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Semin Liver Dis 2009; 29(3): 241-253
DOI: 10.1055/s-0029-1233533
© Thieme Medical Publishers

Autoantibodies and their Antigens in Autoimmune Hepatitis

Dimitrios P. Bogdanos1 , Giorgina Mieli-Vergani1 , Diego Vergani1
  • 1Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, United Kingdom
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Publication History

Publication Date:
12 August 2009 (online)

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ABSTRACT

Autoantibody detection assists in the diagnosis and allows differentiation of autoimmune hepatitis (AIH) type 1 (AIH-1), characterized by antinuclear antibody (ANA) and/or smooth muscle antibody (SMA), and type 2 (AIH-2), distinguished by the presence of antibodies to liver-kidney microsome type 1 (anti-LKM1) and/or antibodies to liver cytosol type 1 (anti-LC1). Detection of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-soluble liver antigen (SLA) antibodies can act as an additional pointer toward the diagnosis of AIH, particularly in the absence of the conventional autoantibodies. Routine autoantibody testing by indirect immunofluorescence has been recently complemented by molecular assays based on purified or recombinant antigens. Although the AIH-1-specific ANA and SMA targets need better definition, those of anti-LKM1 and anti-LC1 in AIH-2 have been clearly identified; the fine specificity of antibody reactivity and its clinical relevance to disease pathogenesis are the focus of ongoing investigation. This article critically discusses the current knowledge of the diagnostic and clinical significance of AIH-related autoantibody reactivities, focusing on key issues that the physician needs to be aware of to be able to request the appropriate testing and to interpret correctly the laboratory results within the clinical context of the patient.

KEYWORDS

Antibody - autoantigen - autoimmunity - disease - liver

REFERENCES

  • 1 Bogdanos D P, Invernizzi P, Mackay I R, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges.  World J Gastroenterol. 2008;  14(21) 3374-3387
    CrossrefPubMedGoogle Scholar
  • 2 Vergani D, Alvarez F, Bianchi F B International Autoimmune Hepatitis Group et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group.  J Hepatol. 2004;  41(4) 677-683
    CrossrefPubMedGoogle Scholar
  • 3 Alvarez F, Berg P A, Bianchi F B et al.. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.  J Hepatol. 1999;  31(5) 929-938
    CrossrefPubMedGoogle Scholar
  • 4 Hennes E M, Zeniya M, Czaja A J International Autoimmune Hepatitis Group et al. Simplified criteria for the diagnosis of autoimmune hepatitis.  Hepatology. 2008;  48(1) 169-176
    CrossrefPubMedGoogle Scholar
  • 5 Gregorio G V, Portmann B, Reid F et al.. Autoimmune hepatitis in childhood: a 20-year experience.  Hepatology. 1997;  25(3) 541-547
    CrossrefPubMedGoogle Scholar
  • 6 Duchini A, McHutchison J G, Pockros P J. LKM-positive autoimmune hepatitis in the western United States: a case series.  Am J Gastroenterol. 2000;  95(11) 3238-3241
    CrossrefPubMedGoogle Scholar
  • 7 Bogdanos D P, Mieli-Vergani G, Vergani D. Liver-kidney microsomal antibody-positive autoimmune hepatitis in the United States.  Am J Gastroenterol. 2001;  96(12) 3447-3448
    CrossrefPubMedGoogle Scholar
  • 8 Waldenstrom J. Leber, blutproteine und Nahrungsweiss.  Dtsch Z Verdau Stoffwechselkr. 1950;  15 113-119
    PubMedGoogle Scholar
  • 9 Zimmerman H J, Heller P, Hill R P. Extreme hyperglobulinemia in subacute hepatic necrosis.  N Engl J Med. 1951;  244(7) 245-249
    PubMedGoogle Scholar
  • 10 Mackay I R. Historical reflections on autoimmune hepatitis.  World J Gastroenterol. 2008;  14(21) 3292-3300
    CrossrefPubMedGoogle Scholar
  • 11 Leoni A. [The specificity of L.E. phenomenon].  Minerva Med. 1954;  45(30) 1022-1027
    PubMedGoogle Scholar
  • 12 Joske R A, King W E. The L.E.-cell phenomenon in active chronic viral hepatitis.  Lancet. 1955;  269(6888) 477-480
    PubMedGoogle Scholar
  • 13 Hargraves M M, Richmond H, Morton R. Presentation of two bone marrow elements; the tart cells and the L.E cell.  Mayo Clin Proc. 1948;  23 25-28
    PubMedGoogle Scholar
  • 14 Cowling D C, Mackay I R, Taft L I. Lupoid hepatitis.  Lancet. 1956;  271(6957) 1323-1326
    PubMedGoogle Scholar
  • 15 Mackay I R, Weiden S, Hasker J. Autoimmune hepatitis.  Ann N Y Acad Sci. 1965;  124(2) 767-780
    CrossrefPubMedGoogle Scholar
  • 16 Johnson P J, McFarlane I G. Meeting report: International Autoimmune Hepatitis Group.  Hepatology. 1993;  18(4) 998-1005
    CrossrefPubMedGoogle Scholar
  • 17 Holborow E J, Asherson G L, Johnson G D, Barnes R D, Carmichael D S. Antinuclear factor and other antibodies in blood and liver diseases.  BMJ. 1963;  1(5331) 656-658
    CrossrefPubMedGoogle Scholar
  • 18 Czaja A J, Morshed S A, Parveen S, Nishioka M. Antibodies to single-stranded and double-stranded DNA in antinuclear antibody-positive type 1-autoimmune hepatitis.  Hepatology. 1997;  26(3) 567-572
    CrossrefPubMedGoogle Scholar
  • 19 Parveen S, Morshed S A, Arima K et al.. Antibodies to Ro/La, Cenp-B, and snRNPs antigens in autoimmune hepatitis of North America versus Asia: patterns of immunofluorescence, ELISA reactivities, and HLA association.  Dig Dis Sci. 1998;  43(6) 1322-1331
    CrossrefPubMedGoogle Scholar
  • 20 Czaja A J, Homburger H A. Autoantibodies in liver disease.  Gastroenterology. 2001;  120(1) 239-249
    PubMedGoogle Scholar
  • 21 Johnson G D, Holborow E J, Glynn L E. Antibody to smooth muscle in patients with liver disease.  Lancet. 1965;  2(7418) 878-879
    PubMedGoogle Scholar
  • 22 Whittingham S, Irwin J, Mackay I R, Smalley M. Smooth muscle autoantibody in “autoimmune” hepatitis.  Gastroenterology. 1966;  51(4) 499-505
    PubMedGoogle Scholar
  • 23 Bottazzo G F, Florin-Christensen A, Fairfax A, Swana G, Doniach D, Groeschel-Stewart U. Classification of smooth muscle autoantibodies detected by immunofluorescence.  J Clin Pathol. 1976;  29(5) 403-410
    PubMedGoogle Scholar
  • 24 Toh B H. Smooth muscle autoantibodies and autoantigens.  Clin Exp Immunol. 1979;  38(3) 621-628
    PubMedGoogle Scholar
  • 25 Gabbiani G, Ryan G B, Lamelin J P et al.. Human smooth muscle autoantibody. Its identification as antiactin antibody and a study of its binding to “nonmuscular” cells.  Am J Pathol. 1973;  72(3) 473-488
    PubMedGoogle Scholar
  • 26 Kurki P, Linder E, Miettinen A, Alfthan O. Smooth muscle antibodies of actin and “non-actin” specificity.  Clin Immunol Immunopathol. 1978;  9(4) 443-453
    CrossrefPubMedGoogle Scholar
  • 27 Lidman K, Biberfeld G, Fagraeus A et al.. Anti-actin specificity of human smooth muscle antibodies in chronic active hepatitis.  Clin Exp Immunol. 1976;  24(2) 266-272
    PubMedGoogle Scholar
  • 28 Czaja A J, Cassani F, Cataleta M, Valentini P, Bianchi F B. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis.  Hepatology. 1996;  24(5) 1068-1073
    CrossrefPubMedGoogle Scholar
  • 29 Liaskos C, Bogdanos D P, Davies E T, Dalekos G N. Diagnostic relevance of anti-filamentous actin antibodies in autoimmune hepatitis.  J Clin Pathol. 2007;  60(1) 107-108
    CrossrefPubMedGoogle Scholar
  • 30 Granito A, Muratori L, Muratori P et al.. Antibodies to filamentous actin (F-actin) in type 1 autoimmune hepatitis.  J Clin Pathol. 2006;  59(3) 280-284
    CrossrefPubMedGoogle Scholar
  • 31 Zamanou A, Tsirogianni A, Terzoglou C, Balafas A, Economidou I, Lymberi P. Anti-smooth muscle antibodies (ASMAs) and anti-cytoskeleton antibodies (ACTAs) in liver diseases: a comparison of classical indirect immunofluorescence with ELISA.  J Clin Lab Anal. 2002;  16(4) 194-201
    CrossrefPubMedGoogle Scholar
  • 32 Villalta D, Bizzaro N, Da Re M, Tozzoli R, Komorowski L, Tonutti E. Diagnostic accuracy of four different immunological methods for the detection of anti-F-actin autoantibodies in type 1 autoimmune hepatitis and other liver-related disorders.  Autoimmunity. 2008;  41(1) 105-110
    CrossrefPubMedGoogle Scholar
  • 33 Rizzetto M, Swana G, Doniach D. Microsomal antibodies in active chronic hepatitis and other disorders.  Clin Exp Immunol. 1973;  15(3) 331-344
    PubMedGoogle Scholar
  • 34 Rizzetto M, Bianchi F B, Doniach D. Characterization of the microsomal antigen related to a subclass of active chronic hepatitis.  Immunology. 1974;  26(3) 589-601
    PubMedGoogle Scholar
  • 35 Homberg J C, Abuaf N, Bernard O et al.. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis.  Hepatology. 1987;  7(6) 1333-1339
    PubMedGoogle Scholar
  • 36 Homberg J C, Andre C, Abuaf N. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis.  Clin Exp Immunol. 1984;  55(3) 561-570
    PubMedGoogle Scholar
  • 37 Crivelli O, Lavarini C, Chiaberge E et al.. Microsomal autoantibodies in chronic infection with the HBsAg associated delta (delta) agent.  Clin Exp Immunol. 1983;  54(1) 232-238
    PubMedGoogle Scholar
  • 38 Clemente M G, Meloni A, Obermayer-Straub P, Frau F, Manns M P, De Virgiliis S. Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1.  Gastroenterology. 1998;  114(2) 324-328
    PubMedGoogle Scholar
  • 39 Gueguen M, Meunier-Rotival M, Bernard O, Alvarez F. Anti-liver kidney microsome antibody recognizes a cytochrome P450 from the IID subfamily.  J Exp Med. 1988;  168(2) 801-806
    CrossrefPubMedGoogle Scholar
  • 40 Manns M P, Johnson E F, Griffin K J, Tan E M, Sullivan K F. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.  J Clin Invest. 1989;  83(3) 1066-1072
    PubMedGoogle Scholar
  • 41 Zanger U M, Hauri H P, Loeper J, Homberg J C, Meyer U A. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.  Proc Natl Acad Sci U S A. 1988;  85(21) 8256-8260
    PubMedGoogle Scholar
  • 42 Manns M P, Obermayer-Straub P. Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease.  Hepatology. 1997;  26(4) 1054-1066
    CrossrefPubMedGoogle Scholar
  • 43 Martini E, Abuaf N, Cavalli F, Durand V, Johanet C, Homberg J C. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2.  Hepatology. 1988;  8(6) 1662-1666
    PubMedGoogle Scholar
  • 44 Lenzi M, Manotti P, Muratori L et al.. Liver cytosolic 1 antigen-antibody system in type 2 autoimmune hepatitis and hepatitis C virus infection.  Gut. 1995;  36(5) 749-754
    PubMedGoogle Scholar
  • 45 Muratori L, Cataleta M, Muratori P, Lenzi M, Bianchi F B. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis.  Gut. 1998;  42(5) 721-726
    CrossrefPubMedGoogle Scholar
  • 46 Lapierre P, Hajoui O, Homberg J C, Alvarez F. Formiminotransferase cyclodeaminase is an organ-specific autoantigen recognized by sera of patients with autoimmune hepatitis.  Gastroenterology. 1999;  116(3) 643-649
    PubMedGoogle Scholar
  • 47 Muratori L, Sztul E, Muratori P et al.. Distinct epitopes on formiminotransferase cyclodeaminase induce autoimmune liver cytosol antibody type 1.  Hepatology. 2001;  34(3) 494-501
    CrossrefPubMedGoogle Scholar
  • 48 Berg P A, Stechemesser E, Strienz J. Hypergammaglobulinamische chronisch aktive Hepatitis mit Nachweis von leberpankreas-spezifischen komplementbindenden Autoantikorpern.  Verh Dtsch Ges Inn Med. 1981;  87 921-927
    PubMedGoogle Scholar
  • 49 Stechemesser E, Klein R, Berg P A. Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis.  Hepatology. 1993;  18(1) 1-9
    CrossrefPubMedGoogle Scholar
  • 50 Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Büschenfelde K H. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen.  Lancet. 1987;  1(8528) 292-294
    PubMedGoogle Scholar
  • 51 Wies I, Brunner S, Henninger J et al.. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis.  Lancet. 2000;  355(9214) 1510-1515
    CrossrefPubMedGoogle Scholar
  • 52 Volkmann M, Martin L, Bäurle A et al.. Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis.  Hepatology. 2001;  33(3) 591-596
    CrossrefPubMedGoogle Scholar
  • 53 Ma Y, Okamoto M, Thomas M G et al.. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease.  Hepatology. 2002;  35(3) 658-664
    CrossrefPubMedGoogle Scholar
  • 54 Gelpi C, Sontheimer E J, Rodriguez-Sanchez J L. Autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion.  Proc Natl Acad Sci U S A. 1992;  89(20) 9739-9743
    PubMedGoogle Scholar
  • 55 McFarlane I G, Hegarty J E, McSorley C G, McFarlane B M, Williams R. Antibodies to liver-specific protein predict outcome of treatment withdrawal in autoimmune chronic active hepatitis.  Lancet. 1984;  2(8409) 954-956
    PubMedGoogle Scholar
  • 56 Czaja A J, Pfeifer K D, Decker R H, Vallari A S. Frequency and significance of antibodies to asialoglycoprotein receptor in type 1 autoimmune hepatitis.  Dig Dis Sci. 1996;  41(9) 1733-1740
    PubMedGoogle Scholar
  • 57 van der Woude F J, Rasmussen N, Lobatto S et al.. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis.  Lancet. 1985;  1(8426) 425-429
    PubMedGoogle Scholar
  • 58 Hagen E C, Andrassy K, Chernok E EEC/BCR Group for ANCA Assay Standardization et al. The value of indirect immunofluorescence and solid phase techniques for ANCA detection. A report on the first phase of an international cooperative study on the standardization of ANCA assays.  J Immunol Methods. 1993;  159(1-2) 1-16
    CrossrefPubMedGoogle Scholar
  • 59 Terjung B, Herzog V, Worman H J et al.. Atypical antineutrophil cytoplasmic antibodies with perinuclear fluorescence in chronic inflammatory bowel diseases and hepatobiliary disorders colocalize with nuclear lamina proteins.  Hepatology. 1998;  28(2) 332-340
    CrossrefPubMedGoogle Scholar
  • 60 Terjung B, Spengler U, Sauerbruch T, Worman H J. “Atypical p-ANCA” in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines.  Gastroenterology. 2000;  119(2) 310-322
    CrossrefPubMedGoogle Scholar
  • 61 Terjung B, Worman H J, Herzog V, Sauerbruch T, Spengler U. Differentiation of antineutrophil nuclear antibodies in inflammatory bowel and autoimmune liver diseases from antineutrophil cytoplasmic antibodies (p-ANCA) using immunofluorescence microscopy.  Clin Exp Immunol. 2001;  126(1) 37-46
    CrossrefPubMedGoogle Scholar
  • 62 Terjung B, Bogsch F, Klein R et al.. Diagnostic accuracy of atypical p-ANCA in autoimmune hepatitis using ROC- and multivariate regression analysis.  Eur J Med Res. 2004;  9(9) 439-448
    PubMedGoogle Scholar
  • 63 Terjung B, Spengler U. Atypical p-ANCA in PSC and AIH: a hint toward a “leaky gut”?.  Clin Rev Allergy Immunol. 2009;  36(1) 40-51
    CrossrefPubMedGoogle Scholar
  • 64 Gregorio G V, McFarlane B, Bracken P, Vergani D, Mieli-Vergani G. Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease.  Autoimmunity. 2002;  35(8) 515-519
    CrossrefPubMedGoogle Scholar
  • 65 Frenzel C, Herkel J, Lüth S, Galle P R, Schramm C, Lohse A W. Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis.  Am J Gastroenterol. 2006;  101(12) 2731-2736
    CrossrefPubMedGoogle Scholar
  • 66 Gregorio G V, Portmann B, Karani J et al.. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.  Hepatology. 2001;  33(3) 544-553
    CrossrefPubMedGoogle Scholar
  • 67 Hov J R, Boberg K M, Karlsen T H. Autoantibodies in primary sclerosing cholangitis.  World J Gastroenterol. 2008;  14(24) 3781-3791
    CrossrefPubMedGoogle Scholar
  • 68 Kerkar N, Hadzić N, Davies E T et al.. De-novo autoimmune hepatitis after liver transplantation.  Lancet. 1998;  351(9100) 409-413
    CrossrefPubMedGoogle Scholar
  • 69 Bogdanos D P, Mieli-Vergani G, Vergani D. Non-organ-specific autoantibodies in hepatitis C virus infection: do they matter?.  Clin Infect Dis. 2005;  40(4) 508-510
    CrossrefPubMedGoogle Scholar
  • 70 Bogdanos D P, Baum H, Vergani D. Antimitochondrial and other autoantibodies.  Clin Liver Dis. 2003;  7(4) 759-777, vi
    CrossrefPubMedGoogle Scholar
  • 71 Rigopoulou E I, Davies E T, Pares A et al.. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis.  Gut. 2005;  54(4) 528-532
    CrossrefPubMedGoogle Scholar
  • 72 Vergani D, Bogdanos D P. Positive markers in AMA-negative PBC.  Am J Gastroenterol. 2003;  98(2) 241-243
    CrossrefPubMedGoogle Scholar
  • 73 Maggiore G, Bernard O, Homberg J C et al.. Liver disease associated with anti-liver-kidney microsome antibody in children.  J Pediatr. 1986;  108(3) 399-404
    PubMedGoogle Scholar
  • 74 Muratori L, Parola M, Ripalti A et al.. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane.  Gut. 2000;  46(4) 553-561
    CrossrefPubMedGoogle Scholar
  • 75 Cassani F, Cataleta M, Valentini P et al.. Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on the disease profile.  Hepatology. 1997;  26(3) 561-566
    PubMedGoogle Scholar
  • 76 Lenzi M, Bellentani S, Saccoccio G et al.. Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population: a nested case-control study of the Dionysos cohort.  Gut. 1999;  45(3) 435-441
    PubMedGoogle Scholar
  • 77 Muratori L, Lenzi M, Cataleta M et al.. Interferon therapy in liver/kidney microsomal antibody type 1-positive patients with chronic hepatitis C.  J Hepatol. 1994;  21(2) 199-203
    CrossrefPubMedGoogle Scholar
  • 78 Bortolotti F, Vajro P, Balli F et al.. Non-organ specific autoantibodies in children with chronic hepatitis C.  J Hepatol. 1996;  25(5) 614-620
    CrossrefPubMedGoogle Scholar
  • 79 Bogdanos D P, Mieli-Vergani G, Vergani D. Virus, liver and autoimmunity.  Dig Liver Dis. 2000;  32(5) 440-446
    CrossrefPubMedGoogle Scholar
  • 80 Ferri S, Muratori L, Quarneti C et al.. Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C.  J Hepatol. 2009;  , March 26 (Epub ahead print)
    PubMedGoogle Scholar
  • 81 Vergani D. LKM antibody: getting in some target practice.  Gut. 2000;  46(4) 449-450
    CrossrefPubMedGoogle Scholar
  • 82 Baeres M, Herkel J, Czaja A J et al.. Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics.  Gut. 2002;  51(2) 259-264
    CrossrefPubMedGoogle Scholar
  • 83 Bogdanos D P, Gilbert D, Bianchi I et al.. Antibodies to soluble liver antigen and alpha-enolase in patients with autoimmune hepatitis.  J Autoimmune Dis. 2004;  1(1) 4
    CrossrefPubMedGoogle Scholar
  • 84 Vitozzi S, Djilali-Saiah I, Lapierre P, Alvarez F. Anti-soluble liver antigen/liver-pancreas (SLA/LP) antibodies in pediatric patients with autoimmune hepatitis.  Autoimmunity. 2002;  35(8) 485-492
    CrossrefPubMedGoogle Scholar
  • 85 Xu X M, Carlson B A, Mix H et al.. Biosynthesis of selenocysteine on its tRNA in eukaryotes.  PLoS Biol. 2007;  5(1) e4
    CrossrefPubMedGoogle Scholar
  • 86 Kerkar N, Ma Y, Davies E T, Cheeseman P, Mieli-Vergani G, Vergani D. Detection of liver kidney microsomal type 1 antibody using molecularly based immunoassays.  J Clin Pathol. 2002;  55(12) 906-909
    CrossrefPubMedGoogle Scholar
  • 87 Vergani D. NOSA in HCV infection: markers or makers of disease?.  Gut. 1999;  45(3) 328-329
    PubMedGoogle Scholar
  • 88 Vergani D, Choudhuri K, Bogdanos D P, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis.  Clin Liver Dis. 2002;  6(3) 727-737
    CrossrefPubMedGoogle Scholar
  • 89 Vergani D, Mieli-Vergani G. The impact of autoimmunity on hepatocytes.  Semin Liver Dis. 2007;  27(2) 140-151
    Article in Thieme ConnectPubMedGoogle Scholar
  • 90 Gregorio G V, Choudhuri K, Ma Y et al.. Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection.  Clin Exp Immunol. 2003;  133(3) 404-413
    CrossrefPubMedGoogle Scholar
  • 91 Kerkar N, Choudhuri K, Ma Y et al.. 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. 2003;  170(3) 1481-1489
    PubMedGoogle Scholar
  • 92 Bogdanos D P, Dalekos G N. Enzymes as target antigens of liver-specific autoimmunity: the case of cytochromes P450s.  Curr Med Chem. 2008;  15(22) 2285-2292
    CrossrefPubMedGoogle Scholar
  • 93 Mullighan C G, Bogdanos D P, Vergani D, Bardy P G. Cytochrome P450 1A2 is a target antigen in hepatitic graft-versus-host disease.  Bone Marrow Transplant. 2006;  38(10) 703-705
    CrossrefPubMedGoogle Scholar
  • 94 Granito A, Stanzani M, Muratori L et al.. LKM1-positive type 2 autoimmune hepatitis following allogenic hematopoietic stem-cell transplantation.  Am J Gastroenterol. 2008;  103(5) 1313-1314
    CrossrefPubMedGoogle Scholar
  • 95 Obermayer-Straub P, Perheentupa J, Braun S et al.. Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.  Gastroenterology. 2001;  121(3) 668-677
    PubMedGoogle Scholar
  • 96 Lanzavecchia A. How can cryptic epitopes trigger autoimmunity?.  J Exp Med. 1995;  181(6) 1945-1948
    CrossrefPubMedGoogle Scholar
  • 97 Bogdanos D P, McFarlane I G. Cytochrome P450 2A6 meets P450 2D6: an enigma of viral infections and autoimmunity.  J Hepatol. 2003;  39(5) 860-863
    CrossrefPubMedGoogle Scholar
  • 98 Beaune P, Pessayre D, Dansette P, Mansuy D, Manns M. Autoantibodies against cytochromes P450: role in human diseases.  Adv Pharmacol. 1994;  30 199-245
    PubMedGoogle Scholar
  • 99 Hasler J A. Pharmacogenetics of cytochromes P450.  Mol Aspects Med. 1999;  20(1-2) 12-24 25-137
    PubMedGoogle Scholar
  • 100 Lin J H, Lu A Y. Interindividual variability in inhibition and induction of cytochrome P450 enzymes.  Annu Rev Pharmacol Toxicol. 2001;  41 535-567
    CrossrefPubMedGoogle Scholar
  • 101 Bogdanos D P, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences.  Liver. 2001;  21(4) 225-232
    CrossrefPubMedGoogle Scholar
  • 102 Dalekos G N, Wedemeyer H, Obermayer-Straub P et al.. Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during alpha-interferon treatment.  J Hepatol. 1999;  30(3) 366-375
    CrossrefPubMedGoogle Scholar
  • 103 Manns M P, Griffin K J, Sullivan K F, Johnson E F. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase.  J Clin Invest. 1991;  88(4) 1370-1378
    PubMedGoogle Scholar
  • 104 Yamamoto A M, Cresteil D, Homberg J C, Alvarez F. Characterization of anti-liver-kidney microsome antibody (anti-LKM1) from hepatitis C virus-positive and -negative sera.  Gastroenterology. 1993;  104(6) 1762-1767
    PubMedGoogle Scholar
  • 105 Bogdanos D P, Lenzi M, Okamoto M et al.. Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus infected patients is associated with the possession of HLA B51.  Int J Immunopathol Pharmacol. 2004;  17(1) 83-92
    PubMedGoogle Scholar
  • 106 Ma Y, Bogdanos D P, Hussain M J et al.. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2.  Gastroenterology. 2006;  130(3) 868-882
    CrossrefPubMedGoogle Scholar
  • 107 Ma Y, Thomas M G, Okamoto M et al.. Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule.  J Immunol. 2002;  169(1) 277-285
    PubMedGoogle Scholar
  • 108 Manns M, Zanger U, Gerken G et al.. Patients with type II autoimmune hepatitis express functionally intact cytochrome P-450 db1 that is inhibited by LKM-1 autoantibodies in vitro but not in vivo.  Hepatology. 1990;  12(1) 127-132
    PubMedGoogle Scholar

Professor Diego VerganiM.D. Ph.D. F.R.C.P. F.R.C.Path. 

Institute of Liver Studies, King's College London School of Medicine at King's College Hospital

Denmark Hill, London SE5 9RS, United Kingdom

Email: diego.vergani@kcl.ac.uk

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