Abstract
The liver is the largest internal organ in the body and contains many cell types that are involved in local and systemic immunity, including those of both the innate and adaptive immune systems. Approximately 10 % of the cells of the liver belong to the immune system, including the largest supply of tissue-specific macrophages and natural killer cells in the body. One of the main roles of immune cells in the liver is to establish an immunotolerant microenvironment, as the liver is the first tissue to receive portal blood flow from the gastrointestinal tract, which includes endotoxin, self-antigens, and ingested antigens. This prevents unwanted systemic immune responses towards these everyday encountered antigens. Kupffer cells and sinusoidal endothelial cells in the liver play important roles in removing pathogens and other possible antigens from the portal blood prior to them reaching the systemic circulation, also preventing unwanted reactions. Autoimmune disease can result if this immunotolerant microenvironment is disrupted. The liver also plays a role in local and systemic inflammation through the production of acute phase proteins, cytokines, and other pro-inflammatory mediators. Immune cells play an important role in many liver diseases of humans and animals, including drug-induced liver injury, viral infection, and neoplasia. In addition, the liver plays an important role in systemic disorders, particularly septicemia. This chapter outlines the normal immunobiology of the liver, including the cell types involved in the immune response, and their roles in various diseases of the liver as well as systemic disorders. Animal models of liver diseases involving the immune system are also discussed.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Abe M, Thomson AW (2007) Antigen processing and presentation in the liver. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 49–59
Abo T (1993) Extrathymic pathways of T-cell differentiation: a primitive and fundamental immune system. Microbiol Immunol 37(4):247–258
Abo T (2001) Extrathymic pathways of T-cell differentiation and immunomodulation. Int Immunopharmacol 1(7):1261–1273
Abrignani S (1997) Bystander activation by cytokines of intrahepatic T cells in chronic viral hepatitis. Semin Liver Dis 17(4):319–322. doi:10.1055/s-2007-1007208
Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A (2010) Liver ischemia/reperfusion injury: processes in inflammatory networks—a review. Liver Transpl 16(9):1016–1032. doi:10.1002/lt.22117
Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG (1994) Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 20:453–460
Adams DH, Ju C, Ramaiah SK, Uetrecht J, Jaeschke H (2010) Mechanisms of immune-mediated liver injury. Toxicol Sci 115(2):307–321
Ahlensteil G, Rehermann B (2007) Hepatic NK, NKT, and T cells. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 71–82
Ahlenstiel G, Edlich B, Hogdal LJ, Rotman Y, Noureddin M, Feld JJ, Holz LE, Titerence RH, Liang TJ, Rehermann B (2011) Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology 141(4):1231–1239. doi:10.1053/j.gastro.2011.06.069
Akbar SM, Onji M, Inaba K, Yamamura K, Ohta Y (1993) Low responsiveness of hepatitis B virus-transgenic mice in antibody response to T-cell-dependent antigen: defect in antigen-presenting activity of dendritic cells. Immunology 78(3):468–475
Alberti A, Diana S, Sculard GH, Eddleston AL, Williams R (1978) Detection of a new antibody system reacting with Dane particles in hepatitis B virus infection. Br Med J 2(6144):1056–1058
Alexandropoulos K, Bonito AJ, Weinstein EG, Herbin O (2015) Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model. Int J Mol Sci 16(1):1980–2000. doi:10.3390/ijms16011980
Amano K, Leung PS, Xu Q, Marik J, Quan C, Kurth MJ, Nantz MH, Ansari AA, Lam KS, Zeniya M, Coppel RL, Gershwin ME (2004) Xenobiotic-induced loss of tolerance in rabbits to the mitochondrial autoantigen of primary biliary cirrhosis is reversible. J Immunol 172(10):6444–6452
Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, Gonzalez-Grande R, Pizarro A, Duran JA, Jimenez M, Rodrigo L, Romero-Gomez M, Navarro JM, Planas R, Costa J, Borras A, Soler A, Salmeron J, Martin-Vivaldi R, Spanish Group for the Study of Drug-Induced Liver D (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129(2):512–520. doi:10.1016/j.gastro.2005.05.006
Aoki CA, Borchers AT, Li M, Flavell RA, Bowlus CL, Ansari AA, Gershwin ME (2005) Transforming growth factor beta (TGF-beta) and autoimmunity. Autoimmun Rev 4(7):450–459. doi:10.1016/j.autrev.2005.03.006
Baeres M, Herkel J, Czaja AJ, Wies I, Kanzler S, Cancado EL, Porta G, Nishioka M, Simon T, Daehnrich C, Schlumberger W, Galle PR, Lohse AW (2002) Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut 51(2):259–264
Bajt ML, Farhood A, Jaeschke H (2001) Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature. Am J Physiol Gastrointest Liver Physiol 281(5):G1188–G1195
Banks AT, Zimmerman HJ, Ishak KG, Harter JG (1995) Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 22(3):820–827
Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115(2):209–218. doi:10.1172/JCI24282
Beijer MR, Kraal G, den Haan JM (2014) Vitamin A and dendritic cell differentiation. Immunology 142(1):39–45
Bendelac A, Lantz O, Quimby ME, Yewdell JW, Bennink JR, Brutkiewicz RR (1995) CD1 recognition by mouse NK1+ T lymphocytes. Science 268(5212):863–865
Berg M, Wingender G, Djandji D, Hegenbarth S, Momburg F, Hammerling G, Limmer A, Knolle P (2006) Cross-presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor-specific CD8+ T cell tolerance. Eur J Immunol 36(11):2960–2970. doi:10.1002/eji.200636033
Bertoletti A, Ferrari C (2003) Kinetics of the immune response during HBV and HCV infection. Hepatology 38(1):4–13. doi:10.1053/jhep.2003.50310
Bertolino P, McCaughan GW, Bowen DG (2002) Role of primary intrahepatic T-cell activation in the 'liver tolerance effect'. Immunol Cell Biol 80:84–92
Bhogal RH, Curbishley SM, Weston CJ, Adams DH, Afford SC (2010) Reactive oxygen species mediate human hepatocyte injury during hypoxia/reoxygenation. Liver Transpl 16(11):1303–1313. doi:10.1002/lt.22157
Biburger M, Tiegs G (2007) Animal models of autoimmune hepatitis. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 293–306
Bilzer M, Roggel F, Gerbes AL (2006) Role of Kupffer cells in host defense and liver disease. Liver Int 26(10):1175–1186. doi:10.1111/j.1478-3231.2006.01342.x
Biron CA, Brossay L (2001) NK cells and NKT cells in innate defense against viral infections. Curr Opin Immunol 13(4):458–464
Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220. doi:10.1146/annurev.immunol.17.1.189
Bissell DM, Wang SS, Jarnagin WR, Roll FJ (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. doi:10.1172/JCI118055
Blazka ME, Elwell MR, Holladay SD, Wilson RE, Luster MI (1997) Histopathology of acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha. Toxicol Pathol 24(2):181–189
Blomhoff R, Green MH, Berg T, Norum KR (1990) Transport and storage of vitamin A. Science 250(4979):399–404
Blouin A, Bolender RP, Weibel ER (1977) Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study. J Cell Biol 72(2):441–455
Bode C, Bode JC (2003) Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol 17(4):575–592
Bode C, Bode JC (2005) Activation of the innate immune system and alcoholic liver disease: effects of ethanol per se or enhanced intestinal translocation of bacterial toxins induced by ethanol? Alcohol Clin Exp Res 29(11 Suppl):166S–171S
Bogdanos DP, Choudhrui K, Vergani D (2001) Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver 21:225–232
Bogdanos DP, Gao B, Gershwin ME (2013) Liver immunology. Compr Physiol 3(2):567–598. doi:10.1002/cphy.c120011
Boisvert J, Kunkel EJ, Campbell JJ, Keeffe EB, Butcher EC, Greenberg HB (2003) Liver-infiltrating lymphocytes in end-stage hepatitis C virus: subsets, activation status, and chemokine receptor phenotypes. J Hepatol 38(1):67–75
Bonacchi A, Romagnani P, Romanelli RG, Efsen E, Annunziato F, Lasagni L, Francalanci M, Serio M, Laffi G, Pinzani M, Gentilini P, Marra F (2001) Signal transduction by the chemokine receptor CXCR3: activation of Ras/ERK, Src, and phosphatidylinositol 3-kinase/Akt controls cell migration and proliferation in human vascular pericytes. J Biol Chem 276(13):9945–9954. doi:10.1074/jbc.M010303200
Bonder CS, Ajuebor MN, Zbytnuik LD, Kubes P, Swain MG (2004) Essential role for neutrophil recruitment to the liver in concanavalin A-induced hepatitis. J Immunol 172(1):45–53
Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege MS, Stassen M, Jonuleit H, Schmitt E (2007) Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 204(6):1303–1310. doi:10.1084/jem.20062129
Bourdi M, Chen W, Peter RM, Martin JL, Buters JT, Nelson SD, Pohl LR (1996) Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 9(7):1159–1166. doi:10.1021/tx960083q
Bowlus CL (2007) Tumor immunology. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 237–249
Braet F, Wisse E (2002) Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol 1(1):1–17
Brandes M, Willimann K, Moser B (2005) Professional antigen-presentation function by human gammadelta T cells. Science 309(5732):264–268. doi:10.1126/science.1110267
Brennan PJ, Brigl M, Brenner MB (2013) Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13(2):101–117. doi:10.1038/nri3369
Breous E, Somanathan S, Vandenberghe LK, Wilson JM (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
Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB (2003) Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol 4(12):1230–1237. doi:10.1038/ni1002
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535. doi:10.1126/science.1092385
Brock RW, Nie RG, Harris KA, Potter RF (2001) Kupffer cell-initiated remote hepatic injury following bilateral hindlimb ischemia is complement dependent. Am J Physiol Gastrointest Liver Physiol 280(2):G279–G284
Broering R, Lu M, Schlaak JF (2011) Role of Toll-like receptors in liver health and disease. Clin Sci (Lond) 121(10):415–426. doi:10.1042/CS20110065
Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF (2006) Neutrophils in development of multiple organ failure in sepsis. Lancet 368(9530):157–169. doi:10.1016/S0140-6736(06)69005-3
Bucks CM, Norton JA, Boesteanu AC, Mueller YM, Katsikis PD (2009) Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J Immunol 182(11):6697–6708. doi:10.4049/jimmunol.0800997
Busca A, Kumar A (2014) Innate immune responses in hepatitis B virus (HBV) infection. Virol J 11(22):1–8
Buschenfelde KH, Kossling FK, Miescher PA (1972) Experimental chronic active hepatitis in rabbits following immunization with human liver proteins. Clin Exp Immunol 11(1):99–108
Buxbaum J, Qian P, Allen PM, Peters MG (2008) Hepatitis resulting from liver-specific expression and recognition of self-antigen. J Autoimmun 31(3):208–215. doi:10.1016/j.jaut.2008.04.015
Caban A, Oczkowicz G, Abdel-Samad O, Cierpka L (2002) Influence of Kupffer cells on the early phase of liver reperfusion. Transplant Proc 34(2):694–697
Caldwell CC, Tschoep J, Lentsch AB (2007) Lymphocyte function during hepatic ischemia/reperfusion injury. J Leukoc Biol 82(3):457–464. doi:10.1189/jlb.0107062
Caldwell-Kenkel JC, Currin RT, Tanaka Y, Thurman RG, Lemasters JJ (1989) Reperfusion injury to endothelial cells following cold ischemic storage of rat livers. Hepatology 10(3):292–299
Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ (2003) Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest 83(5):655–663
Carding SR, Egan PJ (2002) Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2(5):336–345. doi:10.1038/nri797
Carter KC, Post DJ, Papaconstantinou J (1991) Differential expression of the mouse alpha 1-acid glycoprotein genes (AGP-1 and AGP-2) during inflammation and aging. Biochim Biophys Acta 1089(2):197–205
Chen M, Sallberg M, Sonnerborg A, Weiland O, Mattsson L, Jin L, Birkett A, Peterson D, Milich DR (1999) Limited humoral immunity in hepatitis C virus infection. Gastroenterology 116(1):135–143
Chen S, Akbar SM, Tanimoto K, Ninomiya T, Iuchi H, Michitaka K, Horiike N, Onji M (2000) Absence of CD83-positive mature and activated dendritic cells at cancer nodules from patients with hepatocellular carcinoma: relevance to hepatocarcinogenesis. Cancer Lett 148(1):49–57
Chen HH, Lin JH, Fung HP, Ho LL, Yang PC, Lee WC, Lee YP, Chu RM (2003) Serum acute phase proteins and swine health status. Can J Vet Res 67(4):283–290
Chen CH, Kuo LM, Chang Y, Wu W, Goldbach C, Ross MA, Stolz DB, Chen L, Fung JJ, Lu L, Qian S (2006) In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology 44(5):1171–1181. doi:10.1002/hep.21379
Chen Q, Mosovsky KL, Ross AC (2013) Retinoic acid and alpha-galactosylceramide regulate the expression of costimulatory receptors and transcription factors responsible for B cell activation and differentiation. Immunobiology 218(12):1477–1487. doi:10.1016/j.imbio.2013.05.003
Cheng L, You Q, Yin H, Holt MP, Ju C (2010) Involvement of natural killer T cells in halothane-induced liver injury in mice. Biochem Pharmacol 80(2):255–261. doi:10.1016/j.bcp.2010.03.025
Chisari FV, Isogawa M, Wieland SF (2010) Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris) 58(4):258–266. doi:10.1016/j.patbio.2009.11.001
Christen U, Holdener M, Hintermann E (2007) Animal models for autoimmune hepatitis. Autoimmun Rev 6(5):306–311. doi:10.1016/j.autrev.2006.04.001
Clapper JR, Hendricks MD, Gu G, Wittmer C, Dolman CS, Herich J, Athanacio J, Villescaz C, Ghosh SS, Heilig JS, Lowe C, Roth JD (2013) Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment. Am J Physiol Gastrointest Liver Physiol 305(7):G483–G495. doi:10.1152/ajpgi.00079.2013
Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD (2013) Liver involvement in patients with systemic autoimmune diseases. Maedica 8(4):394–397
Crawford JM, Burt AD (2012) Anatomy, pathophysiology, and basic mechanisms of disease. In: Burt A, Portmann B, Ferrell L (eds) MacSween's pathology of the liver, 6th edn. Elsevier, New York, NY, pp 1–78
Crispe IN (2003) Hepatic T cells and liver tolerance. Nat Rev Immunol 3(1):51–62. doi:10.1038/nri981
Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163. doi:10.1146/annurev.immunol.021908.132629
Crispe IN (2011) Liver antigen-presenting cells. J Hepatol 54(2):357–365. doi:10.1016/j.jhep.2010.10.005
Cullen JM, Brown DL (2012) Hepatobiliary system and exocrine pancreas. In: Zachary JF, McGavin MD (eds) Pathologic basis of veterinary disease, 5th edn. Elsevier, St Louis, MO, pp 405–457
Czaja AJ (2008) Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol 6(4):379–388. doi:10.1016/j.cgh.2007.12.048
Czaja AJ (2010) Animal models of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 4(4):429–443
Czaja AJ, Manns MP (1995) The validity and importance of subtypes in autoimmune hepatitis: a point of view. Am J Gastroenterol 90(8):1206–1211
Czaja AJ, Doherty DG, Donaldson PT (2002) Genetic bases of autoimmune hepatitis. Dig Dis Sci 47(10):2139–2150
Dao T, Mehal WZ, Crispe IN (1998) IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol 161:2217–2222
Dasu MR, Cobb JP, Laramie JM, Chung TP, Spies M, Barrow RE (2004) Gene expression profiles of livers from thermally injured rats. Gene 327(1):51–60. doi:10.1016/j.gene.2003.11.015
Day CP, James OF (1998) Steatohepatitis: a tale of two "hits"? Gastroenterology 114(4):842–845
De Creus A, Abe M, Lau AH, Hackstein H, Raimondi G, Thomson AW (2005) Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. J Immunol 174(4):2037–2045
Demetris AJ, Sever C, Kakizoe S, Oguma S, Starzl TE, Jaffe R (1989) S100 protein positive dendritic cells in primary biliary cirrhosis and other chronic inflammatory liver diseases. Relevance to pathogenesis? Am J Pathol 134(4):741–747
Deng X, Stachlewitz RF, Liguori MJ, Blomme EA, Waring JF, Luyendyk JP, Maddox JF, Ganey PE, Roth RA (2006) Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacterial translocation. J Pharmacol Exp Ther 319(3):1191–1199. doi:10.1124/jpet.106.110247
Deng X, Luyendyk JP, Ganey PE, Roth RA (2009) Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol Rev 61(3):262–282. doi:10.1124/pr.109.001727
Derkow K, Loddenkemper C, Mintern J, Kruse N, Klugewitz K, Berg T, Wiedenmann B, Ploegh HL, Schott E (2007) Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis. Hepatology 46(4):1155–1165. doi:10.1002/hep.21796
Dhainaut JF, Marin N, Mignon A, Vinsonneau C (2001) Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med 29(7 Suppl):S42–S47
Diefenbach A, Raulet DH (2002) The innate immune response to tumors and its role in the induction of T-cell immunity. Immunol Rev 188:9–21
Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA (2008) Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 47(1):296–305. doi:10.1002/hep.21965
Dini L, Lentini A, Diez GD, Rocha M, Falasca L, Serafino L, Vidal-Vanaclocha F (1995) Phagocytosis of apoptotic bodies by liver endothelial cells. J Cell Sci 108(Pt 3):967–973
Djilali-Saiah I, Lapierre P, Vittozi S, Alvarez F (2002) DNA vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis. J Immunol 169(9):4889–4896
Doherty DG, Norris S, Madrigal-Estebas L, McEntee G, Traynor O, Hegarty JE, O'Farrelly C (1999) The human liver contains multiple populations of NK cells, T cells, and CD3+ CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J Immunol 163:2314–2321
Dorner M, Horwitz JA, Robbins JB, Barry WT, Feng Q, Mu K, Jones CT, Schoggins JW, Catanese MT, Burton DR, Law M, Rice CM, Ploss A (2011) A genetically humanized mouse model for hepatitis C virus infection. Nature 474(7350):208–211. doi:10.1038/nature10168
Dranoff JA, Wells RG (2010) Portal fibroblasts: Underappreciated mediators of biliary fibrosis. Hepatology 51(4):1438–1444. doi:10.1002/hep.23405
Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P, Das A, Lopes AR, Borrow P, Williams K, Humphreys E, Afford S, Adams DH, Bertoletti A, Maini MK (2007) Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 204(3):667–680. doi:10.1084/jem.20061287
Dupuy AM, Terrier N, Senecal L, Morena M, Leray H, Canaud B, Cristol JP (2003) Is C-reactive protein a marker of inflammation? Nephrologie 24(7):337–341
Durham SK, Brouwer A, Barelds RJ, Horan MA, Knook DL (1990) Comparative endotoxin-induced hepatic injury in young and aged rats. J Pathol 162(4):341–349. doi:10.1002/path.1711620412
Eberl G, Lees R, Smiley ST, Taniguchi M, Grusby MJ, MacDonald HR (1999) Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells. J Immunol 162(11):6410–6419
Edwards L, Wanless IR (2013) Mechanisms of liver involvement in systemic disease. Best Pract Res Clin Gastroenterol 27(4):471–483. doi:10.1016/j.bpg.2013.08.002
Eissmann P, Evans JH, Mehrabi M, Rose EL, Nedvetzki S, Davis DM (2010) Multiple mechanisms downstream of TLR-4 stimulation allow expression of NKG2D ligands to facilitate macrophage/NK cell crosstalk. J Immunol 184(12):6901–6909. doi:10.4049/jimmunol.0903985
Evans EW (2011) Proteins, lipids, and carbohydrates. In: Latimer KS (ed) Duncan and Prasse's veterinary laboratory medicine: clinical pathology, 5th edn. Blackwell, Ames, IA, pp 173–209
Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S (2008) Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134(2):424–431. doi:10.1053/j.gastro.2007.11.038
Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, Iredale JP (2007) Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 178(8):5288–5295
Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P, Granito A, Hussain MJ, Ma Y, Lenzi M, Mieli-Vergani G, Bianchi FB, Vergani D, Muratori L (2010) A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 52(3):999–1007. doi:10.1002/hep.23792
Fey G, Hocke G, Wilson DV, Ripperger J, Juan T, Cui MZ, Darlington G (1994) Cytokines and the acute phase response of the liver. In: Arias I, Boyer J, Fausto N, Jacoby W, Schachter D, Shafritz D (eds) The liver: biology and pathobiology. Raven Press Ltd., New York, NY, pp 113–143
Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, Krause R, Lammert F, Langner C, Zatloukal K, Marschall HU, Denk H, Trauner M (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127(1):261–274
Fickert P, Fuchsbichler A, Marschall HU, Wagner M, Zollner G, Krause R, Zatloukal K, Jaeschke H, Denk H, Trauner M (2006) Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice. Am J Pathol 168(2):410–422. doi:10.2353/ajpath.2006.050404
Fickert P, Stoger U, Fuchsbichler A, Moustafa T, Marschall HU, Weiglein AH, Tsybrovskyy O, Jaeschke H, Zatloukal K, Denk H, Trauner M (2007) A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am J Pathol 171(2):525–536. doi:10.2353/ajpath.2007.061133
Fondevila C, Busuttil RW, Kupiec-Weglinski JW (2003) Hepatic ischemia/reperfusion injury—a fresh look. Exp Mol Pathol 74(2):86–93
Fondevila C, Shen XD, Tsuchihashi S, Uchida Y, Freitas MC, Ke B, Busuttil RW, Kupiec-Weglinski JW (2008) The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury. Liver Transpl 14(8):1133–1141. doi:10.1002/lt.21496
Foster GR (1997) Interferons in host defense. Semin Liver Dis 17(4):287–295. doi:10.1055/s-2007-1007205
Fraser R, Rogers GWT, Bowler LM (1991) Defenestration and vitamin A status in a rat model of cirrhosis. In: Wisse E, Knook DL, McCuskey RS (eds) Cells of the hepatic sinusoid 3. Kupffer Cell Foundation, Leiden, pp 195–198
Friedman SL (2008a) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88(1):125–172. doi:10.1152/physrev.00013.2007
Friedman SL (2008b) Mechanisms of hepatic fibrogenesis. Gastroenterology 134(6):1655–1669. doi:10.1053/j.gastro.2008.03.003
Friedman SL (2010) Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7(8):425–436. doi:10.1038/nrgastro.2010.97
Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340(6):448–454. doi:10.1056/NEJM199902113400607
Gale M Jr, Foy EM (2005) Evasion of intracellular host defence by hepatitis C virus. Nature 436(7053):939–945. doi:10.1038/nature04078
Galli A, Pinaire J, Fischer M, Dorris R, Crabb DW (2001) The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. J Biol Chem 276(1):68–75. doi:10.1074/jbc.M008791200
Gao B, Bataller R (2011) Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141(5):1572–1585. doi:10.1053/j.gastro.2011.09.002
Gao B, Radaeva S (2013) Natural killer and natural killer T cells in liver fibrosis. Biochim Biophys Acta 1832(7):1061–1069. doi:10.1016/j.bbadis.2012.09.008
Gao B, Jeong WI, Tian Z (2008) Liver: an organ with predominant innate immunity. Hepatology 47(2):729–736. doi:10.1002/hep.22034
Gao B, Radaeva S, Park O (2009) Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol 86(3):513–528. doi:10.1189/JLB.0309135
Garcia-Monzon C, Martin-Perez E, Iacono OL, Fernandez-Bermejo M, Majano PL, Apolinario A, Larranaga E, Moreno-Otero R (2000) Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity. J Hepatol 33(5):716–724
Gershwin ME, Mackay IR, Sturgess A, Coppel RL (1987) Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 138(10):3525–3531
Glassner A, Eisenhardt M, Kramer B, Korner C, Coenen M, Sauerbruch T, Spengler U, Nattermann J (2012) NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Invest 92(7):967–977. doi:10.1038/labinvest.2012.54
Golden-Mason L, Rosen HR (2006) Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transpl 12(3):363–372. doi:10.1002/lt.20708
Gomez CR, Acuna-Castillo C, Perez C, Leiva-Salcedo E, Riquelme DM, Ordenes G, Oshima K, Aravena M, Perez VI, Nishimura S, Sabaj V, Walter R, Sierra F (2008) Diminished acute phase response and increased hepatic inflammation of aged rats in response to intraperitoneal injection of lipopolysaccharide. J Gerontol A Biol Sci Med Sci 63(12):1299–1306
Gorczynski RM (1994) Adoptive transfer of unresponsiveness to allogeneic skin grafts with hepatic gamma delta + T cells. Immunology 81(1):27–35
Gordon S (1998) The role of the macrophage in immune regulation. Res Immunol 149(7-8):685–688
Gorham JD, Lin JT, Sung JL, Rudner LA, French MA (2001) Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis. J Immunol 166(10):6413–6422
Graham DY, Opekun AR, Smith JL, Schwartz JT (1985) Ranitidine and hepatotoxicity. Ann Intern Med 102(3):416
Grant AJ, Goddard S, Ahmed-Choudhury J, Reynolds G, Jackson DG, Briskin M, Wu L, Hubscher SG, Adams DH (2002) Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am J Pathol 160(4):1445–1455. doi:10.1016/S0002-9440(10)62570-9
Gressner AM, Weiskirchen R, Breitkopf K, Dooley S (2002) Roles of TGF-beta in hepatic fibrosis. Front Biosci 7:d793–d807
Griffin JM, Gilbert KM, Lamps LW, Pumford NR (2000) CD4(+) T-cell activation and induction of autoimmune hepatitis following trichloroethylene treatment in MRL+/+ mice. Toxicol Sci 57(2):345–352
Guidotti LG, Chisari FV (2006) Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 1:23–61. doi:10.1146/annurev.pathol.1.110304.100230
Guidotti LG, Matzke B, Schaller H, Chisari FV (1995) High-level hepatitis B virus replication in transgenic mice. J Virol 69(10):6158–6169
Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science 284(5415):825–829
Gujral JS, Bucci TJ, Farhood A, Jaeschke H (2001) Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis? Hepatology 33(2):397–405. doi:10.1053/jhep.2001.22002
Guy CS, Mulrooney-Cousins PM, Churchill ND, Michalak TI (2008) Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. J Virol 82(17):8579–8591. doi:10.1128/JVI.01022-08
Hanschen M, Zahler S, Krombach F, Khandoga A (2008) Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion. Transplantation 86(5):710–718. doi:10.1097/TP.0b013e3181821aa7
Harada K, Nakanuma Y (2010) Biliary innate immunity: function and modulation. Mediators Inflamm. doi:10.1155/2010/373878
Harada K, Tsuneyama K, Yasoshima M, Kanemori Y, Ohta H, Masuda S, Onai N, Matsushima K, Nakanuma Y (2002) Type1 and type2 memory T cells imbalance shown by expression of intrahepatic chemokine receptors relates to pathogenesis of primary biliary cirrhosis. Hepatol Res 24(3):290
Hata K, Zhang XR, Iwatsuki S, Van Thiel DH, Herberman RB, Whiteside TL (1990) Isolation, phenotyping, and functional analysis of lymphocytes from human liver. Clin Immunol Immunopathol 56(3):401–419
Hendriks HF, Blaner WS, Wennekers HM, Piantedosi R, Brouwer A, de Leeuw AM, Goodman DS, Knook DL (1988) Distributions of retinoids, retinoid-binding proteins and related parameters in different types of liver cells isolated from young and old rats. Eur J Biochem 171(1-2):237–244
Herkel J, Jagemann B, Wiegard C, Lazaro JF, Lueth S, Kanzler S, Blessing M, Schmitt E, Lohse AW (2003) MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes. Hepatology 37(5):1079–1085. doi:10.1053/jhep.2003.50191
Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V (2003) NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 171(10):5140–5147
Hernandez-Gea V, Friedman SL (2011) Pathogenesis of liver fibrosis. Annu Rev Pathol 6:425–456. doi:10.1146/annurev-pathol-011110-130246
Heydtmann M, Hardie D, Shields PL, Faint J, Buckley CD, Campbell JJ, Salmon M, Adams DH (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(1):729–738
Hiasa Y, Akbar SM, Abe M, Michitaka K, Horiike N, Onji M (2002) Dendritic cell subtypes in autoimmune liver diseases; decreased expression of HLA DR and CD123 on type 2 dendritic cells. Hepatol Res 22(4):241–249
Hijona E, Hijona L, Arenas JI, Bujanda L (2010) Inflammatory mediators of hepatic steatosis. Mediators Inflamm 2010:837419. doi:10.1155/2010/837419
Hill-Baskin AE, Markiewski MM, Buchner DA, Shao H, DeSantis D, Hsiao G, Subramaniam S, Berger NA, Croniger C, Lambris JD, Nadeau JH (2009) Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum Mol Genet 18(16):2975–2988. doi:10.1093/hmg/ddp236
Hilmer SN, Cogger VC, Le Couteur DG (2007) Basal activity of Kupffer cells increases with old age. J Gerontol A Biol Sci Med Sci 62(9):973–978
Hirschfield GM, Gershwin ME (2013) The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 8:303–330. doi:10.1146/annurev-pathol-020712-164014
Holt AP, Salmon M, Buckley CD, Adams DH (2008a) Immune interactions in hepatic fibrosis. Clin Liver Dis 12(4):861–882. doi:10.1016/j.cld.2008.07.002, x
Holt MP, Cheng L, Ju C (2008b) Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol 84(6):1410–1420. doi:10.1189/jlb.0308173
Holt AP, Haughton EL, Lalor PF, Filer A, Buckley CD, Adams DH (2009) Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 136(2):705–714. doi:10.1053/j.gastro.2008.10.020
Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113(12):1774–1783. doi:10.1172/JCI20513
Hosel M, Quasdorff M, Wiegmann K, Webb D, Zedler U, Broxtermann M, Tedjokusumo R, Esser K, Arzberger S, Kirschning CJ, Langenkamp A, Falk C, Buning H, Rose-John S, Protzer U (2009) Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 50(6):1773–1782. doi:10.1002/hep.23226
Hsu W, Shu SA, Gershwin E, Lian ZX (2007) The current immune function of hepatic dendritic cells. Cell Mol Immunol 4(5):321–328
Hsu W, Zhang W, Tsuneyama K, Moritoki Y, Ridgway WM, Ansari AA, Coppel RL, Lian ZX, Mackay I, Gershwin ME (2009) Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(-/-) mice. Hepatology 49(1):133–140. doi:10.1002/hep.22591
Hussaini SH, Farrington EA (2007) Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Saf 6(6):673–684. doi:10.1517/14740338.6.6.673
Invernizzi P, Bianchi I, Locati M, Bonecchi R, Selmi C (2007) Cytokines in liver health and disease. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 83–93
Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R, Peterson LB, Leung PS, Cheng C, Mackay IR, Gershwin ME, Ridgway WM (2006) NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 203(5):1209–1219. doi:10.1084/jem.20051911
Ito Y, Sorensen KK, Bethea NW, Svistounov D, McCuskey MK, Smedsrod BH, McCuskey RS (2007) Age-related changes in the hepatic microcirculation in mice. Exp Gerontol 42(8):789–797
Jaeschke H (2002) Neutrophil-mediated tissue injury in alcoholic hepatitis. Alcohol 27(1):23–27
Jaeschke H (2006) Mechanisms of liver injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. Am J Physiol Gastrointest Liver Physiol 290(6):G1083–G1088. doi:10.1152/ajpgi.00568.2005
Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 26(Suppl 1):173–179. doi:10.1111/j.1440-1746.2010.06592.x
Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89(1):31–41. doi:10.1093/toxsci/kfi336
Jaeschke H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ (1993) Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol 264(4 Pt 1):G801–G809
Jaeschke H, Williams CD, Ramachandran A, Bajt ML (2012) Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 32(1):8–20. doi:10.1111/j.1478-3231.2011.02501.x
Jamieson HA, Hilmer SN, Cogger VC, Warren A, Cheluvappa R, Abernethy DR, Everitt AV, Fraser R, De Cabo R, Le Couteur DG (2007) Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid. Exp Gerontol 42(4):374–378
Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissell DM (1994) Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol 127(6 Pt 2):2037–2048
Jenne CN, Kubes P (2013) Immune surveillance by the liver. Nat Immunol 14(10):996–1006. doi:10.1038/ni.2691
Jeong WI, Park O, Gao B (2008) Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology 134(1):248–258. doi:10.1053/j.gastro.2007.09.034
Jezequel AM, Novelli G, Venturini C, Orlandi F (1984) Quantitative analysis of the perisinusoidal cells in human liver; the lipocytes. Front Gastr Res 8:85–90
Jin C, Henao-Mejia J, Flavell RA (2013) Innate immune receptors: key regulators of metabolic disease progression. Cell Metab 17(6):873–882. doi:10.1016/j.cmet.2013.05.011
Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T, Kanazawa Y, Hiramatsu N, Hayashi N (2004) Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 173(10):6072–6081
Jinushi M, Takehara T, Tatsumi T, Yamaguchi S, Sakamori R, Hiramatsu N, Kanto T, Ohkawa K, Hayashi N (2007) Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities. Immunology 120(1):73–82. doi:10.1111/j.1365-2567.2006.02479.x
John B, Crispe IN (2004) Passive and active mechanisms trap activated CD8+ T cells in the liver. J Immunol 172(9):5222–5229. doi:10.4049/jimmunol.172.9.5222
Ju C, Reilly T (2012) Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev 44(1):107–115. doi:10.3109/03602532.2011.645579
Ju C, Uetrecht JP (2002) Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Curr Drug Metab 3(4):367–377
Jung UJ, Choi MS (2014) Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 15(4):6184–6223. doi:10.3390/ijms15046184
Kanuri G, Bergheim I (2013) In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD). Int J Mol Sci 14(6):11963–11980. doi:10.3390/ijms140611963
Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis. N Engl J Med 353(12):1261–1273. doi:10.1056/NEJMra043898
Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F (2009) Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50(1):261–274. doi:10.1002/hep.22950
Kato J, Okamoto T, Motoyama H, Uchiyama R, Kirchhofer D, Van Rooijen N, Enomoto H, Nishiguchi S, Kawada N, Fujimoto J, Tsutsui H (2013) Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice. Hepatology 57(1):362–372. doi:10.1002/hep.26027
Katsargyris A, Klonaris C, Alexandrou A, Giakoustidis AE, Vasileiou I, Theocharis S (2009) Toll-like receptors in liver ischemia reperfusion injury: a novel target for therapeutic modulation? Expert Opin Ther Targets 13(4):427–442. doi:10.1517/14728220902794939
Katz SC, Pillarisetty VG, Bleier JI, Shah AB, DeMatteo RP (2004) Liver sinusoidal endothelial cells are insufficient to activate T cells. J Immunol 173(1):230–235. doi:10.4049/jimmunol.173.1.230
Kawabata T, Kinoshita M, Inatsu A, Habu Y, Nakashima H, Shinomiya N, Seki S (2008) Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide. Hepatology 48(5):1586–1597. doi:10.1002/hep.22489
Khandoga A, Hanschen M, Kessler JS, Krombach F (2006) CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets. Hepatology 43(2):306–315. doi:10.1002/hep.21017
Kharasch ED, Hankins D, Mautz D, Thummel KE (1996) Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis. Lancet 347(9012):1367–1371
Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW (2007) Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100(11):1589–1596. doi:10.1161/CIRCRESAHA.106.142851
Kimura K, Kohara M (2011) An experimental mouse model for hepatitis C virus. Exp Anim 60(2):93–100
Kimura M, Watanabe H, Sato S, Abo T (1994) Female predominance of extrathymic T cells in mice: statistical analysis. Immunol Lett 39(3):259–267
Kimura M, Hanawa H, Watanabe H, Ogawa M, Abo T (1995) Synchronous expansion of intermediate TCR cells in the liver and uterus during pregnancy. Cell Immunol 162(1):16–25. doi:10.1006/cimm.1995.1046
Kingham TP, Chaudhry UI, Plitas G, Katz SC, Raab J, DeMatteo RP (2007) Murine liver plasmacytoid dendritic cells become potent immunostimulatory cells after Flt-3 ligand expansion. Hepatology 45(2):445–454. doi:10.1002/hep.21457
Kinnman N, Hultcrantz R, Barbu V, Rey C, Wendum D, Poupon R, Housset C (2000) PDGF-mediated chemoattraction of hepatic stellate cells by bile duct segments in cholestatic liver injury. Lab Invest 80(5):697–707
Klenerman P, Thimme R (2012) T cell responses in hepatitis C: the good, the bad and the unconventional. Gut 61(8):1226–1234. doi:10.1136/gutjnl-2011-300620
Kluwe J, Wongsiriroj N, Troeger JS, Gwak GY, Dapito DH, Pradere JP, Jiang H, Siddiqi M, Piantedosi R, O'Byrne SM, Blaner WS, Schwabe RF (2011) Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis. Gut 60(9):1260–1268. doi:10.1136/gut.2010.209551
Knolle PA (2007) Role and function of liver sinusoidal endothelial cells. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 25–39
Knolle PA, Gerken G (2000) Local control of the immune response in the liver. Immunol Rev 174:21–34
Knolle PA, Limmer A (2003) Control of immune responses by scavenger liver endothelial cells. Swiss Med Wkly 133:501–506
Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Buschenfelde KH, Gerken G (1995) Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 22:226–229
Knolle PA, Uhrig A, Hegenbarth S, Loser E, Schmitt E, Gerken G, Lohse AW (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, Schmitt E, Jin S, Germann T, Duchmann R, Hegenbarth S, Gerken G, Lohse AW (1999) Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 116(6):1428–1440
Kong X, Feng D, Wang H, Hong F, Bertola A, Wang FS, Gao B (2012) Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56(3):1150–1159. doi:10.1002/hep.25744
Koo GC, Dumont FJ, Tutt M, Hackett J Jr, Kumar V (1986) The NK-1.1(-) mouse: a model to study differentiation of murine NK cells. J Immunol 137(12):3742–3747
Kowalewska PM, Patrick AL, Fox-Robichaud AE (2011) Innate immunity of the liver microcirculation. Cell Tissue Res 343(1):85–96. doi:10.1007/s00441-010-1058-5
Koziel MJ (1999) Cytokines in viral hepatitis. Semin Liver Dis 19(2):157–169. doi:10.1055/s-2007-1007107
Krams SM, Dorshkind K, Gershwin ME (1989) Generation of biliary lesions after transfer of human lymphocytes into severe combined immunodeficient (SCID) mice. J Exp Med 170(6):1919–1930
Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134(4):657–667. doi:10.1016/j.cell.2008.06.049
Kruglov EA, Nathanson RA, Nguyen T, Dranoff JA (2006) Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. Am J Physiol Gastrointest Liver Physiol 290(4):G765–G771. doi:10.1152/ajpgi.00308.2005
Kuboki S, Sakai N, Tschop J, Edwards MJ, Lentsch AB, Caldwell CC (2009) Distinct contributions of CD4+ T cell subsets in hepatic ischemia/reperfusion injury. Am J Physiol Gastrointest Liver Physiol 296(5):G1054–G1059. doi:10.1152/ajpgi.90464.2008
Kumagai K, Kiyosawa N, Ito K, Yamoto T, Teranishi M, Nakayama H, Manabe S (2007) Influence of Kupffer cell inactivation on cycloheximide-induced hepatic injury. Toxicology 241(3):106–118. doi:10.1016/j.tox.2007.08.090
Kumagai K, Ito K, Ando Y, Hakamata S, Teranishi M, Nakayama H, Manabe S (2009) Neutralization of IL-10 exacerbates cycloheximide-induced hepatocellular apoptosis and necrosis. Toxicol Pathol 37(4):536–546. doi:10.1177/0192623309336153
Kuriki J, Murakami H, Kakumu S, Sakamoto N, Yokochi T, Nakashima I, Kato N (1983) Experimental autoimmune hepatitis in mice after immunization with syngeneic liver proteins together with the polysaccharide of Klebsiella pneumoniae. Gastroenterology 84(3):596–603
Kusters S, Tiegs G, Alexopoulou L, Pasparakis M, Douni E, Kunstle G, Bluethmann H, Wendel A, Pfizenmaier K, Kollias G, Grell M (1997) In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis. Eur J Immunol 27(11):2870–2875. doi:10.1002/eji.1830271119
Lafdil F, Miller AM, Ki SH, Gao B (2010) Th17 cells and their associated cytokines in liver diseases. Cell Mol Immunol 7(4):250–254. doi:10.1038/cmi.2010.5
Lalazar G, Preston S, Zigmond E, Ben Yaacov A, Ilan Y (2006) Glycolipids as immune modulatory tools. Mini Rev Med Chem 6(11):1249–1253
Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S, Adams DH (2002) Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J Immunol 169(2):983–992
Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274. doi:10.1146/annurev.immunol.23.021704.115526
Larrubia JR, Lokhande MU, Garcia-Garzon S, Miquel J, Subira D, Sanz-de-Villalobos E (2013) Role of T cell death in maintaining immune tolerance during persistent viral hepatitis. World J Gastroenterol 19(12):1877–1889. doi:10.3748/wjg.v19.i12.1877
Laskin DL, Gardner CR, Price VF, Jollow DJ (1995) Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 21(4):1045–1050
Le Couteur DG, Fraser R, Cogger VC, McLean AJ (2002) Hepatic pseudocapillarisation and atherosclerosis in ageing. Lancet 359(9317):1612–1615. doi:10.1016/S0140-6736(02)08524-0
Le Couteur DG, Fraser R, Hilmer S, Rivory LP, McLean AJ (2005) The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet 44(2):187–200
Le Couteur DG, Warren A, Cogger VC, Smedsrod B, Sorensen KK, De Cabo R, Fraser R, McCuskey RS (2008) Old age and the hepatic sinusoid. Anat Rec (Hoboken) 291(6):672–683. doi:10.1002/ar.20661
Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC (2002) Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295(5561):1898–1901. doi:10.1126/science.1069540
Lee WC, Chiang YJ, Wang HC, Wang MR, Lia SR, Chen MF (2004) Functional impairment of dendritic cells caused by murine hepatocellular carcinoma. J Clin Immunol 24(2):145–154. doi:10.1023/B:JOCI.0000019779.56180.a2
Lemmers A, Moreno C, Gustot T, Marechal R, Degre D, Demetter P, de Nadai P, Geerts A, Quertinmont E, Vercruysse V, Le Moine O, Deviere J (2009) The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 49(2):646–657. doi:10.1002/hep.22680
Leung PS, Park O, Tsuneyama K, Kurth MJ, Lam KS, Ansari AA, Coppel RL, Gershwin ME (2007) Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. J Immunol 179(4):2651–2657
Li K, Lemon SM (2013) Innate immune responses in hepatitis C virus infection. Semin Immunopathol 35(1):53–72. doi:10.1007/s00281-012-0332-x
Li F, Tian Z (2013) The liver works as a school to educate regulatory immune cells. Cell Mol Immunol 10(4):292–302. doi:10.1038/cmi.2013.7
Li Z, Lin H, Yang S, Diehl AM (2002) Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. Gastroenterology 123(4):1304–1310
Li Z, Oben JA, Yang S, Lin H, Stafford EA, Soloski MJ, Thomas SA, Diehl AM (2004) Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis. Hepatology 40(2):434–441. doi:10.1002/hep.20320
Li Z, Soloski MJ, Diehl AM (2005) Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 42(4):880–885. doi:10.1002/hep.20826
Liaskou E, Karikoski M, Reynolds GM, Lalor PF, Weston CJ, Pullen N, Salmi M, Jalkanen S, Adams DH (2011) Regulation of mucosal addressin cell adhesion molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity. Hepatology 53(2):661–672. doi:10.1002/hep.24085
Liaskou E, Wilson DV, Oo YH (2012) Innate immune cells in liver inflammation. Mediators Inflamm 2012:949157. doi:10.1155/2012/949157
Liberal R, Grant CR, Mieli-Vergani G, Vergani D (2013) Autoimmune hepatitis: a comprehensive review. J Autoimmun 41:126–139. doi:10.1016/j.jaut.2012.11.002
Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, Groettrup M, Momburg F, Arnold B, Knolle PA (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
Limmer A, Ohl J, Wingender G, Berg M, Jungerkes F, Schumak B, Djandji D, Scholz K, Klevenz A, Hegenbarth S, Momburg F, Hammerling GJ, Arnold B, Knolle PA (2005) Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. Eur J Immunol 35(10):2970–2981. doi:10.1002/eji.200526034
Liu ZX, Kaplowitz N (2007) Immune mechanisms in drug-induced hepatotoxicity. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 363–374
Liu W, Tang L, Zhang G, Wei H, Cui Y, Guo L, Gou Z, Chen X, Jiang D, Zhu Y, Kang G, He F (2004) Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem 279(18):18748–18758. doi:10.1074/jbc.M311227200
Loggi E, Gamal N, Bihl F, Bernardi M, Andreone P (2014) Adaptive response in hepatitis B virus infection. J Viral Hepat 21(5):305–313. doi:10.1111/jvh.12255
Lohse AW, Manns M, Dienes HP, Meyer zum Buschenfelde KH, Cohen IR (1990) Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity. Hepatology 11(1):24–30
Longhi MS, Liberal R, Holder B, Robson SC, Ma Y, Mieli-Vergani G, Vergani D (2012) Inhibition of interleukin-17 promotes differentiation of CD25(-) cells into stable T regulatory cells in patients with autoimmune hepatitis. Gastroenterology 142(7):1526–1535. doi:10.1053/j.gastro.2012.02.041, e1526
Lotan R, Belloni PN, Tressler RJ, Lotan D, Xu XC, Nicolson GL (1994) Expression of galectins on microvessel endothelial cells and their involvement in tumour cell adhesion. Glycoconj J 11(5):462–468
Lovdal T, Berg T (2001) Transcription of Fc(gamma) receptors in different rat liver cells. Cell Biol Int 25(8):821–824. doi:10.1006/cbir.2001.0761
Lovdal T, Andersen E, Brech A, Berg T (2000) Fc receptor mediated endocytosis of small soluble immunoglobulin G immune complexes in Kuppfer and endothelial cells from rat liver. J Cell Sci 113:3255–3266
Lu L, Ikizawa K, Hu D, Werneck MB, Wucherpfennig KW, Cantor H (2007) Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity 26(5):593–604. doi:10.1016/j.immuni.2007.03.017
Lumley C (1990) Clinical toxicity: could it have been prevented? Premarketing experience. In: Lumley CR, Walker SW (eds) CMR workshop – animals toxicity studies – their relevance for man. Quay, Lancaster, pp 49–56
Lunam CA, Cousins MJ, Hall PD (1985) Guinea-pig model of halothane-associated hepatotoxicity in the absence of enzyme induction and hypoxia. J Pharmacol Exp Ther 232(3):802–809
Luo D, Vermijlen D, Vanderkerken K, Kuppen PJ, Seynaeve C, Eddouks M, Baekeland M, Wisse E (1999) Involvement of LFA-1 in hepatic NK cell (pit cell)-mediated cytolysis and apoptosis of colon carcinoma cells. J Hepatol 31(1):110–116
Luth S, Huber S, Schramm C, Buch T, Zander S, Stadelmann C, Bruck W, Wraith DC, Herkel J, Lohse AW (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. doi:10.1172/JCI32132
Luyendyk JP, Maddox JF, Cosma GN, Ganey PE, Cockerell GL, Roth RA (2003) Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats. J Pharmacol Exp Ther 307(1):9–16. doi:10.1124/jpet.103.054288
Ma TY, Nguyen D, Bui V, Nguyen H, Hoa N (1999) Ethanol modulation of intestinal epithelial tight junction barrier. Am J Physiol 276(4 Pt 1):G965–G974
Machado MV, Cortez-Pinto H (2011) Cell death and nonalcoholic steatohepatitis: where is ballooning relevant? Expert Rev Gastroenterol Hepatol 5(2):213–222. doi:10.1586/egh.11.16
Machida K, Tsukiyama-Kohara K, Seike E, Tone S, Shibasaki F, Shimizu M, Takahashi H, Hayashi Y, Funata N, Taya C, Yonekawa H, Kohara M (2001) Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins. J Biol Chem 276(15):12140–12146. doi:10.1074/jbc.M010137200
Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ (2007) Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56(8):1124–1131. doi:10.1136/gut.2006.118059
Malovic I, Sorensen KK, Elvevold KH, Nedredal GI, Paulsen S, Erofeev AV, Smedsrod BH, McCourt PA (2007) The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor. Hepatology 45(6):1454–1461. doi:10.1002/hep.21639
Mandrekar P, Szabo G (2009) Signalling pathways in alcohol-induced liver inflammation. J Hepatol 50(6):1258–1266. doi:10.1016/j.jhep.2009.03.007
Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, Romanelli RG, Laffi G, Gentilini P (1998) Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol 152(2):423–430
Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F (2004) Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5(12):1260–1265. doi:10.1038/ni1138
Martins EB, Graham AK, Chapman RW, Fleming KA (1996) Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases. Hepatology 23(5):988–993. doi:10.1002/hep.510230508
Masuda T, Ohteki T, Abo T, Seki S, Nose M, Nagura H, Kumagai K (1991) Expansion of the population of double negative CD4-8- Talphabeta-cells in the liver is a common feature of autoimmune mice. J Immunol 147(9):2907–2912
Matsuda JL, Mallevaey T, Scott-Browne J, Gapin L (2008) CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system. Curr Opin Immunol 20(3):358–368. doi:10.1016/j.coi.2008.03.018
Matsuno K, Nomiyama H, Yoneyama H, Uwatoku R (2002) Kupffer cell-mediated recruitment of dendritic cells to the liver crucial for a host defense. Dev Immunol 9(3):143–149
McCourt PA, Smedsrod BH, Melkko J, Johansson S (1999) Characterization of a hyaluronan receptor on rat sinusoidal liver endothelial cells and its functional relationship to scavenger receptors. Hepatology 30(5):1276–1286. doi:10.1002/hep.510300521
McCuskey RS (2008) The hepatic microvascular system in health and its response to toxicants. Anat Rec (Hoboken) 291(6):661–671. doi:10.1002/ar.20663
McDonald B, Kubes P (2012) Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol Pathol 40(2):157–165. doi:10.1177/0192623311427570
McDonald B, McAvoy EF, Lam F, Gill V, de la Motte C, Savani RC, Kubes P (2008) Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids. J Exp Med 205(4):915–927. doi:10.1084/jem.20071765
McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, Beck PL, Muruve DA, Kubes P (2010) Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330(6002):362–366. doi:10.1126/science.1195491
McFarlane IG, Heneghan MA (2004) Autoimmunity and the female liver. Hepatol Res 28(4):171–176. doi:10.1016/j.hepres.2003.12.002
Mclean MR, Rees KR (1958) Hyperplasia of bile-ducts induced by alpha-naphthyl-iso-thiocyanate: experimental biliary cirrhosis free from biliary obstruction. J Pathol Bacteriol 76(1):175–188
Mehal WZ, Friedman SL (2007) The role of inflammation and immunity in the pathogenesis of liver fibrosis. In: Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice. Humana, Totowa, NJ, pp 111–121
Mehal WZ, Juedes AE, Crispe IN (1999) Selective retention of activated CD8+ T cells by the normal liver. J Immunol 163:3202–3210
Melkko J, Hellevik T, Risteli L, Risteli J, Smedsrod B (1994) Clearance of NH2-terminal propeptides of types I and III procollagen is a physiological function of the scavenger receptor in liver endothelial cells. J Exp Med 179(2):405–412
Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, Rinfret A, Addison WR, Fischer KP, Churchill TA, Lakey JR, Tyrrell DL, Kneteman NM (2001) Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7(8):927–933. doi:10.1038/90968
Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A (2009) Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49(6):1877–1887. doi:10.1002/hep.22848
Miethke AG, Saxena V, Shivakumar P, Sabla GE, Simmons J, Chougnet CA (2010) Post-natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia. J Hepatol 52(5):718–726. doi:10.1016/j.jhep.2009.12.027
Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E (2013) Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57(2):577–589. doi:10.1002/hep.26081
Mizoguchi Y, Tsutsui H, Miyajima K, Sakagami Y, Seki S, Kobayashi K, Yamamoto S, Morisawa S (1987) The protective effects of prostaglandin E1 in an experimental massive hepatic cell necrosis model. Hepatology 7(6):1184–1188
Mocchegiani E, Giacconi R, Cipriano C, Gasparini N, Bernardini G, Malavolta M, Menegazzi M, Cavalieri E, Muzzioli M, Ciampa AR, Suzuki H (2004) The variations during the circadian cycle of liver CD1d-unrestricted NK1.1 + TCR gamma/delta + cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice. Exp Gerontol 39(5):775–788. doi:10.1016/j.exger.2004.01.014
Montalvo-Jave EE, Escalante-Tattersfield T, Ortega-Salgado JA, Pina E, Geller DA (2008) Factors in the pathophysiology of the liver ischemia-reperfusion injury. J Surg Res 147(1):153–159. doi:10.1016/j.jss.2007.06.015
Moretta A (2002) Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2(12):957–964. doi:10.1038/nri956
Moretta L, Bottino C, Pende D, Castriconi R, Mingari MC, Moretta A (2006) Surface NK receptors and their ligands on tumor cells. Semin Immunol 18(3):151–158. doi:10.1016/j.smim.2006.03.002
Moriyama T, Guilhot S, Klopchin K, Moss B, Pinkert CA, Palmiter RD, Brinster RL, Kanagawa O, Chisari FV (1990) Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science 248(4953):361–364
Motegi A, Kinoshita M, Inatsu A, Habu Y, Saitoh D, Seki S (2008) IL-15-induced CD8 + CD122+ T cells increase antibacterial and anti-tumor immune responses: implications for immune function in aged mice. J Leukoc Biol 84(4):1047–1056. doi:10.1189/jlb.0807530
Muhanna N, Horani A, Doron S, Safadi R (2007) Lymphocyte-hepatic stellate cell proximity suggests a direct interaction. Clin Exp Immunol 148(2):338–347. doi:10.1111/j.1365-2249.2007.03353.x
Muhanna N, Doron S, Wald O, Horani A, Eid A, Pappo O, Friedman SL, Safadi R (2008) Activation of hepatic stellate cells after phagocytosis of lymphocytes: a novel pathway of fibrogenesis. Hepatology 48(3):963–977. doi:10.1002/hep.22413
Mulder AH, Horst G, Haagsma EB, Limburg PC, Kleibeuker JH, Kallenberg CG (1993) Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology 17(3):411–417
Murai M, Yoneyama H, Harada A, Yi Z, Vestergaard C, Guo B, Suzuki K, Asakura H, Matsushima K (1999) Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J Clin Invest 104(1):49–57. doi:10.1172/JCI6642
Mustafa A, Holladay SD, Witonsky S, Zimmerman K, Reilly CM, Sponenberg DP, Weinstein DA, Karpuzoglu E, Gogal RM Jr (2009) Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin disrupts B-cell lymphopoiesis and exacerbates autoimmune disease in 24-week-old SNF1 mice. Toxicol Sci 112(1):133–143. doi:10.1093/toxsci/kfp177
Naito M, Hasegawa G, Ebe Y, Yamamoto T (2004) Differentiation and function of Kupffer cells. Med Electron Microsc 37(1):16–28. doi:10.1007/s00795-003-0228-x
Nakagawa R, Nagafune I, Tazunoki Y, Ehara H, Tomura H, Iijima R, Motoki K, Kamishohara M, Seki S (2001) Mechanisms of the antimetastatic effect in the liver and of the hepatocyte injury induced by alpha-galactosylceramide in mice. J Immunol 166(11):6578–6584
Nakamoto N, Kanai T (2014) Role of toll-like receptors in immune activation and tolerance in the liver. Front Immunol 5:220. doi:10.3389/fimmu.2014.00221
Nakamura A, Terauchi Y (2013) Lessons from mouse models of high-fat diet-induced NAFLD. Int J Mol Sci 14(11):21240–21257. doi:10.3390/ijms141121240
Nakano Y, Kondo T, Matsuo R, Hashimoto I, Kawasaki T, Kohno K, Myronovych A, Tadano S, Hisakura K, Ikeda O, Watanabe M, Murata S, Fukunaga K, Ohkohchi N (2008) Platelet dynamics in the early phase of postischemic liver in vivo. J Surg Res 149(2):192–198. doi:10.1016/j.jss.2007.09.016
Nakatani K, Kaneda K, Seki S, Nakajima Y (2004) Pit cells as liver-associated natural killer cells: morphology and function. Med Electron Microsc 37(1):29–36. doi:10.1007/s00795-003-0229-9
Nakayama H, Otabe S, Ueno T, Hirota N, Yuan X, Fukutani T, Hashinaga T, Wada N, Yamada K (2007) Transgenic mice expressing nuclear sterol regulatory element-binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis. Metabolism 56(4):470–475. doi:10.1016/j.metabol.2006.11.004
Nathan C (2006) Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6:173–182
Nattermann J, Feldmann G, Ahlenstiel G, Langhans B, Sauerbruch T, Spengler U (2006) Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 55(6):869–877. doi:10.1136/gut.2005.076463
Njoku DB (2014) Drug-induced hepatotoxicity: metabolic, genetic and immunological basis. Int J Mol Sci 15(4):6990–7003. doi:10.3390/ijms15046990
Njoku DB, Mellerson JL, Talor MV, Kerr DR, Faraday NR, Outschoorn I, Rose NR (2006) Role of CYP2E1 immunoglobulin G4 subclass antibodies and complement in pathogenesis of idiosyncratic drug-induced hepatitis. Clin Vaccine Immunol 13(2):258–265. doi:10.1128/CVI.13.2.258-265.2006
Nolan JP (2010) The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology 52(5):1829–1835. doi:10.1002/hep.23917
Norris S, Collins C, Doherty DG, Smith F, McEntee G, Traynor O, Nolan N, Hegarty J, O'Farrelly C (1998) Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol 28(1):84–90
Novo E, Marra F, Zamara E, Valfre di Bonzo L, Caligiuri A, Cannito S, Antonaci C, Colombatto S, Pinzani M, Parola M (2006) Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells. Gut 55(1):90–97. doi:10.1136/gut.2005.069633
O'Connell J, Bennett MW, Nally K, Houston A, O'Sullivan GC, Shanahan F (2000) Altered mechanisms of apoptosis in colon cancer: Fas resistance and counterattack in the tumor-immune conflict. Ann N Y Acad Sci 910:178–192, discussion 193-175
O'Connell PJ, Logar AJ, Thomson AW (2001) Differential regulation of T-cell proliferation and apoptosis by hepatic CD8alpha(+) (lymphoid-related) and CD8alpha(-) (myeloid) dendritic cells. Transplant Proc 33(1-2):250–251
Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, Ridgway WM, Ansari AA, Coppel RL, Li MO, Flavell RA, Kronenberg M, Mackay IR, Gershwin ME (2006) Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 177(3):1655–1660
O'Farrelly C (2004) Immunoregulation in the liver and its extrahepatic relevance. J Pediatr Gastroenterol Nutr 39(Suppl 3):S727–S728
Ohteki T, Okuyama R, Seki S, Abo T, Sugiura K, Kusumi A, Ohmori T, Watanabe H, Kumagai K (1992) Age-dependent increase of extrathymic T cells in the liver and their appearance in the periphery of older mice. J Immunol 149(5):1562–1570
Onoe T, Ohdan H, Tokita D, Shishida M, Tanaka Y, Hara H, Zhou W, Ishiyama K, Mitsuta H, Ide K, Asahara T (2005) Liver sinusoidal endothelial cells tolerize T cells across MHC barriers in mice. J Immunol 175(1):139–146. doi:10.4049/jimmunol.175.1.139
Orme IM (1987) Aging and immunity to tuberculosis: increased susceptibility of old mice reflects a decreased capacity to generate mediator T lymphocytes. J Immunol 138(12):4414–4418
Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM, Group USALFS (2002) Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137(12):947–954
Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA (2003) Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37(5):1043–1055. doi:10.1053/jhep.2003.50182
Park WB, Lee KD, Lee CS, Jang HC, Kim HB, Lee HS, Oh MD, Choe KW (2005) Production of C-reactive protein in Escherichia coli-infected patients with liver dysfunction due to liver cirrhosis. Diagn Microbiol Infect Dis 51(4):227–230. doi:10.1016/j.diagmicrobio.2004.11.014
Park O, Jeong WI, Wang L, Wang H, Lian ZX, Gershwin ME, Gao B (2009) Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology 49(5):1683–1694. doi:10.1002/hep.22813
Parker GA, Picut CA (2005) Liver immunobiology. Toxicol Pathol 33(1):52–62. doi:10.1080/01926230590522365
Parker GA, Picut CA (2012) Immune functioning in non lymphoid organs: the liver. Toxicol Pathol 40(2):237–247. doi:10.1177/0192623311428475
Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA (2014) Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14(3):181–194. doi:10.1038/nri3623
Penna A, Pilli M, Zerbini A, Orlandini A, Mezzadri S, Sacchelli L, Missale G, Ferrari C (2007) Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45(3):588–601. doi:10.1002/hep.21541
Penz-Osterreicher M, Osterreicher CH, Trauner M (2011) Fibrosis in autoimmune and cholestatic liver disease. Best Pract Res Clin Gastroenterol 25(2):245–258. doi:10.1016/j.bpg.2011.02.001
Perillo NL, Pace KE, Seilhamer JJ, Baum LG (1995) Apoptosis of T cells mediated by galectin-1. Nature 378(6558):736–739. doi:10.1038/378736a0
Petrovic V, Teng S, Piquette-Miller M (2007) Regulation of drug transporters during infection and inflammation. Mol Interv 7(2):99–111. doi:10.1124/mi.7.2.10
Peverill W, Powell LW, Skoien R (2014) Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 15(5):8591–8638. doi:10.3390/ijms15058591
Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP (2004) Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J Immunol 172(2):1009–1017
Pinzani M (2002) PDGF and signal transduction in hepatic stellate cells. Front Biosci 7:d1720–d1726
Pinzani M, Macias-Barragan J (2010) Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol 4(4):459–472
Pirmohamed M, Naisbitt DJ, Gordon F, Park BK (2002) The danger hypothesis--potential role in idiosyncratic drug reactions. Toxicology 181–182:55–63
Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, Jang MK, Guenther ND, Mederacke I, Friedman R, Dragomir AC, Aloman C, Schwabe RF (2013) Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58(4):1461–1473. doi:10.1002/hep.26429
Prickett TC, McKenzie JL, Hart DN (1988) Characterization of interstitial dendritic cells in human liver. Transplantation 46(5):754–761
Pritchard MT, McMullen MR, Stavitsky AB, Cohen JI, Lin F, Medof ME, Nagy LE (2007) Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice. Gastroenterology 132(3):1117–1126. doi:10.1053/j.gastro.2007.01.053
Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M (2005) Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6(3):280–286. doi:10.1038/ni1165
Rabinovich GA, Iglesias MM, Modesti NM, Castagna LF, Wolfenstein-Todel C, Riera CM, Sotomayor CE (1998) Activated rat macrophages produce a galectin-1-like protein that induces apoptosis of T cells: biochemical and functional characterization. J Immunol 160(10):4831–4840
Racanelli V, Rehermann B (2006) The liver as an immunological organ. Hepatology 43(2 Suppl 1):S54–S62. doi:10.1002/hep.21060
Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B (2006) Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 130(2):435–452. doi:10.1053/j.gastro.2005.10.055
Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, Hartland SN, Snowdon VK, Cappon A, Gordon-Walker TT, Williams MJ, Dunbar DR, Manning JR, van Rooijen N, Fallowfield JA, Forbes SJ, Iredale JP (2012) Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 109(46):E3186–E3195. doi:10.1073/pnas.1119964109
Rao R (2009) Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50(2):638–644. doi:10.1002/hep.23009
Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3(10):781–790. doi:10.1038/nri1199
Rehermann B (2013) Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 19(7):859–868. doi:10.1038/nm.3251
Rehermann B, Ferrari C, Pasquinelli C, Chisari FV (1996) The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 2(10):1104–1108
Rinella ME, Green RM (2004) The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol 40(1):47–51
Rockey DC, Boyles JK, Gabbiani G, Friedman SL (1992) Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture. J Submicrosc Cytol Pathol 24(2):193–203
Romagnani S, Maggi E, Liotta F, Cosmi L, Annunziato F (2009) Properties and origin of human Th17 cells. Mol Immunol 47(1):3–7. doi:10.1016/j.molimm.2008.12.019
Rowell DL, Eckmann L, Dwinell MB, Carpenter SP, Raucy JL, Yang SK, Kagnoff MF (1997) Human hepatocytes express an array of proinflammatory cytokines after agonist stimulation or bacterial invasion. Am J Physiol 273(2 Pt 1):G322–G332
Rubinstein D, Roska AK, Lipsky PE (1986) Liver sinusoidal lining cells express class II major histocompatibility antigens but are poor stimulators of fresh allogeneic T lymphocytes. J Immunol 137(6):1803–1810
Rubinstein D, Roska AK, Lipsky PE (1987) Antigen presentation by liver sinusoidal lining cells after antigen exposure in vivo. J Immunol 138(5):1377–1382
Safadi R, Ohta M, Alvarez CE, Fiel MI, Bansal M, Mehal WZ, Friedman SL (2004) Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. Gastroenterology 127(3):870–882
Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787. doi:10.1016/j.cell.2008.05.009
Santodomingo-Garzon T, Han J, Le T, Yang Y, Swain MG (2009) Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice. Hepatology 49(4):1267–1276. doi:10.1002/hep.22761
Sato T, Yamamoto H, Sasaki C, Wake K (1998) Maturation of rat dendritic cells during intrahepatic translocation evaluated using monoclonal antibodies and electron microscopy. Cell Tissue Res 294(3):503–514
Sato K, Kinoshita M, Motegi A, Habu Y, Takayama E, Nonoyama S, Hiraide H, Seki S (2005) Critical role of the liver CD8+ CD122+ T cells in the generalized Shwartzman reaction of mice. Eur J Immunol 35(2):593–602. doi:10.1002/eji.200425520
Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418(6894):191–195. doi:10.1038/nature00858
Schildberg FA, Hegenbarth SI, Schumak B, Scholz K, Limmer A, Knolle PA (2008) Liver sinusoidal endothelial cells veto CD8 T cell activation by antigen-presenting dendritic cells. Eur J Immunol 38(4):957–967. doi:10.1002/eji.200738060
Schiodt FV, Atillasoy E, Shakil AO, Schiff ER, Caldwell C, Kowdley KV, Stribling R, Crippin JS, Flamm S, Somberg KA, Rosen H, McCashland TM, Hay JE, Lee WM (1999) Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transpl Surg 5(1):29–34
Schleinitz N, Vely F, Harle JR, Vivier E (2010) Natural killer cells in human autoimmune diseases. Immunology 131(4):451–458. doi:10.1111/j.1365-2567.2010.03360.x
Schrage A, Wechsung K, Neumann K, Schumann M, Schulzke JD, Engelhardt B, Zeitz M, Hamann A, Klugewitz K (2008) Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines. Hepatology 48(4):1262–1272. doi:10.1002/hep.22443
Seguin B, Uetrecht J (2003) The danger hypothesis applied to idiosyncratic drug reactions. Curr Opin Allergy Clin Immunol 3(4):235–242. doi:10.1097/01.all.0000083953.99396.a2
Seki E, Schnabl B (2012) Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 590(Pt 3):447–458. doi:10.1113/jphysiol.2011.219691
Seki S, Habu Y, Kawamura T, Takeda K, Dobashi H, Ohkawa T, Hiraide H (2000) The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag + T cells in T helper 1 immune responses. Immunol Rev 174:35–46
Seki S, Nakashima H, Nakashima M, Kinoshita M (2011) Antitumor immunity produced by the liver Kupffer cells, NK cells, NKT cells, and CD8 CD122 T cells. Clin Dev Immunol 2011:868345. doi:10.1155/2011/868345
Selmi C, Lleo A, Pasini S, Zuin M, Gershwin ME (2009) Innate immunity and primary biliary cirrhosis. Curr Mol Med 9(1):45–51
Selmi C, De Santis M, Cavaciocchi F, Gershwin ME (2010) Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis. Dis Markers 29(6):287–299. doi:10.3233/DMA-2010-0746
Selzner M, Selzner N, Jochum W, Graf R, Clavien PA (2007) Increased ischemic injury in old mouse liver: an ATP-dependent mechanism. Liver Transpl 13(3):382–390. doi:10.1002/lt.21100
Shaw PJ, Ganey PE, Roth RA (2010) Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci 118(1):7–18. doi:10.1093/toxsci/kfq168
Shen X, Wang Y, Gao F, Ren F, Busuttil RW, Kupiec-Weglinski JW, Zhai Y (2009) CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury. Hepatology 50(5):1537–1546. doi:10.1002/hep.23153
Shi TY, Zhang FC (2012) Role of autoimmunity in primary biliary cirrhosis. World J Gastroenterol 18(48):7141–7148. doi:10.3748/wjg.v18.i48.7141
Shi J, Gilbert GE, Kokubo Y, Ohashi T (2001) Role of the liver in regulating numbers of circulating neutrophils. Blood 98(4):1226–1230
Shi FD, Ljunggren HG, La Cava A, Van Kaer L (2011) Organ-specific features of natural killer cells. Nat Rev Immunol 11(10):658–671. doi:10.1038/nri3065
Shimamura M, Ohteki T, Launois P, Garcia AM, MacDonald HR (1997) Thymus-independent generation of NK1+ T cells in vitro from fetal liver precursors. J Immunol 158(8):3682–3689
Shimoda S, Harada K, Niiro H, Shirabe K, Taketomi A, Maehara Y, Tsuneyama K, Nakanuma Y, Leung P, Ansari AA, Gershwin ME, Akashi K (2011) Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis. Hepatology 53(4):1270–1281. doi:10.1002/hep.24194
Singh P, Coskun ZZ, Goode C, Dean A, Thompson-Snipes L, Darlington G (2008) Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 47(5):1680–1690. doi:10.1002/hep.22224
Sleyster EC, Knook DL (1982) Relation between localization and function of rat liver Kupffer cells. Lab Invest 47(5):484–490
Smedsrod B, Johansson S, Pertoft H (1985a) Studies in vivo and in vitro on the uptake and degradation of soluble collagen alpha 1(I) chains in rat liver endothelial and Kupffer cells. Biochem J 228(2):415–424
Smedsrod B, Pertoft H, Eggertsen G, Sundstrom C (1985b) Functional and morphological characterization of cultures of Kupffer cells and liver endothelial cells prepared by means of density separation in Percoll, and selective substrate adherence. Cell Tissue Res 241(3):639–649
Smedsrod B, Pertoft H, Gustafson S, Laurent TC (1990) Scavenger functions of the liver endothelial cell. Biochem J 266:313–327
Soehnlein O, Lindbom L (2010) Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol 10(6):427–439. doi:10.1038/nri2779
Sorensen KK, McCourt P, Berg T, Crossley C, Le Couteur D, Wake K, Smedsrod B (2012) The scavenger endothelial cell: a new player in homeostasis and immunity. Am J Physiol Regul Integr Comp Physiol 303(12):R1217–R1230. doi:10.1152/ajpregu.00686.2011
Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt RR, Bazan F, Kastelein RA, Liu YJ (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3(7):673–680. doi:10.1038/ni805
Steffan AM, Gendrault JL, McCuskey RS, McCuskey PA, Kirn A (1986) Phagocytosis, an unrecognized property of murine endothelial liver cells. Hepatology 6(5):830–836
Stegmann KA, Bjorkstrom NK, Veber H, Ciesek S, Riese P, Wiegand J, Hadem J, Suneetha PV, Jaroszewicz J, Wang C, Schlaphoff V, Fytili P, Cornberg M, Manns MP, Geffers R, Pietschmann T, Guzman CA, Ljunggren HG, Wedemeyer H (2010) Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology 138(5):1885–1897. doi:10.1053/j.gastro.2010.01.051
Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH (1997) Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159(10):4772–4780
Stephensen CB (2001) Vitamin A, infection, and immune function. Annu Rev Nutr 21:167–192. doi:10.1146/annurev.nutr.20.1.167
Steptoe RJ, Patel RK, Subbotin VM, Thomson AW (2000) Comparative analysis of dendritic cell density and total number in commonly transplanted organs: morphometric estimation in normal mice. Transpl Immunol 8(1):49–56
Stockham SL, Scott MA (2008) Fundamentals of veterinary clinical pathology, 2nd edn. Blackwell, Ames, IA
Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, Janssen HL (2005) Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41(4):771–778. doi:10.1002/hep.20649
Su GL (2002) Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256–G265
Subleski JJ, Hall VL, Back TC, Ortaldo JR, Wiltrout RH (2006) Enhanced antitumor response by divergent modulation of natural killer and natural killer T cells in the liver. Cancer Res 66(22):11005–11012. doi:10.1158/0008-5472.CAN-06-0811
Sugahara S, Shimizu T, Yoshida Y, Aiba T, Yamagiwa S, Asakura H, Abo T (1999) Extrathymic derivation of gut lymphocytes in parabiotic mice. Immunology 96(1):57–65
Sun R, Gao B (2004) Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma). Gastroenterology 127(5):1525–1539
Sung JY, Costerton JW, Shaffer EA (1992) Defense system in the biliary tract against bacterial infection. Dig Dis Sci 37(5):689–696
Syal G, Fausther M, Dranoff JA (2012) Advances in cholangiocyte immunobiology. Am J Physiol Gastrointest Liver Physiol 303(10):G1077–G1086. doi:10.1152/ajpgi.00227.2012
Szabo G, Romics L Jr, Frendl G (2002) Liver in sepsis and systemic inflammatory response syndrome. Clin Liver Dis 6(4):1045–1066, x
Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K (2000) Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci U S A 97(10):5498–5503. doi:10.1073/pnas.040566697
Tamaki S, Homma S, Enomoto Y, Komita H, Zeniya M, Ohno T, Toda G (2005) Autoimmune hepatic inflammation by vaccination of mice with dendritic cells loaded with well-differentiated hepatocellular carcinoma cells and administration of interleukin-12. Clin Immunol 117(3):280–293. doi:10.1016/j.clim.2005.08.010
Taniai H, Hines IN, Bharwani S, Maloney RE, Nimura Y, Gao B, Flores SC, McCord JM, Grisham MB, Aw TY (2004) Susceptibility of murine periportal hepatocytes to hypoxia-reoxygenation: role for NO and Kupffer cell-derived oxidants. Hepatology 39(6):1544–1552. doi:10.1002/hep.20217
Taniguchi H, Toyoshima T, Fukao K, Nakauchi H (1996) Presence of hematopoietic stem cells in the adult liver. Nat Med 2(2):198–203
Terilli RR, Cox AL (2013) Immunity and hepatitis C: a review. Curr HIV/AIDS Rep 10(1):51–58. doi:10.1007/s11904-012-0146-4
Thomson AW, Knolle PA (2010) Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10(11):753–766. doi:10.1038/nri2858
Thomson AW, Lu L, Murase N, Demetris AJ, Rao AS, Starzl TE (1995) Microchimerism, dendritic cell progenitors and transplantation tolerance. Stem Cells 13(6):622–639. doi:10.1002/stem.5530130607
Thomson CW, Lee BP, Zhang L (2006) Double-negative regulatory T cells: non-conventional regulators. Immunol Res 35(1-2):163–178. doi:10.1385/IR:35:1:163
Tian Z, Chen Y, Gao B (2013) Natural killer cells in liver disease. Hepatology 57(4):1654–1662. doi:10.1002/hep.26115
Tiegs G, Hentschel J, Wendel A (1992) A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest 90(1):196–203. doi:10.1172/JCI115836
Tiggelman AM, Boers W, Linthorst C, Brand HS, Sala M, Chamuleau RA (1995) Interleukin-6 production by human liver (myo)fibroblasts in culture. Evidence for a regulatory role of LPS, IL-1 beta and TNF alpha. J Hepatol 23(3):295–306
Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52(5):1836–1846. doi:10.1002/hep.24001
Toyonaga T, Hino O, Sugai S, Wakasugi S, Abe K, Shichiri M, Yamamura K (1994) Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver. Proc Natl Acad Sci U S A 91(2):614–618
Trivedi PJ, Adams DH (2013) Mucosal immunity in liver autoimmunity: a comprehensive review. J Autoimmun 46:97–111. doi:10.1016/j.jaut.2013.06.013
Tsuge M, Hiraga N, Takaishi H, Noguchi C, Oga H, Imamura M, Takahashi S, Iwao E, Fujimoto Y, Ochi H, Chayama K, Tateno C, Yoshizato K (2005) Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis B virus. Hepatology 42(5):1046–1054. doi:10.1002/hep.20892
Tsukahara A, Seki S, Iiai T, Moroda T, Watanabe H, Suzuki S, Tada T, Hiraide H, Hatakeyama K, Abo T (1997) Mouse liver T cells: their change with aging and in comparison with peripheral T cells. Hepatology 26(2):301–309. doi:10.1002/hep.510260208
Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TR (2005) The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med 201(7):1135–1143. doi:10.1084/jem.20042614
Tsutsui H, Nishiguchi S (2014) Importance of Kupffer cells in the development of acute liver injuries in mice. Int J Mol Sci 15(5):7711–7730. doi:10.3390/ijms15057711
Tsutsui H, Nakanishi K, Matsui K, Higashino K, Okamura H, Miyazawa Y, Kaneda K (1996) IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. J Immunol 157(9):3967–3973
Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS (2008) TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 205(1):233–244. doi:10.1084/jem.20072195
Uddin MN, Nishio N, Ito S, Suzuki H, Isobe K (2012) Autophagic activity in thymus and liver during aging. Age (Dordr) 34(1):75–85. doi:10.1007/s11357-011-9221-9
van Golen RF, van Gulik TM, Heger M (2012) The sterile immune response during hepatic ischemia/reperfusion. Cytokine Growth Factor Rev 23(3):69–84. doi:10.1016/j.cytogfr.2012.04.006
van Oosten M, van Amersfoort ES, van Berkel TJ, Kuiper J (2001) Scavenger receptor-like receptors for the binding of lipopolysaccharide and lipoteichoic acid to liver endothelial and Kupffer cells. J Endotoxin Res 7(5):381–384
Vermijlen D, Luo D, Robaye B, Seynaeve C, Baekeland M, Wisse E (1999) Pit cells (Hepatic natural killer cells) of the rat induce apoptosis in colon carcinoma cells by the perforin/granzyme pathway. Hepatology 29(1):51–56. doi:10.1002/hep.510290143
Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E, Braet F, Wisse E (2002) Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway. J Leukoc Biol 72:668–676
Vial T, Goubier C, Bergeret A, Cabrera F, Evreux JC, Descotes J (1991) Side effects of ranitidine. Drug Saf 6(2):94–117
Videla LA, Tapia G, Fernandez V (2001) Influence of aging on Kupffer cell respiratory activity in relation to particle phagocytosis and oxidative stress parameters in mouse liver. Redox Rep 6(3):155–159. doi:10.1179/135100001101536265
Vinas O, Bataller R, Sancho-Bru P, Gines P, Berenguer C, Enrich C, Nicolas JM, Ercilla G, Gallart T, Vives J, Arroyo V, Rodes J (2003) Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte production. Hepatology 38:919–929
Voehringer D, Blaser C, Grawitz AB, Chisari FV, Buerki K, Pircher H (2000) Break of T cell ignorance to a viral antigen in the liver induces hepatitis. J Immunol 165(5):2415–2422
von Hahn T, Yoon JC, Alter H, Rice CM, Rehermann B, Balfe P, McKeating JA (2007) Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology 132(2):667–678. doi:10.1053/j.gastro.2006.12.008
Wagner S, Lynch NJ, Walter W, Schwaeble WJ, Loos M (2003) Differential expression of the murine mannose-binding lectins A and C in lymphoid and nonlymphoid organs and tissues. J Immunol 170(3):1462–1465
Wahl C, Bochtler P, Schirmbeck R, Reimann J (2007) Type I IFN-producing CD4 Valpha14i NKT cells facilitate priming of IL-10-producing CD8 T cells by hepatocytes. J Immunol 178(4):2083–2093
Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH, Yang GX, Ridgway W, Ueno Y, Ansari AA, Coppel RL, Mackay IR, Gershwin ME (2006) IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis. Hepatology 44(5):1240–1249. doi:10.1002/hep.21385
Wakabayashi K, Lian ZX, Leung PS, Moritoki Y, Tsuneyama K, Kurth MJ, Lam KS, Yoshida K, Yang GX, Hibi T, Ansari AA, Ridgway WM, Coppel RL, Mackay IR, Gershwin ME (2008) Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 48(2):531–540. doi:10.1002/hep.22390
Wakabayashi K, Yoshida K, Leung PS, Moritoki Y, Yang GX, Tsuneyama K, Lian ZX, Hibi T, Ansari AA, Wicker LS, Ridgway WM, Coppel RL, Mackay IR, Gershwin ME (2009) Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol 155(3):577–586. doi:10.1111/j.1365-2249.2008.03837.x
Wake K (1980) Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 66:303–353
Wake K (1995) Structure of the sinusoidal wall in the liver. In: Wisse E, Knook DL, Wake K (eds) Cells of the hepatic sinusoid. The Kupffer Cell Foundation, Leiden, pp 241–246
Walker JG, Doniach D, Roitt IM, Sherlock S (1965) Serological tests in diagnosis of primary biliary cirrhosis. Lancet 1(7390):827–831
Wang SH, Huang CX, Ye L, Wang X, Song L, Wang YJ, Liang H, Huang XY, Ho WZ (2008) Natural killer cells suppress full cycle HCV infection of human hepatocytes. J Viral Hepat 15(12):855–864. doi:10.1111/j.1365-2893.2008.01014.x
Warren A, Bertolino P, Cogger VC, McLean AJ, Fraser R, Le Couteur DG (2005) Hepatic pseudocapillarization in aged mice. Exp Gerontol 40(10):807–812. doi:10.1016/j.exger.2005.06.012
Warren A, Le Couteur DG, Fraser R, Bowen DG, McCaughan GW, Bertolino P (2006) T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44(5):1182–1190. doi:10.1002/hep.21378
Watanabe Y, Kawakami H, Kawamoto H, Ikemoto Y, Masuda K, Takezaki E, Nakanishi T, Kajiyama G, Takeno H (1987) Effect of neonatal thymectomy on experimental autoimmune hepatitis in mice. Clin Exp Immunol 67(1):105–113
Watanabe H, Miyaji C, Seki S, Abo T (1996) c-kit + stem cells and thymocyte precursors in the livers of adult mice. J Exp Med 184:687–693
Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH, Liang TJ, Alter H, Rehermann B (2002) Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 169(6):3447–3458
Weiskirchen R, Tacke F (2014) Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr 3(6):344–363. doi:10.3978/j.issn.2304-3881.2014.11.03
Wells RG, Kruglov E, Dranoff JA (2004) Autocrine release of TGF-beta by portal fibroblasts regulates cell growth. FEBS Lett 559(1-3):107–110. doi:10.1016/S0014-5793(04)00037-7
Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C (1998) Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 27(1):128–133. doi:10.1002/hep.510270121
Wen L, Peakman M, Mieli-Vergani G, Vergani D (1992) Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease. Clin Exp Immunol 89(1):78–82
Wiegard C, Wolint P, Frenzel C, Cheruti U, Schmitt E, Oxenius A, Lohse AW, Herkel J (2007) Defective T helper response of hepatocyte-stimulated CD4 T cells impairs antiviral CD8 response and viral clearance. Gastroenterology 133(6):2010–2018. doi:10.1053/j.gastro.2007.09.007
Wieland SF, Spangenberg HC, Thimme R, Purcell RH, Chisari FV (2004) Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. Proc Natl Acad Sci U S A 101(7):2129–2134. doi:10.1073/pnas.0308478100
Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SH (2007) Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26(1):117–129. doi:10.1016/j.immuni.2006.11.011
Wisse E, De Zanger RB, Charels K, Van Der Smissen P, McCuskey RS (1985) The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 5(4):683–692
Wisse E, Braet F, Luo D, De Zanger R, Jans D, Crabbe E, Vermoesen A (1996) Structure and function of sinusoidal lining cells in the liver. Toxicol Pathol 24(1):100–111
Wondimu Z, Santodomingo-Garzon T, Le T, Swain MG (2010) Protective role of interleukin-17 in murine NKT cell-driven acute experimental hepatitis. Am J Pathol 177(5):2334–2346. doi:10.2353/ajpath.2010.100028
Wong J, Johnston B, Lee SS, Bullard DC, Smith CW, Beaudet AL, Kubes P (1997) A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest 99(11):2782–2790. doi:10.1172/JCI119468
Woof JM, Mestecky J (2005) Mucosal immunoglobulins. Immunol Rev 206:64–82. doi:10.1111/j.0105-2896.2005.00290.x
Wright PFA, Stacey NH (1991) A species/strain comparison of hepatic natural lymphocytotoxic activities in rats and mice. Carcinogenesis 12(8):1365–1370
Xu R, Zhang Z, Wang FS (2012) Liver fibrosis: mechanisms of immune-mediated liver injury. Cell Mol Immunol 9(4):296–301. doi:10.1038/cmi.2011.53
Yahata T, Kurabayashi T, Honda A, Tojo Y, Tanaka K, Abo T (1996) Physiological dose of estrogen regulates extrathymic T cells in female mice. Cell Immunol 171(2):269–276. doi:10.1006/cimm.1996.0203
Yamagiwa S, Matsuda Y, Ichida T, Honda Y, Takamura M, Sugahara S, Ishikawa T, Ohkoshi S, Sato Y, Aoyagi Y (2008) Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells. Hepatol Res 38(7):664–672. doi:10.1111/j.1872-034X.2008.00317.x
Yamamoto S, Sato Y, Shimizu T, Halder RC, Oya H, Bannai M, Suzuki K, Ishikawa H, Hatakeyama K, Abo T (1999) Consistent infiltration of thymus-derived T cells into the parenchymal space of the liver in normal mice. Hepatology 30(3):705–713. doi:10.1002/hep.510300331
Yamano T, DeCicco LA, Rikans LE (2000) Attenuation of cadmium-induced liver injury in senescent male fischer 344 rats: role of Kupffer cells and inflammatory cytokines. Toxicol Appl Pharmacol 162(1):68–75. doi:10.1006/taap.1999.8833
Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1):79–91. doi:10.1016/j.immuni.2012.12.001
Yoneyama H, Matsuno K, Zhang Y, Murai M, Itakura M, Ishikawa S, Hasegawa G, Naito M, Asakura H, Matsushima K (2001) Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease. J Exp Med 193(1):35–49
Yoong KF, Afford SC, Randhawa S, Hubscher SG, Adams DH (1999) Fas/Fas ligand interaction in human colorectal hepatic metastases: A mechanism of hepatocyte destruction to facilitate local tumor invasion. Am J Pathol 154(3):693–703. doi:10.1016/S0002-9440(10)65316-3
You Q, Cheng L, Reilly TP, Wegmann D, Ju C (2006) Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology 44(6):1421–1431. doi:10.1002/hep.21425
You Q, Cheng L, Kedl RM, Ju C (2008) Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48(3):978–990. doi:10.1002/hep.22395
Yu S, Rao S, Reddy JK (2003) Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis. Curr Mol Med 3(6):561–572
Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S (2004) Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 40(6):1312–1320. doi:10.1002/hep.20488
Yuksel M, Laukens D, Heindryckx F, Van Vlierberghe H, Geerts A, Wong FS, Wen L, Colle I (2014) Hepatitis mouse models: from acute-to-chronic autoimmune hepatitis. Int J Exp Pathol 95(5):309–320. doi:10.1111/iep.12090
Zhai Y, Busuttil RW, Kupiec-Weglinski JW (2011) Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am J Transplant 11(8):1563–1569. doi:10.1111/j.1600-6143.2011.03579.x
Zhang W, Sharma R, Ju ST, He XS, Tao Y, Tsuneyama K, Tian Z, Lian ZX, Fu SM, Gershwin ME (2009) Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology 49(2):545–552. doi:10.1002/hep.22651
Zierden M, Kuhnen E, Odenthal M, Dienes HP (2010) Effects and regulation of autoreactive CD8+ T cells in a transgenic mouse model of autoimmune hepatitis. Gastroenterology 139(3):971–986. doi:10.1053/j.gastro.2010.05.075
Zimmerman H (1999) Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. Lippincott Williams and Wilkins, Philadelphia, PA
Zimmerman HJ (2000) Drug-induced liver disease. Clin Liver Dis 4(1):73–96, vi
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Brown, D.L. (2017). Immunopathology of the Hepatobiliary System. In: Parker, G. (eds) Immunopathology in Toxicology and Drug Development. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-47385-7_7
Download citation
DOI: https://doi.org/10.1007/978-3-319-47385-7_7
Published:
Publisher Name: Humana Press, Cham
Print ISBN: 978-3-319-47384-0
Online ISBN: 978-3-319-47385-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)