Semin Liver Dis 2002; 22(4): 339-352
DOI: 10.1055/s-2002-35704
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Autoantibodies and Autoantigens in Autoimmune Hepatitis

Christian P. Strassburg, Michael P. Manns
  • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Further Information

Publication History

Publication Date:
25 November 2002 (online)

ABSTRACT

The diagnosis of autoimmune hepatitis (AIH) relies on the exclusion of viral, metabolic, genetic, and toxic etiologies of chronic hepatitis or hepatic injury. There are few parameters that positively predict the presence of AIH. Autoantibodies have been intensively evaluated in this respect and have led to the classification of AIH into three serological subgroups: antinuclear and smooth muscle antibody-positive (ANA/SMA, type 1), liver-kidney microsomal antibody-positive (LKM-1, type 2), and soluble liver antigen/liver-pancreas antigen antibody-positive (SLA/LP, type 3) AIH. Although there are few clinical implications resulting from this classification, autoantibody profiles indicate that AIH is a heterogenous group of entities. The molecular characterization of B cell autoimmunity has led to the identification of major phase I and phase II metabolic enzymes as well as structural and functional components of the cell nucleus as immunologic targets. Autoantibodies and their corresponding autoantigens are intensively studied to provide clues to the understanding of disease initiation, tissue specificity, and propagation of hepatic autoimmune diseases.

REFERENCES

  • 1 Waldenström J. Leber, Blutproteine und Nahrungseiweisse.  Dtsch Gesellsch Verd Stoffw . 1950;  15 113-119
  • 2 Manns M P, Strassburg C P, Obermayer-Straub P. Autoimmune hepatitis. In: Theofilopoulos AN, Bona CA, eds. The Molecules Pathology of Autoimmune Diseases, 2nd ed New York: Marcel Dekker 2000: 915-950
  • 3 Manns M P, Paumgartner G, Leuschner U. Immunology and Liver Boston, MA: Kluwer 2000
  • 4 Strassburg C P, Obermayer-Straub P, Manns M P. Autoimmunity in liver diseases.  Clin Rev Allergy Immunol . 2000;  18 127-139
  • 5 Mackay I R, Taft L I, Cowling D C. Lupoid hepatitis.  Lancet . 1956;  2 1323-1326
  • 6 Mackay I R. Immunological aspects of chronic active hepatitis.  Hepatology . 1983;  3 724-728
  • 7 Manns M P, Strassburg C P. Autoimmune hepatitis: clinical challenges.  Gastroenterology . 2001;  120 1502-17
  • 8 Czaja A J, Manns M P. The validity and importance of subtypes in autoimmune hepatitis: a point of view.  Am J Gastroenterol . 1995;  90 1206-1211
  • 9 Zanger U M, Hauri H P, Loeper J, Homberg J C, Meyer U A. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type 2.  Proc Natl Acad Sci USA . 1988;  85 8256-8260
  • 10 Guenguen 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;  168 801
  • 11 Homberg J C, Abuaf N, Bernard O. Chronic active hepatitis associated with anti liver/kidney microsome type 1: a second type of ``autoimmune'' hepatitis.  Hepatology . 1987;  7 1333-1339
  • 12 Manns M, Meyer zum Büschenfelde K H, Slusarczyk J, Dienes H P. Detection of liver-kidney microsomal autoantibodies by radioimmunoassay and their relation to antimitochondrial antibodies in inflammatory liver disease.  Clin Exp Immunol . 1984;  54 600-608
  • 13 Manns M P, Johnson E F, Griffin K J, Tan E M, Sullivan K F. Major antigen of liver kidney microsomal antibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.  J Clin Invest . 1989;  83 1066-1072
  • 14 Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Büschenfelde K H. Characterization of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen.  Lancet . 1987;  I 292-294
  • 15 Berg P A, Stechemesser E, Strienz J. Hypergammaglobulinaemische chronisch aktive Hepatitis mit Nachweis von Leber-Pankreas-spezifischen komplementbindenden Antikörpern.  Verh Dtsch Ges Inn Med . 1981;  87 821-827
  • 16 Stechemesser E, Klein R, Berg P A. Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis.  Hepatology . 1993;  18 1-9
  • 17 Costa M, Rodriguez-Sanchez J L, Czaja A J, Gelpi C. Isolation and characterization of cDNA encoding the antigenic protein of the human tRNP(Ser)Sec complex recognized by autoantibodies from patients with type-1 autoimmune hepatitis.  Clin Exp Immunol . 2000;  121 364-374
  • 18 Gelpi C, Sontheimer E, Rodriguez-Sanchez J. Autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion.  Proc Natl Acad Sci USA . 1992;  89 9739-9743
  • 19 Wies I, Brunner S, Henninger J. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis.  Lancet . 2000;  355 1510-1515
  • 20 Volkmann M, Martin L, Bäurle A. Soluble liver antigen: isolation of a 35 kD recombinant protein (SLA-P35) specifically recognizing sera from patients with autoimmune hepatitis type 3.  Hepatology . 2001;  33 591-596
  • 21 Kanzler S, Weidemann C, Gerken G. Clinical significance of autoantibodies to soluble liver antigen in autoimmune hepatitis.  J Hepatol . 1999;  31 635-640
  • 22 Obermayer-Straub P, Strassburg C P, Manns M P. Autoimmune hepatitis.  J Hepatol . 2000;  32 181-197
  • 23 Obermayer-Straub P, Perheentupa J, Braun S. Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.  Gastroenterology . 2001;  121 668-677
  • 24 Clemente M G, Obermayer-Straub P, Meloni A. Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1.  J Clin Endocrinol Metabol . 1997;  82 1353-1361
  • 25 Clemente M G, Meloni A, Obermayer-Straub P. Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1.  Gastroenterology . 1998;  114 324-328
  • 26 Obermayer-Straub P, Strassburg C P, Manns M P. Autoimmune polyglandular syndrome type 1.  Clin Rev Allergy Immunol . 2000;  18 167-183
  • 27 Aaltonen J, Börses P, Sandkuijl L, Perheentupa J, Peltonen L. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21.  Nature Genet . 1994;  8 83-87
  • 28 Rinderle C, Christensen H M, Schweiger S, Lehrach H, Yaspo M L. AIRE encodes a nuclear protein co-localizing with cytoskeletal filaments: altered sub-cellular distribution of mutants lacking the PHD zinc fingers.  Hum Mol Genet . 1999;  8 277-290
  • 29 Vogel A, Liermann H, Harms A. Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1.  Hepatology . 2001;  33 1047-1052
  • 30 Alvarez F, Berg P A, Bianchi F B. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis.  J Hepatol . 1999;  31 929-938
  • 31 Johnson P J, McFarlane I G. Meeting report: International Autoimmune Hepatitis Group.  Hepatology . 1993;  18 998-1005
  • 32 Strassburg C P, Manns M P. Antinuclear antibody (ANA) patterns in hepatic and extrahepatic autoimmune disease.  J Hepatol . 1999;  31 751
  • 33 Strassburg C, Alex B, Zindy F. Identification of cyclin A as a molecular target of antinuclear antibodies (ANA) in hepatic and non-hepatic diseases.  J Hepatol . 1996;  25 859-866
  • 34 Tan M T. Autoantibodies in pathology and cell biology.  Cell . 1991;  67 841-842
  • 35 Czaja A J, Nishioka M, Morhed S A, Haciya T. Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis.  Gastroenterology . 1994;  107 200-207
  • 36 Czaja A J, Ming C, Shirai M, Nishioka M. Frequency and significance of antibodies to histones in autoimmune hepatitis.  J Hepatol . 1995;  23 32-38
  • 37 Czaja A J, Cassani F, Cataleta M, Valenti P, Bianchi F B. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis.  Hepatology . 1996;  24 1068-1073
  • 38 Toh B H. Smooth muscles autoantibodies and autoantigens.  Clin Exp Immunol . 1979;  38 621-628
  • 39 Manns M P, Obermayer-Straub P, Lüttig B. Autoimmune diseases: the liver. In: Rose NR, Mackay IR, eds. Part 2: Organs and Tissues, 3rd ed San Diego, CA: Academic Press 1998: 511-544
  • 40 Tan E M, Chan E KL, Sullivan K F, Rubin R L. Antinuclear antibodies (ANAs): diagnostically specific immune markers and clues toward the understanding of systemic autoimmunity.  Clin Immunol Immunopathol . 1988;  47 121-141
  • 41 Lassoued K, Brenard R, Degos F. Antinuclear antibodies directed to a 200-kilodalton polypeptide of the nuclear envelope in primary biliary cirrhosis. A clinical and immunological study of a series of 150 patients with primary biliary cirrhosis.  Gastroenterology . 1990;  99 181-186
  • 42 Nickowitz R E, Wozniak R W, Schaffner F, Worman H J. Autoantibodies against integral membrane proteins of the nuclear envelope in patients with primary biliary cirrhosis.  Gastroenterology . 1994;  106 193-199
  • 43 Bandin O, Courvalin J C, Poupon R. Specificity and sensitivity of gp210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis.  Hepatology . 1996;  23 1020-1024
  • 44 Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis.  Gastroenterology . 1996;  110 840-847
  • 45 Szostecki C, Krippner H, Penner E, Bautz F A. Autoimmune sera recognize a 100 kD nuclear protein antigen (sp-100).  Clin Exp Immunol . 1987;  68 108-116
  • 46 Lin F, Noyer C M, Ye Q, Courvalin J C, Worman H J. Autoantibodies from patients with primary biliary cirrhosis recognize a region within the nucleoplasmic domain of inner nuclear membrane protein LBR.  Hepatology . 1996;  23 57-61
  • 47 Sternsdorf T, Guldner H H, Szostecki C, Grotzinger T, Will H. Two nuclear dot-associated proteins, PML and Sp100, are often co-autoimmunogenic in patients with primary biliary cirrhosis.  Scand J Immunol . 1995;  42 257-268
  • 48 Czaja A J. Frequency and nature of the variant syndromes of autoimmune liver disease.  Hepatology . 1998;  28 360-365
  • 49 Manns M P, Krüger M. Genetics in liver diseases.  Gastroenterology . 1994;  106 1676-1697
  • 50 Ben-Ari Z, Dhillon A P, Sherlock S. Autoimmune cholangiopathy: part of the spectrum of autoimmune chronic active hepatitis.  Hepatology . 1993;  18 10-15
  • 51 Michieletti P, Wanless I R, Katz A. Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis.  Gut . 1994;  35 260-265
  • 52 Colombato L A, Alvarez F, Cote J, Huet P M. Autoimmune cholangiopathy: the result of consecutive primary biliary cirrhosis and autoimmune hepatitis?.  Gastroenterology . 1994;  107 1839-1843
  • 53 Obermayer-Straub P, Strassburg C P, Manns M P. Target proteins in human autoimmunity: cytochromes P450 and UDP-glucuronosyltransferases.  Can J Gastroenterol . 2000;  14 429-439
  • 54 Tukey R H, Johnson E F. Molecular aspects of drug-metabolizing enzymes. In: Pratt W, Taylor P, eds. Principles of Drug Action New York: Churchill Livingston 1990: 423-468
  • 55 Tukey R H, Strassburg C P. Human UDP-glucuronosyltransferases: metabolism, expression, and disease.  Annu Rev Pharmacol Toxicol . 2000;  40 581-616
  • 56 Tukey R H, Strassburg C P. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract.  Mol Pharmacol . 2001;  59 405-414
  • 57 Rizzetto M, Swana G, Doniach D. Microsomal antibodies in active chronic hepatitis and other disorders.  Clin Exp Immunol . 1973;  15 331-344
  • 58 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 1370-1378
  • 59 Manns M, Zanger U, Gerken G. Patients with type II autoimmune hepatitis express functionally intact cytochrome P450 db1 that is inhibited by LKM1 autoantibodies in vitro but not in vivo.  Hepatology . 1990;  12 127-132
  • 60 Löhr H F, Schlaak J F, Lohse A W. Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis.  Hepatology . 1996;  24 1416-1421
  • 61 Duclos-Vallee J C, Hajoui O, Yamamoto A M, Jacqz-Aigrin E, Alvarez F. Conformational epitopes on CYP2D6 are recognized by liver/kidney microsomal antibodies.  Gastroenterology . 1995;  108 470-476
  • 62 Dalekos G N, Wedemeyer H, Obermayer-Straub P. Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during a-interferon treatment.  J Hepatol . 1999;  30 366-375
  • 63 Ma Y, Peakman M, Lobo-Yeo A. Differences in immune recognition of cytochrome P4502D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection.  Clin Exp Immunol . 1994;  97 94-99
  • 64 Yamamoto A M, Cresteil D, Boniface O, Clerc F F, Alvarez F. Identification and analysis of cytochrome P450IID6 antigenic sites recognized by anti-liver-kidney microsome type-1 antibodies (LKM1).  Eur J Immunol . 1993;  23 1105-1111
  • 65 Muratori L, Parola M, Ripalti A. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane.  Gut . 2000;  46 553-561
  • 66 Loeper J, Descartoire V, Maurice M. Cytochromes P450 in human hepatocyte plasma membrane: recognition by several autoantibodies.  Gastroenterology . 1993;  104 203-216
  • 67 Trautwein C, Ramadori G, Gerken G, Meyer zum Büschenfelde K H, Manns M P. Regulation of cytochrome P450 2D by acute phase mediators in C3H/HeJ mice.  Biochem Biophys Res Comm . 1992;  182 617-623
  • 68 Zimmerman H J, Lewis J H, Ishak K G, Maddrey W. Ticrynafen-associated hepatic injury: analysis of 340 cases.  Hepatology . 1984;  4 315-323
  • 69 Beaune P H, Pessayre D, Dansette P, Mansuy D, Manns M P. Autoantibodies against cytochromes P450: role in human diseases.  Adv Pharmacol . 1994;  30 199-245
  • 70 Homberg J C, Abuaf N, Helmy-Khalil S. Drug induced hepatitis associated with anticytoplasmic organelle autoantibodies.  Hepatology . 1985;  5 722-725
  • 71 Manns M P, Griffin K J, Quattrochi L. Identification of cytochrome P450 IA2 as a human autoantigen.  Arch Biochem Biophys . 1990;  280 229-232
  • 72 Strassburg C P, Obermayer-Straub P, Manns M P. Autoimmunity in hepatitis C and D virus infection.  J Viral Hepat . 1996;  3 49-59
  • 73 Gebre-Medhin G, Husebye E S, Gustafsson J. Cytochrome P450IA2 and aromatic L-amino acid decarboxylase are hepatic autoantigens in autoimmune polyendocrine syndrome type I.  FEBS Lett . 1997;  412 439-445
  • 74 Dalekos G N, Obermayer-Straub P, Maeda T, Tsianos E V, Manns M P. Antibodies against cytochrome P4502A6 (CYP2A6) in patients with chronic viral hepatitis are mainly linked to hepatitis C virus infection.  Digestion . 1998;  59 S36
  • 75 Bourdi M, Larrey D, Nataf J. Anti-liver endoplasmic reticulum antibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine hepatitis.  J Clin Invest . 1990;  85 1967-1973
  • 76 Sacher M, Blümel P, Thaler H, Manns M. Chronic active hepatitis associated with vitiligo, nail dystrophy, alopecia and a new variant of LKM antibodies.  J Hepatol . 1990;  10 364-369
  • 77 Bourdi M, Gautier J C, Mircheva J. Anti-liver microsomes autoantibodies and dihydralazine induced hepatitis: Specificity of autoantibodies and inductive capacity of the drug.  Mol Pharmacol . 1992;  42 280-285
  • 78 Van Pelt F, Straub P, Manns M. Molecular basis of drug-induced immunological liver injury.  Semin Liver Dis . 1995;  15 283-300
  • 79 Crivelli O, Lavarini C, Chiaberge E. Microsomal autoantibodies in chronic infection with HBsAg associated delta (delta) agent.  Clin Exp Immunol . 1983;  54 232-238
  • 80 Philipp T, Durazzo M, Trautwein C. Recognition of uridine diphosphate glucuronosyl transferases by LKM-3 antibodies in chronic hepatitis D.  Lancet . 1994;  344 578-581
  • 81 Strassburg C, Obermayer-Straub P, Alex B. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis.  Gastroenterology . 1996;  11 1582-1592
  • 82 Strassburg C P, Manns M P, Tukey R H. Expression of the UDP-glucuronosyltransferase 1A locus in human colon. Identification and characterization of the novel extrahepatic UGTIA8.  J Biol Chem . 1998;  273 8719-8726
  • 83 Kenna J G, Neuberger J M. Immunopathology and treatment of halothane hepatitis.  Clin Immunother . 1995;  3 108-124
  • 84 Kenna J G. Immunoallergic drug-induced hepatitis: lessons from halothane.  J Hepatol . 1997;  26 5-12
  • 85 Pohl L R, Pumford N R, Martin J L. Mechanisms, chemical structures and drug metabolism.  Eur J Haematol . 1996;  57 98-104
  • 86 Pessayre D. Toxic and immune mechanisms leading to acute and subacute drug induced liver injury. In: Miguet JP, Dhumeaux D, eds. Progress in Hepatology Paris: John Libbey Eurotext 1993: 23-39
  • 87 Beaune P, Dansette P M, Mansuy D. Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug.  Proc Natl Acad Sci USA . 1987;  84 551-555
  • 88 Eliasson E, Kenna G. Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis.  Mol Pharmacol . 1996;  50 573-582
  • 89 Leeder J S, Riley R J, Cook V A, Spielberg S P. Human anti-cytochrome P450 antibodies in aromatic anticonvulsant-induced hypersensitivity reactions.  J Pharmacol Exp Ther . 1992;  263 360-367
  • 90 Albano E, Clot P, Morimoto M. Role of cytochrome P450 2E1-dependent formation if hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol.  Hepatology . 1996;  23 155-163
  • 91 Clot P, Albano E, Eliasson E. Cytochrome P450 2E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics.  Gastroenterology . 1996;  111 206-216
  • 92 Durazzo M, Philipp T, Van Pelt F A M N. Heterogeneity of microsomal autoantibodies (LKM) in chronic hepatitis C and D virus infection.  Gastroenterology . 1995;  108 455-462
  • 93 Czaja A J, Manns M P, Homburger H A. Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis.  Gastroenterology . 1992;  103 1290-1295
  • 94 Manns M P, Jentzsch M, Mergener K. Discordant manifestation of LKM-1 antibody positive autoimmune hepatitis in identical twins.  Hepatology . 1990;  12 840
  • 95 Agnello V, Chung R T, Kaplan L. A role of hepatitis C virus infection in type II cryoglobulinemia.  N Engl J Med . 1992;  19 1490
  • 96 Cacoub P, Lunel-Fabiani F, Huong Du T L. Polyarteritis nodosa and hepatitis C infection.  Ann Intern Med . 1992;  116 605-606
  • 97 Haddad J, Deny P, Munz-Gotheil C. Lymphocytic sialadenitis of Sjörgen's syndrome associated with chronic hepatitis c virus liver disease.  Lancet . 1992;  339 321-323
  • 98 Johnson R J, Gretch D R, Yamabe C. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection.  N Engl J Med . 1993;  18 465-470
  • 99 Michel G, Ritter A, Gerken G. Anti-GOR and hepatitis C virus in autoimmune liver diseases.  Lancet . 1992;  339 267-269
  • 100 Yamamoto A M, Cresteil D, Homberg J C, Alvarez F. Characterization of anti-liver-kidney microsome antobody (anti-LKM1) from hepatitis C virus-positive and -negative sera.  Gastroenterology . 1993;  104 1762-1767
  • 101 Muratori L, Lenzi M, Ma Y. Heterogeneity of liver/kidney microsomal antibody type 1 in autoimmune hepatitis and hepatitis C virus related liver disease.  Gut . 1995;  37 406-412
  • 102 Yamamoto A M, Johanet C, Duclos-Vallee J C. A new approach to cytochrome CYP2D6 antibody detection in autoimmune hepatitis type-2 (AIH-2) and chronic hepatitis C virus (HCV) infection: a sensitive and quantitative radioligand assay.  Clin Exp Immunol . 1997;  108 396-400
  • 103 Todros L, Touscoz G, D'Urso N. Hepatitis C virus-related chronic liver disease with autoantibodies to liver-kidney microsomes (LKM). Clinical characterization from idiopathic LKM-positive disorders.  J Hepatol . 1991;  13 128-131
  • 104 Muratori L, Lenzi M, Cataleta M, Giostra F, Ballardini G. Interferon therapy in liver/kidney microsomal antibody type 1-positive patients with chronic hepatitis C.  J Hepatol . 1994;  21 199-203
  • 105 Strassburg C P, Manns M P. Jaundice, genes and promoters.  J Hepatol . 2000;  33 476-479
  • 106 Strassburg C P, Vogel A, Kneip S, Tukey R H, Manns M P. Polymorphisms of the UDP-glucuronosyltransferase (UGT) 1A7 gene in colorectal cancer.  Gut . 2002;  50 851-856
  • 107 Vogel A, Kneip S, Barut S. Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGTIA7 gene.  Gastroenterology . 2001;  121 1136-1144
  • 108 Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.  N Engl J Med . 1990;  322 1829-1836
  • 109 Betterle C, Greggio N A, Volpato M. Autoimmune polyglandular syndrome type 1.  J Clin Endocrinol Metab . 1998;  83 1049-1055
  • 110 Nagamine K, Peterson P, Scott H S. Positional cloning of the APECED gene.  Nature Genet . 1997;  17 393-398
  • 111 Baeres M, Herkel J, Czaja A J. Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics.  Gut . 2002;  51 259-264
  • 112 Ma Y, Okamoto M, Thomas M G. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease.  Hepatology . 2002;  35 658-664
  • 113 Czaja A J, Donaldson P T, Lohse A W. Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis.  Am J Gastroenterol . 2002;  97 413-419
  • 114 Poralla T, Treichel U, Löhr H, Fleischer B. The asialoglycoprotein receptor as target structure in autoimmune liver diseases.  Semin Liver Dis . 1991;  11 215-222
  • 115 Treichel U, Gerken G, Rossol S. Autoantibodies against the human asialoglycoprotein receptor: effects of therapy in autoimmune and virus-induced chronic active hepatitis.  J Hepatol . 1993;  19 55-63
  • 116 Lenzi M, Manotti P, Muratori L. Liver cytosolic 1 antigen-antibody system in type 2 autoimmune hepatitis and hepatitis C virus infection.  Gut . 1995;  36 749-754
  • 117 Martini E, Abuaf N, Cavalli F. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2.  Hepatology . 1988;  8 1662-1666
  • 118 Lapierre P, Hajoui O, Homberg J-C, Alvarez F. Fomiminotransferase cyclodeaminase is an organ specific autoantigen recognized by sera of patients with autoimmune hepatitis.  Gastroenterology . 1999;  116 643-649
  • 119 Mulder A HL, Horst G, Haagsma E B. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases.  Hepatology . 1993;  17 411-417
  • 120 Targan S R, Landers C, Vidrich A, Czaja A J. High titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis.  Gastroenterology . 1995;  108 1159-1166
    >