Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Seminars in Immunopathology
Published in: Seminars in Immunopathology 5/2014

01-09-2014 | Review

Mechanisms of tissue injury in autoimmune liver diseases

Authors: Evaggelia Liaskou, Gideon M. Hirschfield, M. Eric Gershwin

Published in: Seminars in Immunopathology | Issue 5/2014

Login to get access

Abstract

Autoimmune diseases affecting the liver are mainly represented by autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The characteristic morphologic patterns of injury are a chronic hepatitis pattern of damage in AIH, destruction of small intrahepatic bile ducts in PBC and periductal fibrosis and inflammation involving larger bile ducts in PSC. The factors responsible for initiation and perpetuation of the injury in all the three autoimmune liver diseases are not understood completely but are likely to be environmental triggers on the background of genetic variation in immune regulation. In this review, we summarise the current understanding of the mechanisms underlying the breakdown of self-tolerance in autoimmune liver diseases.
Literature
1.
Hirschfield GM, Gershwin ME (2013) The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 8:303–330PubMed
2.
Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis. N Engl J Med 353:1261–1273PubMed
3.
Hirschfield GM, Karlsen TH, Lindor KD, Adams DH (2013) Primary sclerosing cholangitis. Lancet 382:1587–1599PubMed
4.
Trivedi PJ, Hirschfield GM (2012) Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 36:517–533PubMed
5.
Trivedi PJ, Adams DH (2013) Mucosal immunity in liver autoimmunity: a comprehensive review. J Autoimmun 46:97–111PubMed
6.
Bowlus CL (2011) Cutting edge issues in primary sclerosing cholangitis. Clin Rev Allergy Immunol 41:139–150PubMed
7.
Bergquist A, Lindberg G, Saarinen S, Broome U (2005) Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol 42:252–256PubMed
8.
Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD et al (2005) Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 42:1194–1202PubMedPubMedCentral
9.
Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC et al (2004) Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 127:485–492PubMed
10.
Yoshida O, Abe M, Furukawa S, Murata Y, Hamada M, Hiasa Y, Matsuura B et al (2009) A familial case of autoimmune hepatitis. Intern Med 48:315–319PubMed
11.
Ohira H, Shinzawa J, Suzuki T, Tojo J, Sato H, Nishimaki T, Morito T et al (1998) Two sister cases of autoimmune hepatitis. Fukushima J Med Sci 44:113–120PubMed
12.
Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, Gu X et al (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 360:2544–2555PubMedPubMedCentral
13.
Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, Podda M et al (2010) Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 42:658–660PubMedPubMedCentral
14.
Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY, Heneghan MA et al (2011) Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 43:329–332PubMedPubMedCentral
15.
Nakamura M, Nishida N, Kawashima M, Aiba Y, Tanaka A, Yasunami M, Nakamura H et al (2012) Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet 91:721–728PubMedPubMedCentral
16.
Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R et al (2012) Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet 21:5209–5221PubMedPubMedCentral
17.
Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, Ducker SJ et al (2012) Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet 44:1137–1141PubMedPubMedCentral
18.
Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C, Lu Y et al (2010) Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 42:655–657PubMedPubMedCentral
19.
Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, Lie BA et al (2010) Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 138:1102–1111PubMed
20.
Melum E, Franke A, Schramm C, Weismuller TJ, Gotthardt DN, Offner FA, Juran BD et al (2011) Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet 43:17–19PubMed
21.
Lamberts LE, Janse M, Haagsma EB, van den Berg AP, Weersma RK (2011) Immune-mediated diseases in primary sclerosing cholangitis. Dig Liver Dis 43:802–806PubMed
22.
Janse M, Lamberts LE, Franke L, Raychaudhuri S, Ellinghaus E, Muri Boberg K, Melum E et al (2011) Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9. Hepatology 53:1977–1985PubMedPubMedCentral
23.
Folseraas T, Melum E, Rausch P, Juran BD, Ellinghaus E, Shiryaev A, Laerdahl JK et al (2012) Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J Hepatol 57:366–375PubMedPubMedCentral
24.
Srivastava B, Mells GF, Cordell HJ, Muriithi A, Brown M, Ellinghaus E, Franke A et al (2012) Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis. Scand J Gastroenterol 47:820–826PubMed
25.
Ellinghaus D, Folseraas T, Holm K, Ellinghaus E, Melum E, Balschun T, Laerdahl JK et al (2013) Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 58:1074–1083PubMed
26.
Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, Andreassen OA et al (2013) Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 45:670–675PubMedPubMedCentral
27.
Carbone M, Neuberger JM (2014) Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 60:210–223PubMed
28.
Spurkland A, Saarinen S, Boberg KM, Mitchell S, Broome U, Caballeria L, Ciusani E et al (1999) HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations. Tissue Antigens 53:459–469PubMed
29.
Donaldson PT, Norris S (2002) Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity 35:555–564PubMed
30.
31.
Donaldson PT, Baragiotta A, Heneghan MA, Floreani A, Venturi C, Underhill JA, Jones DE et al (2006) HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study. Hepatology 44:667–674PubMed
32.
Goldberg AC, Bittencourt PL, Mougin B, Cancado EL, Porta G, Carrilho F, Kalil J (2001) Analysis of HLA haplotypes in autoimmune hepatitis type 1: identifying the major susceptibility locus. Hum Immunol 62:165–169PubMed
33.
Czaja AJ, Donaldson PT (2000) Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev 174:250–259PubMed
34.
Czaja AJ, Kruger M, Santrach PJ, Moore SB, Manns MP (1997) Genetic distinctions between types 1 and 2 autoimmune hepatitis. Am J Gastroenterol 92:2197–2200PubMed
35.
Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL (2013) The genetics of complex cholestatic disorders. Gastroenterology 144:1357–1374PubMedPubMedCentral
36.
Folseraas T, Melum E, Franke A, Karlsen TH (2011) Genetics in primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 25:713–726PubMed
37.
Mells GF, Kaser A, Karlsen TH (2013) Novel insights into autoimmune liver diseases provided by genome-wide association studies. J Autoimmun 46:41–54PubMed
38.
Mitchell MM, Lleo A, Zammataro L, Mayo MJ, Invernizzi P, Bach N, Shimoda S et al (2011) Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis. Epigenetics 6:95–102PubMedPubMedCentral
39.
Bakalov VK, Gutin L, Cheng CM, Zhou J, Sheth P, Shah K, Arepalli S et al (2012) Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency. J Autoimmun 38:315–321PubMedPubMedCentral
40.
Miller FW, Pollard KM, Parks CG, Germolec DR, Leung PS, Selmi C, Humble MC et al (2012) Criteria for environmentally associated autoimmune diseases. J Autoimmun 39:253–258PubMedPubMedCentral
41.
Selmi C, Leung PS, Sherr DH, Diaz M, Nyland JF, Monestier M, Rose NR et al (2012) Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop. J Autoimmun 39:272–284PubMed
42.
Ngu JH, Gearry RB, Frampton CM, Stedman CA (2013) Autoimmune hepatitis: the role of environmental risk factors: a population-based study. Hepatol Int 7:869–875
43.
Liang Y, Yang Z, Zhong R (2011) Smoking, family history and urinary tract infection are associated with primary biliary cirrhosis: a meta-analysis. Hepatol Res 41:572–578PubMed
44.
Andersen IM, Tengesdal G, Lie BA, Boberg KM, Karlsen TH, Hov JR (2013) Effects of coffee consumption, smoking, and hormones on risk for primary sclerosing cholangitis. Clin Gastroenterol Hepatol
45.
Florin TH, Pandeya N, Radford-Smith GL (2004) Epidemiology of appendicectomy in primary sclerosing cholangitis and ulcerative colitis: its influence on the clinical behaviour of these diseases. Gut 53:973–979PubMedPubMedCentral
46.
Mitchell SA, Thyssen M, Orchard TR, Jewell DP, Fleming KA, Chapman RW (2002) Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study. Gut 51:567–573PubMedPubMedCentral
47.
Kerkar N, Choudhuri K, Ma Y, Mahmoud A, Bogdanos DP, Muratori L, Bianchi F et al (2003) Cytochrome P4502D6(193–212): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease. J Immunol 170:1481–1489PubMed
48.
Hopf U, Moller B, Stemerowicz R, Lobeck H, Rodloff A, Freudenberg M, Galanos C et al (1989) Relation between Escherichia coli R(rough)-forms in gut, lipid A in liver, and primary biliary cirrhosis. Lancet 2:1419–1422PubMed
49.
Bogdanos DP, Baum H, Grasso A, Okamoto M, Butler P, Ma Y, Rigopoulou E et al (2004) Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol 40:31–39PubMed
50.
Berg CP, Kannan TR, Klein R, Gregor M, Baseman JB, Wesselborg S, Lauber K et al (2009) Mycoplasma antigens as a possible trigger for the induction of antimitochondrial antibodies in primary biliary cirrhosis. Liver Int 29:797–809PubMed
51.
Padgett KA, Selmi C, Kenny TP, Leung PS, Balkwill DL, Ansari AA, Coppel RL et al (2005) Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun 24:209–219PubMed
52.
53.
Rieger R, Leung PS, Jeddeloh MR, Kurth MJ, Nantz MH, Lam KS, Barsky D et al (2006) Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun 27:7–16PubMed
54.
Leung PS, Wang J, Naiyanetr P, Kenny TP, Lam KS, Kurth MJ, Gershwin ME (2013) Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA. J Autoimmun 41:79–86PubMedPubMedCentral
55.
Bogdanos DP, Mieli-Vergani G, Vergani D (2009) Autoantibodies and their antigens in autoimmune hepatitis. Semin Liver Dis 29:241–253PubMed
56.
Vergani D, Mieli-Vergani G, Mondelli M, Portmann B, Eddleston AL (1987) Immunoglobulin on the surface of isolated hepatocytes is associated with antibody-dependent cell-mediated cytotoxicity and liver damage. Liver 7:307–315PubMed
57.
Muratori L, Parola M, Ripalti A, Robino G, Muratori P, Bellomo G, Carini R et al (2000) Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane. Gut 46:553–561PubMedPubMedCentral
58.
Folci M, Meda F, Gershwin ME, Selmi C (2012) Cutting-edge issues in primary biliary cirrhosis. Clin Rev Allergy Immunol 42:342–354PubMed
59.
Oertelt S, Rieger R, Selmi C, Invernizzi P, Ansari AA, Coppel RL, Podda M et al (2007) A sensitive bead assay for antimitochondrial antibodies: chipping away at AMA-negative primary biliary cirrhosis. Hepatology 45:659–665PubMed
60.
Courvalin JC, Lassoued K, Bartnik E, Blobel G, Wozniak RW (1990) The 210-kD nuclear envelope polypeptide recognized by human autoantibodies in primary biliary cirrhosis is the major glycoprotein of the nuclear pore. J Clin Invest 86:279–285PubMedPubMedCentral
61.
Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E (1996) Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology 110:840–847PubMed
62.
Wesierska-Gadek J, Penner E, Battezzati PM, Selmi C, Zuin M, Hitchman E, Worman HJ et al (2006) Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology 43:1135–1144PubMed
63.
Szostecki C, Guldner HH, Will H (1997) Autoantibodies against “nuclear dots” in primary biliary cirrhosis. Semin Liver Dis 17:71–78PubMed
64.
Yang WH, Yu JH, Nakajima A, Neuberg D, Lindor K, Bloch DB (2004) Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure? Clin Gastroenterol Hepatol 2:1116–1122PubMed
65.
Pollheimer MJ, Halilbasic E, Fickert P, Trauner M (2011) Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 25:727–739PubMedPubMedCentral
66.
Terjung B, Herzog V, Worman HJ, Gestmann I, Bauer C, Sauerbruch T, Spengler U (1998) Atypical antineutrophil cytoplasmic antibodies with perinuclear fluorescence in chronic inflammatory bowel diseases and hepatobiliary disorders colocalize with nuclear lamina proteins. Hepatology 28:332–340PubMed
67.
Terjung B, Sohne J, Lechtenberg B, Gottwein J, Muennich M, Herzog V, Mahler M et al (2010) p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut 59:808–816PubMed
68.
Xu B, Broome U, Ericzon BG, Sumitran-Holgersson S (2002) High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6. Gut 51:120–127PubMedPubMedCentral
69.
Karrar A, Broome U, Sodergren T, Jaksch M, Bergquist A, Bjornstedt M, Sumitran-Holgersson S (2007) Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis. Gastroenterology 132:1504–1514PubMed
70.
O’Toole A, Alakkari A, Keegan D, Doherty G, Mulcahy H, O’Donoghue D (2012) Primary sclerosing cholangitis and disease distribution in inflammatory bowel disease. Clin Gastroenterol Hepatol 10:439–441PubMed
71.
Sano H, Nakazawa T, Ando T, Hayashi K, Naitoh I, Okumura F, Miyabe K et al (2011) Clinical characteristics of inflammatory bowel disease associated with primary sclerosing cholangitis. J Hepato-Biliary-Pancreat Sci 18:154–161
72.
Eksteen B, Liaskou E, Adams DH (2008) Lymphocyte homing and its role in the pathogenesis of IBD. Inflamm Bowel Dis 14:1298–1312PubMed
73.
O’Mahony CA, Vierling JM (2006) Etiopathogenesis of primary sclerosing cholangitis. Semin Liver Dis 26:3–21PubMed
74.
Rudolph G, Gotthardt D, Kloters-Plachky P, Kulaksiz H, Rost D, Stiehl A (2009) Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis. J Hepatol 51:149–155PubMed
75.
Miyake Y, Yamamoto K (2013) Role of gut microbiota in liver diseases. Hepatol Res 43:139–146PubMed
76.
Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMed
77.
78.
O’Hara SP, Splinter PL, Trussoni CE, Gajdos GB, Lineswala PN, LaRusso NF (2011) Cholangiocyte N-Ras protein mediates lipopolysaccharide-induced interleukin 6 secretion and proliferation. J Biol Chem 286:30352–30360PubMedPubMedCentral
79.
80.
Mueller T, Beutler C, Pico AH, Shibolet O, Pratt DS, Pascher A, Neuhaus P et al (2011) Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int 31:1574–1588PubMed
81.
Sheth P, Delos Santos N, Seth A, LaRusso NF, Rao RK (2007) Lipopolysaccharide disrupts tight junctions in cholangiocyte monolayers by a c-Src-, TLR4-, and LBP-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 293:G308–G318PubMed
82.
Guo S, Al-Sadi R, Said HM, Ma TY (2013) Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol 182:375–387PubMedPubMedCentral
83.
Fickert P, Fuchsbichler A, Marschall HU, Wagner M, Zollner G, Krause R, Zatloukal K et al (2006) Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice. Am J Pathol 168:410–422PubMedPubMedCentral
84.
Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, Krause R et al (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127:261–274PubMed
85.
Foell D, Wittkowski H, Roth J (2007) Mechanisms of disease: a ‘DAMP’ view of inflammatory arthritis. Nat Clin Pract Rheumatol 3:382–390PubMed
86.
O’Hara SP, Tabibian JH, Splinter PL, LaRusso NF (2013) The dynamic biliary epithelia: molecules, pathways, and disease. J Hepatol 58:575–582PubMed
87.
Hov JR, Boberg KM, Karlsen TH (2008) Autoantibodies in primary sclerosing cholangitis. World J Gastroenterol 14:3781–3791PubMedPubMedCentral
88.
Panasiuk A, Prokopowicz D, Zak J, Panasiuk B, Wysocka J (2004) Lymphocyte subpopulations in peripheral blood in primary sclerosing cholangitis. Hepatogastroenterology 51:1289–1291PubMed
89.
Bo X, Broome U, Remberger M, Sumitran-Holgersson S (2001) Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis. Gut 49:131–141PubMedPubMedCentral
90.
Takeda K, Kojima Y, Ikejima K, Harada K, Yamashina S, Okumura K, Aoyama T et al (2008) Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease. Proc Natl Acad Sci U S A 105:10895–10900PubMedPubMedCentral
91.
Mao TK, Lian ZX, Selmi C, Ichiki Y, Ashwood P, Ansari AA, Coppel RL et al (2005) Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology 42:802–808PubMed
92.
Chuang YH, Lian ZX, Tsuneyama K, Chiang BL, Ansari AA, Coppel RL, Gershwin ME (2006) Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun 26:232–240PubMed
93.
Adams DH, Eksteen B (2006) Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nat Rev Immunol 6:244–251PubMed
94.
Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hubscher SG, Briskin M et al (2004) Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med 200:1511–1517PubMedPubMedCentral
95.
Grant AJ, Lalor PF, Hubscher SG, Briskin M, Adams DH (2001) MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 33:1065–1072PubMed
96.
Liaskou E, Karikoski M, Reynolds GM, Lalor PF, Weston CJ, Pullen N, Salmi M et al (2011) Regulation of mucosal addressin cell adhesion molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity. Hepatology 53:661–672PubMedPubMedCentral
97.
Shen SH, Wertz DL, Klinman JP (2012) Implication for functions of the ectopic adipocyte copper amine oxidase (AOC3) from purified enzyme and cell-based kinetic studies. PLoS One 7:e29270PubMedPubMedCentral
98.
Miles A, Liaskou E, Eksteen B, Lalor PF, Adams DH (2008) CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow. Am J Physiol Gastrointest Liver Physiol 294:G1257–G1267PubMed
99.
Wright N, Hidalgo A, Rodriguez-Frade JM, Soriano SF, Mellado M, Parmo-Cabanas M, Briskin MJ et al (2002) The chemokine stromal cell-derived factor-1 alpha modulates alpha 4 beta 7 integrin-mediated lymphocyte adhesion to mucosal addressin cell adhesion molecule-1 and fibronectin. J Immunol 168:5268–5277PubMed
100.
Eksteen B, Mora JR, Haughton EL, Henderson NC, Lee-Turner L, Villablanca EJ, Curbishley SM et al (2009) Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells. Gastroenterology 137:320–329PubMedPubMedCentral
101.
Neumann K, Kruse N, Szilagyi B, Erben U, Rudolph C, Flach A, Zeitz M et al (2012) Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid. Hepatology 55:1976–1984PubMed
102.
Teufel A, Weinmann A, Kahaly GJ, Centner C, Piendl A, Worns M, Lohse AW et al (2010) Concurrent autoimmune diseases in patients with autoimmune hepatitis. J Clin Gastroenterol 44:208–213PubMed
103.
Tsuda M, Ambrosini YM, Zhang W, Yang GX, Ando Y, Rong G, Tsuneyama K et al (2011) Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis. Hepatology 54:1293–1302PubMedPubMedCentral
104.
Feld JJ, Meddings J, Heathcote EJ (2006) Abnormal intestinal permeability in primary biliary cirrhosis. Dig Dis Sci 51:1607–1613PubMed
105.
Palak J, Trivedi SC (2013) Etiopathogenesis of primary biliary cirrhosis: an overview of recent developments. Hepatol Int 7:28–47
106.
Senaldi G, Portmann B, Mowat AP, Mieli-Vergani G, Vergani D (1992) Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis. Arch Dis Child 67:1447–1453PubMedPubMedCentral
107.
Lapierre P, Hajoui O, Homberg JC, Alvarez F (1999) Formiminotransferase cyclodeaminase is an organ-specific autoantigen recognized by sera of patients with autoimmune hepatitis. Gastroenterology 116:643–649PubMed
108.
Zhao L, Tang Y, You Z, Wang Q, Liang S, Han X, Qiu D et al (2011) Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One 6:e18909PubMedPubMedCentral
109.
Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P, Granito A, Hussain MJ et al (2010) A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 52:999–1007PubMed
110.
Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, Coppel RL et al (2002) Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest 109:1231–1240PubMedPubMedCentral
111.
Van de Water J, Ansari A, Prindiville T, Coppel RL, Ricalton N, Kotzin BL, Liu S et al (1995) Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. J Exp Med 181:723–733PubMed
112.
Martinez OM, Villanueva JC, Gershwin ME, Krams SM (1995) Cytokine patterns and cytotoxic mediators in primary biliary cirrhosis. Hepatology 21:113–119PubMed
113.
Yang GX, Lian ZX, Chuang YH, Moritoki Y, Lan RY, Wakabayashi K, Ansari AA et al (2008) Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice. Hepatology 47:1974–1982PubMedPubMedCentral
114.
Kita H, Lian ZX, Van de Water J, He XS, Matsumura S, Kaplan M, Luketic V et al (2002) Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med 195:113–123PubMedPubMedCentral
115.
Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y (1995) HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med 181:1835–1845PubMed
116.
Arai O, Ikeda H, Mouri H, Notohara K, Matsueda K (2010) Two cases of inflammatory bowel disease diagnosed in the course of primary biliary cirrhosis. Nihon Shokakibyo Gakkai Zasshi 107:900–908PubMed
117.
Hashimoto E, Lindor KD, Homburger HA, Dickson ER, Czaja AJ, Wiesner RH, Ludwig J (1993) Immunohistochemical characterization of hepatic lymphocytes in primary biliary cirrhosis in comparison with primary sclerosing cholangitis and autoimmune chronic active hepatitis. Mayo Clin Proc 68:1049–1055PubMed
118.
Cameron RG, Blendis LM, Neuman MG (2001) Accumulation of macrophages in primary sclerosing cholangitis. Clin Biochem 34:195–201PubMed
119.
Ponsioen CY, Kuiper H, Ten Kate FJ, Ponsioen CY, Kuiper H, Ten Kate FJ, van Milligen de Wit M, van Deventer SJ, Tytgat GN (1999) Immunohistochemical analysis of inflammation in primary sclerosing cholangitis. Eur J Gastroenterol Hepatol 11:769–774PubMed
120.
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 23:988–993PubMed
121.
Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y (2009) Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol 157:261–270PubMedPubMedCentral
122.
Katt J, Schwinge D, Schoknecht T, Quaas A, Sobottka I, Burandt E, Becker C et al (2013) Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis. Hepatology 58:1084–1093PubMed
123.
Rong G, Zhou Y, Xiong Y, Zhou L, Geng H, Jiang T, Zhu Y et al (2009) Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population. Clin Exp Immunol 156:217–225PubMedPubMedCentral
124.
Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H et al (2008) ATP drives lamina propria T(H)17 cell differentiation. Nature 455:808–812PubMed
125.
Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, O’Connor W Jr et al (2011) Control of TH17 cells occurs in the small intestine. Nature 475:514–518PubMedPubMedCentral
126.
Dusseaux M, Martin E, Serriari N, Peguillet I, Premel V, Louis D, Milder M et al (2011) Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117:1250–1259PubMed
127.
Yang CY, Ma X, Tsuneyama K, Huang S, Takahashi T, Chalasani NP, Bowlus CL, et al (2013) IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy. Hepatology
128.
Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H (2013) The plasticity and stability of regulatory T cells. Nat Rev Immunol 13:461–467PubMed
129.
Tan Z, Qian X, Jiang R, Liu Q, Wang Y, Chen C, Wang X et al (2013) IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol 191:1835–1844PubMed
130.
Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M et al (2012) Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143:765–776, e761-763PubMedPubMedCentral
131.
Weaver CT, Hatton RD (2009) Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nat Rev Immunol 9:883–889PubMed
132.
Alvarado-Sanchez B, Hernandez-Castro B, Portales-Perez D, Baranda L, Layseca-Espinosa E, Abud-Mendoza C, Cubillas-Tejeda AC et al (2006) Regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 27:110–118PubMed
133.
Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D, Ma Y (2006) Functional study of CD4 + CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol 176:4484–4491PubMed
134.
Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, Baron U et al (2012) FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 57:125–132PubMed
135.
Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D (2004) Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 41:31–37PubMed
136.
Longhi MS, Mitry RR, Samyn M, Scalori A, Hussain MJ, Quaglia A, Mieli-Vergani G et al (2009) Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells. Hepatology 50:130–142PubMed
137.
Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH et al (2006) Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 43:729–737PubMed
138.
Sebode M, Peiseler M, Franke B, Schwinge D, Schoknecht T, Wortmann F, Quaas A, et al (2014) Reduced FOXP3+ regulatory T cells in patients with primary sclerosing cholangitis are associated with IL-2RA gene polymorphisms. J Hepatol
139.
Lamireau T, Zoltowska M, Levy E, Yousef I, Rosenbaum J, Tuchweber B, Desmouliere A (2003) Effects of bile acids on biliary epithelial cells: proliferation, cytotoxicity, and cytokine secretion. Life Sci 72:1401–1411PubMed
140.
Oude Elferink RP, Paulusma CC (2007) Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch 453:601–610PubMed
141.
Trauner M, Fickert P, Wagner M (2007) MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 27:77–98PubMed
142.
Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C et al (2003) Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 113:286–292PubMed
143.
Medina JF, Martinez A, Vazquez JJ, Prieto J (1997) Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 25:12–17PubMed
144.
Melero S, Spirli C, Zsembery A, Medina JF, Joplin RE, Duner E, Zuin M et al (2002) Defective regulation of cholangiocyte Cl-/HCO3(−) and Na+/H+ exchanger activities in primary biliary cirrhosis. Hepatology 35:1513–1521PubMed
145.
Shibao K, Hirata K, Robert ME, Nathanson MH (2003) Loss of inositol 1,4,5-trisphosphate receptors from bile duct epithelia is a common event in cholestasis. Gastroenterology 125:1175–1187PubMedPubMedCentral
146.
Takeyama Y, Kanegae K, Inomata S, Takata K, Tanaka T, Ueda S, Yokoyama K et al (2010) Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7alpha-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis. Med Mol Morphol 43:134–138PubMed
147.
Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P et al (2001) Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33:633–646PubMed
148.
Harada K, Isse K, Nakanuma Y (2006) Interferon gamma accelerates NF-kappaB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction. J Clin Pathol 59:184–190PubMedPubMedCentral
149.
Lazaridis KN, Strazzabosco M, Larusso NF (2004) The cholangiopathies: disorders of biliary epithelia. Gastroenterology 127:1565–1577PubMed
150.
Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A (2001) Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 108:223–232PubMedPubMedCentral
151.
Lleo A, Bowlus CL, Yang GX, Invernizzi P, Podda M, Van de Water J, Ansari AA et al (2010) Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 52:987–998PubMedPubMedCentral
152.
Allina J, Hu B, Sullivan DM, Fiel MI, Thung SN, Bronk SF, Huebert RC et al (2006) T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. J Autoimmun 27:232–241PubMed
153.
Savill J, Dransfield I, Gregory C, Haslett C (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965–975PubMed
154.
Chamulitrat W, Burhenne J, Rehlen T, Pathil A, Stremmel W (2009) Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide as a hepatoprotective agent. Hepatology 50:143–154PubMed
155.
Inamura K, Tsuji H, Nakamoto Y, Suzuki M, Kaneko S (2006) Transgenic mice aberrantly expressing pyruvate dehydrogenase complex E2 component on biliary epithelial cells do not show primary biliary cirrhosis. Clin Exp Immunol 145:93–100PubMedPubMedCentral
156.
Sasaki M, Ikeda H, Haga H, Manabe T, Nakanuma Y (2005) Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss. J Pathol 205:451–459PubMed
157.
Sasaki M, Ikeda H, Yamaguchi J, Nakada S, Nakanuma Y (2008) Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence. Hepatology 48:186–195PubMed
158.
Sasaki M, Nakanuma Y (2012) Novel approach to bile duct damage in primary biliary cirrhosis: participation of cellular senescence and autophagy. Int J Hepatol 2012:452143PubMedPubMedCentral
159.
Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y (2010) Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J Hepatol 53:318–325PubMed
160.
Lunz JG 3rd, Contrucci S, Ruppert K, Murase N, Fung JJ, Starzl TE, Demetris AJ (2001) Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs. Am J Pathol 158:1379–1390PubMedPubMedCentral
161.
Laish I, Katz H, Sulayev Y, Liberman M, Naftali T, Benjaminov F, Stein A et al (2013) Increased TERC gene copy number and cells in senescence in primary sclerosing cholangitis compared to colitis and control patients. Gene 529:245–249PubMed
162.
Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y (2010) Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis. Lab Investig 90:835–843PubMed
163.
Senaldi G, Lobo-Yeo A, Mowat AP, Mieli-Vergani G, Vergani D (1991) Class I and class II major histocompatibility complex antigens on hepatocytes: importance of the method of detection and expression in histologically normal and diseased livers. J Clin Pathol 44:107–114PubMedPubMedCentral
164.
Wen L, Peakman M, Lobo-Yeo A, McFarlane BM, Mowat AP, Mieli-Vergani G, Vergani D (1990) T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet 336:1527–1530PubMed
165.
Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH, Yang GX et al (2006) IL-2 receptor alpha(−/−) mice and the development of primary biliary cirrhosis. Hepatology 44:1240–1249PubMed
166.
Kawata K, Yang GX, Ando Y, Tanaka H, Zhang W, Kobayashi Y, Tsuneyama K et al (2013) Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFbetaRII mice. Hepatology 58:1094–1104PubMedPubMedCentral
167.
Leung PS, Yang GX, Dhirapong A, Tsuneyama K, Ridgway WM, Gershwin ME (2012) Animal models of primary biliary cirrhosis: materials and methods. Methods Mol Biol 900:291–316PubMed
168.
Tanaka H, Yang GX, Iwakoshi N, Knechtle SJ, Kawata K, Tsuneyama K, Leung P et al (2013) Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. Clin Exp Immunol 174:364–371PubMed
169.
Lapierre P, Djilali-Saiah I, Vitozzi S, Alvarez F (2004) A murine model of type 2 autoimmune hepatitis: xenoimmunization with human antigens. Hepatology 39:1066–1074PubMed
170.
Holdener M, Hintermann E, Bayer M, Rhode A, Rodrigo E, Hintereder G, Johnson EF et al (2008) Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection. J Exp Med 205:1409–1422PubMedPubMedCentral
Metadata
Title
Mechanisms of tissue injury in autoimmune liver diseases
Authors
Evaggelia Liaskou
Gideon M. Hirschfield
M. Eric Gershwin
Publication date
01-09-2014
Publisher
Springer Berlin Heidelberg
Published in
Seminars in Immunopathology / Issue 5/2014
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-014-0439-3

Other articles of this Issue 5/2014

Seminars in Immunopathology 5/2014 Go to the issue

Review

Immune sensing of nucleic acids in inflammatory skin diseases

Review

Insulitis in human type 1 diabetes: a comparison between patients and animal models

Review

Beyond canonical inflammasomes: emerging pathways in IL-1-mediated autoinflammatory disease

Editorial

Introduction: mechanisms of tissue injury in autoimmune diseases

Review

Mechanisms of tissue damage in arthritis

Review

Autoimmune and autoinflammatory mechanisms in uveitis
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits