (2010) An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat Immunol 11(4):295–302
Limmer A et al (2000) Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 6(12):1348–1354
Lopes AR et al (2008) Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J Clin Invest 118(5):1835–1845
Lumsden AB, Henderson JM, Kutner MH (1988) Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 8(2):232–236
Lunz JG 3rd et al (2007) Gut-derived commensal bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin-6/signal transducer and activator of transcription 3 activity. Hepatology 46(6):1946–1959
Luth S et al (2008) Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest 118(10):3403–3410
Oo YH et al (2010) Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 184(6):2886–2898
Petrova M, Kamburov V (2010) Epstein-Barr virus: silent companion or causative agent of chronic liver disease? World J Gastroenterol (WJG) 16(33):4130–4134
Pileri P et al (1998) Binding of hepatitis C virus to CD81. Science 282(5390):938–941
Pohlmann S et al (2003) Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J Virol 77(7):4070–4080
Qian S et al (1994) Murine liver allograft transplantation: tolerance and donor cell chimerism. Hepatology 19(4):916–924
Radziewicz H et al (2008) Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection. J Virol 82(20):9808–9822
Rasmussen A et al (1995) Combined transplantation of liver and kidney from the same donor protects the kidney from rejection and improves kidney graft survival. Transplantation 59(6):919–921
Rehermann B, Nascimbeni M (2005) Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5(3):215–229
Rieder H et al (1990) Prostanoid release of cultured liver sinusoidal endothelial cells in response to endotoxin and tumor necrosis factor. Comparison with umbilical vein endothelial cells. J Hepatol 11(3):359–366
Rizzetto M (2009) Hepatitis D: thirty years after. J Hepatol 50(5):1043–1050
Rosen HR (2011) Clinical practice. Chronic hepatitis C infection. N Engl J Med 364(25):2429–2438
Saito T et al (2008) Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454(7203):523–527
Sato K et al (1996) Role of Kupffer cells in the induction of tolerance after liver transplantation. J Surg Res 63(2):433–438
Scarselli E et al (2002) The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 21(19):5017–5025
Schildberg FA et al (2008) Liver sinusoidal endothelial cells veto CD8 T cell activation by antigen-presenting dendritic cells. Eur J Immunol 38(4):957–967
Schurich A et al (2010) Dynamic regulation of CD8 T cell tolerance induction by liver sinusoidal endothelial cells. J Immunol 184(8):4107–4114
Sitia G et al (2011) Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog 7(6):e1002061
Starzl TE et al (1965) Factors determining short- and long-term survival after orthotopic liver homotransplantation in the dog. Surgery 58:131–155
Villadangos JA, Young L (2008) Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29(3):352–361
Warren A et al (2006) T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology (Baltimore, Md) 44(5):1182–1190
Watanabe T et al (2002) Administration of an antigen at a high dose generates regulatory CD4+ T cells expressing CD95 ligand and secreting IL-4 in the liver. J Immunol 168(5):2188–2199
Watanabe T et al (2003) A liver tolerates a portal antigen by generating CD11c + cells, which select Fas ligand + Th2 cells via apoptosis. Hepatology 38(2):403–412
Werle-Lapostolle B et al (2004) Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126(7):1750–1758
Wiegard C et al (2005) Murine liver antigen presenting cells control suppressor activity of CD4 + CD25+ regulatory T cells. Hepatology 42(1):193–199
You Q et al (2008) Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48(3):978–990
Zhang Z et al (2008) Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology 134(7):1938–493, 1949 e1-3
Zimmermann FA et al (1984) Orthotopic liver allografts in the rat. The influence of strain combination on the fate of the graft. Transplantation 37(4):406–410
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Wohlleber, D., Knolle, P.A. (2012). The Liver as an Immune-Privileged Site. In: Stein-Streilein, J. (eds) Infection, Immune Homeostasis and Immune Privilege. Birkhäuser Advances in Infectious Diseases. Springer, Basel. https://doi.org/10.1007/978-3-0348-0445-5_4
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DOI: https://doi.org/10.1007/978-3-0348-0445-5_4
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