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Autoantibodies in primary biliary cirrhosis

  • Primary Biliary Cirrhosis
  • Published:
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Conclusions

  1. 1.

    Anti-M2 and anti-M9 antibodies are specific marker for the diagnosis of PBC especially when demonstrated by ELISA and Western blotting in parallel.

  2. 2.

    Anti-M4 and anti-M8 always occur in association with anti-M2 and can be related to disease activity. In contrast, anti-M9 can be positive in the absence of anti-M2 and seems to be associated with a benign course of PBC.

  3. 3.

    The analysis of the clinical relevance of the four different AMA profiles revealed that they correlate with the two different courses of PBC. Thus, the profiles A/B are associated with a benign course, and the profiles C/D with a more progressive course of the disease. These AMA profiles did not change greatly during the observation period of up to 18 years.

  4. 4.

    Among the different ANA types which can be detected by IFL on cell cultures only two are of diagnostic relevance, namely the antibodies against nuclear dots and the antibodies against nuclear lamina. The latter can be demonstrated also by Western blotting and react with the disease-specific determinant at 200 kDa.

  5. 5.

    A variety of other antibodies can also be detected in sera from PBC patients which are directed against highly conserved antigens such as actin, laminin, nuclear antigens or thyroglobulin. They may indicate heightened B cell activity but are of no clinical or diagnostic relevance.

  6. 6.

    In sera from contact persons of PBC patients a further AMA type could be detected which seems to belong to the group of NOMA. By Western blotting it revealed the same specificity as sera from patients with different infectious disorders.

  7. 7.

    The increased NOMA production in family members and the low incidence of NOMA in PBC patients suggest the presence of a stimulatory agent as well as a B cell defect in PBC patients, which is defined by the lack of the production of NOMA. This defect may also be responsible for a lowered resistance, hereby facilitating the chronic inflammatory process affecting small- and medium-seized bile ducts.

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References

  1. Alvarez F, Bernard O, Homberg JC, Kreibich JC (1985) Anti-liver-kidney microsome antibody recognizes a 50 000 molecular weight protein of the endoplasmic reticulum. J Exp Med 161: 1231

    Google Scholar 

  2. Baum H, Berg PA (1981) The complex nature of mitochondrial antibodies and their relation to primary biliary cirrhosis. Semin Liver Dis 4: 309

    Google Scholar 

  3. Berg PA, Baum H (1980) The serology of primary biliary cirrhosis. Springer Semin Immunopathol 3: 355

    Google Scholar 

  4. Berg PA, Klein R (1985) Clinical and prognostic rlevance of different mitochondrial antibody profiles in primary biliary cirrhosis (PBC). Mol Aspects Med 8: 235

    Google Scholar 

  5. Berg PA, Klein R (1987) Immunology of primary biliary cirrhosis. Ballières Clin Gastroenterol 1: 675

    Google Scholar 

  6. Berg PA, Klein R (1989) Heterogeneity of antimitochondrial antibodies. Semin Liver Dis 9: 103

    Google Scholar 

  7. Berg PA, Doniach D, Roitt IM (1967) Mitochondrial antibodies in primary biliary cirrhosis. I. Localization of the antigen to mitochondrial membranes. J Exp Med 126: 277

    Google Scholar 

  8. Berg PA, Wiedmann KH, Sayers TJ, Klöppel G, Lindner H (1980) Serological classification of chronic cholestatic liver disease by the use of two different types of antimitochondrial antibodies. Lancet II: 1329

    Google Scholar 

  9. Berg PA, Klein R, Lindenborn-Fotinos J, Klöppel G (1982) ATPase associated antigen (M2): marker antigen for serological diagnosis of primary biliary cirrhosis. Lancet II: 1423

    Google Scholar 

  10. Berg PA, Weber P, Oehringer J, Lindenborn-Fotinos J, Stechemesser E (1985) Significance of different types of mitochondrial antibodies in primary biliary cirrhosis. In: Brunner H, Thaler H (eds) Hepatology: a Festschrift for Hans Popper. Raven Press, New York, pp 231–242

    Google Scholar 

  11. Bernstein RM, Neuberger JM, Bunn CC, Callander ME, Hughes GRV, Williams R (1984) Diversity of autoantibodies in primary biliary cirrhosis and chronic active hepatitis. Clin Exp Immunol 55: 553

    Google Scholar 

  12. Beswick DR, Klatskin G, Boyer JL (1985) Asymptomatic primary biliary cirrhosis. A progress report on long-term follow up and natural history. Gastroenterology 89: 267

    Google Scholar 

  13. Burroughs AK, Rosenstein IJ, Epstein O, Hamilton-Miller JMT, Brumfitt W, Sherlock S (1984) Bacteriuria and primary biliary cirrhosis. Gut 25: 133

    Google Scholar 

  14. Cohen IR, Cooke A (1986) Natural autoantibodies might prevent autoimmune disease. Immunol Today 7: 363

    Google Scholar 

  15. Coppel RL, McNeilage LJ, Surh CD, van de Water J, Spithill TW, Whittingham S, Gershwin E (1988) Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase. Proc Natl Acad Sci USA 85: 7317

    Google Scholar 

  16. Feizi T, Naccarato R, Sherlock S, Doniach D (1972) Mitochondrial and other tissue antibodies in relatives of patients with primary biliary cirrhosis. Clin Exp Immunol 10: 609

    Google Scholar 

  17. Frazer IM, Mackay IR, Jordan TW, Whittingham S, Marzuki S (1985) Reactivity of antimitochondrial autoantibodies in primary biliary cirrhosis: definition of two novel mitochondrial polypeptide autoantigens. J Immunol 3: 1739

    Google Scholar 

  18. Fussey SPM, Guest JR, James OFW, Bassendine M, Yeaman SJ (1988) Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis. Proc Natl Acad Sci USA 85: 8654

    Google Scholar 

  19. Gajdusek DC (1957) An autoimmune reaction against human tissue antigens in certain acute and chronic diseases. Nature 179: 666

    Google Scholar 

  20. Galbraith RM, Smith M, Mackenzie RM, Tee DE, Doniach D, Williams R (1974) High prevalence of seroimmunologic abnormalities in relatives of patients with active chronic hepatitis or primary biliary cirrhosis. N Engl J Med 290: 63

    Google Scholar 

  21. Gershwin ME, Mackay IR, Sturgess A, Coppel RL (1987) Identification and specificity of a cDNA encoding the 70 kDa mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 138: 3525

    Google Scholar 

  22. Holmberg D, Coutinho A (1985) Natural antibodies and autoimmunity. Immunol Today 6: 356

    Google Scholar 

  23. Ishii H, Saifuku K, Namihisa T (1987) Reactivities and clinical relevance of anti-mitochondrial antibodies to four mitochondrial inner membrane proteins in sera of patients with primary biliary cirrhosis. Hepatology 7: 134

    Google Scholar 

  24. Johnson GD, Holborow EJ, Glynn LE (1965) Antibody to smooth muscle in patients with liver disease. Lancet II: 878

    Google Scholar 

  25. Klein R, Berg PA (1984) Organ specific antibodies against liver mitochondria (anti-M9) in patients with primary biliary cirrhosis (PBC) and their relatives. Hepatology 4: 750

    Google Scholar 

  26. Klein R, Berg PA (1988) Prognostische Bedeutung der antimitochondrialen Antikörper-Profile A-D bei Patienten mit primär-biliärer Zirrhose. Dtsch Med Wochenschr 113: 1549

    Google Scholar 

  27. Klein R, Berg PA (1988) Characterization of a new mitochondrial antigen-antibody system (M9/anti-M9) in patients with anti-M2-positive and anti-M2-negative primary biliary cirrhosis. Clin Exp Immunol 74: 68

    Google Scholar 

  28. Klein R, Berg PA (1990) Demonstration of “naturally occurring mitochondrial antibodies” in family members of patients with primary biliary cirrhosis. Hepatology (in press)

  29. Klein R, Klöppel G, Fischer R, Fintelmann V, Müting D, Berg PA (1988) The mitochondrial antibody anti-M9: a marker for the diagnosis of early primary biliary cirrhosis. J Hepatol 6: 299

    Google Scholar 

  30. Klein R, Timpl R, Zanetti FR, Plester D, Berg PA (1989) High antibody levels against mouse laminin with specificity for galactosyl (α 1–3)galactose in patients with inner ear disease. Ann Otorhinolaryngol 98: 537

    Google Scholar 

  31. Klöppel G, Seifert G, Lindner H, Dammermann R, Sack HJ, Berg PA (1977) Histopathological features in mixed types of chronic aggressive hepatitis and primary biliary cirrhosis. Virchows Arch [A] 373: 143

    Google Scholar 

  32. Kunkel HG, Ahrens EH, Eisenmenger WJ, Bongiovanni AM, Slater RJ (1951) Extreme hypergammaglobulinemia in young women with liver disease of unknown etiology. J Clin Invest 30: 654

    Google Scholar 

  33. Kurki P, Miettinen A, Salaspuro M, Virtanen I, Stenman S (1983) Cytoskeleton antibodies inchronic active hepatitis, primary biliary cirrhosis, and alcoholic liver disease. Hepatology 3: 297

    Google Scholar 

  34. Kyriatsoulis A, Manns M, Gerken G, Lohse IW, Maelicke A, Wessler I, Reske K, Meyer zum Büschenfelde KH (1988) Immunochemical characterization of anti-acetylcholine receptor antibodies in primary biliary cirrhosis. J Hepatol 6: 283

    Google Scholar 

  35. Lassoued K, Guilly MN, Danon F, Andre C, Dhumeaux D, Clauvel JP, Brouet JC, Seligmann M, Courvalin JC (1988) Antinuclear antibodies specific for lamins. Characterization and clinical relevance. Ann Intern Med 108: 829

    Google Scholar 

  36. Lee RG, Epstein O, Jauregui H, Sherlock S, Scheuer P (1981) Granulomas in primary biliary cirrhosis: a prognostic feature. Gastroenterology 81: 983

    Google Scholar 

  37. Lindenborn-Fotinos J, Sayers TJ, Berg PA (1982) Mitochondrial antibodies in primary biliary cirrhosis. VI. Association of the complement-fixing antigen with a component of the mitochondrial F1-ATPase complex. Clin Exp Immunol 50: 267

    Google Scholar 

  38. Lindenborn-Fotinos J, Baum H, Berg PA (1985) Mitochondrial antibodies in primary biliary cirrhosis. Further characterization of the M2 antigen by immunoblotting, revealing species and non-species specific determinants. Hepatology 5: 763

    Google Scholar 

  39. Lippmann SM, Arnett FC, Conley CL, Ness PM, Meyers DA, Bias WB (1982) Genetic factors predisposing to autoimmune diseases: autoimmune hemolytic anemia, chronic thrombocytopenic purpuras, and systemic lupus erythematosus. Am J Med 73: 827

    Google Scholar 

  40. Lozano F, Rarés A, Borche L, Plana M, Gallart T, Rodés J, Vives J (1988) Autoantibodies against nuclear envelope-associated proteins in primary biliary cirrhosis. Hepatology 8: 930

    Google Scholar 

  41. Manns M, Gerken G, Kyriatsoulis A, Trautwein C, Reske K, Meyer zum Büschenfelde KH (1987) Two different subtypes of antimitochondrial antibodies are associated with primary biliary cirrhosis: identification and characterization by radioimmunoassay and immunoblotting. Hepatology 7: 893

    Google Scholar 

  42. McFarlane BM, McSorley CG, Vergani D, McFarlane IG, Williams R (1986) Serum autoantibodies reacting with the hepatic asialoglycoprotein receptor protein (hepatic lectin) in acute and chronic liver disease. J Hepatol 3: 196

    Google Scholar 

  43. Mendel-Hartvig I, Nelson BD, Lööf L, Töttermann TH (1985) Primary biliary cirrhosis: further biochemical and immunological characterization of mitochondrial antigens. Clin Exp Immunol 62: 371

    Google Scholar 

  44. Mendel-Hartvig I, Frostell A, Nelson BD (1986) Primary biliary cirrhosis: assessment of the quantitative importance of the adenine nucleotide translocator protein as a major mitochondrial protein. Clin Exp Immunol 66: 399

    Google Scholar 

  45. Miyachi K, Gupta RC, Dickson ER, Tan EM (1980) Precipitating antibodies to mitochondrial antigens in patients with primary biliary cirrhosis. Clin Exp Immunol 39: 599

    Google Scholar 

  46. Pisi E, Bianchi FB, Ballardini G, Cassani F, Bottazzo GF (1986) New immunopathologic features in primary biliary cirrhosis. Front Gastroenterol Res 9: 132

    Google Scholar 

  47. Powell F, Schroeter AL, Dickson ER (1984) Antinuclear antibodies in primary biliary cirrhosis. Lancet I: 288

    Google Scholar 

  48. Rizzetto M, Swana G, Doniach D (1973) Microsomal antibodies in chronic active hepatitis and other disorders. Clin Exp Immunol 15: 331

    Google Scholar 

  49. Sayers TJ, Leoutsakos A, Berg PA, Baum H (1981) Antimitochondrial antibodies (AMA) in primary bliary cirrhosis. I. Separation of the PBC antigen activity from mitochondrial ATPase activity. J Bioenerg Biomem 13: 255

    Google Scholar 

  50. Schnaitman C, Greenawalt JW (1968) Enzymatic properties of the inner and outer membrane of rat liver mitochondria. J cell Biol 38: 158

    Google Scholar 

  51. Schulthei\ HP, Berg PA, Klingenberg M (1983) The mitochondrial adenine nucleotide translocator is an antigen in primary biliary cirrhosis. Clin Exp Immunol 54: 648

    Google Scholar 

  52. Schulthei\ HP, Berg PA, Klingenberg M (1984) Inhibition of the adenine nucleotide translocator by organ specific autoantibodies in primary biliary cirrhosis. Clin Exp Immunol 58: 596

    Google Scholar 

  53. Shapiro JM, Smith H, Schaffner F (1979) Serum bilirubin: a prognostic factor in primary biliary cirrhosis. Gut 20: 137

    Google Scholar 

  54. Srikanta S, Ganda OP, Rabizadeh A, Soeldner S, Eisenbarth GS (1985) First degree relatives of patients with type I diabetes mellitus. Islet-cell antibodies and abnormal insulin secretion. N Engl J Med 313: 461

    Google Scholar 

  55. Stechemesser E, Strienz J, Berg PA (1987) Serological definition of new subgroup of patients with autoimmune chronic active hepatitis. Lancet I: 683

    Google Scholar 

  56. Stemerowicz R, Hopf U, Möller B (1988) Are mitochondrial antibodies in primary biliary cirrhosis induced by r(ough) mutants of enterobacteriaceae? Lancet II: 1166

    Google Scholar 

  57. Surh CD, Danner DJ, Ahmed A, Coppel RL, Mackay IR, Dickson ER, Gershwin E (1989) Reactivity of PBC sera with a human fetal liver cDNA clone of branched chain alpha-ketoacid dehydrogenase (BCKD) dihydrolipoamide acyltransferase, the 52 kDa mitochondrial autoantigen. Hepatology 9: 63

    Google Scholar 

  58. Tan EM (1983) Autoantibodies to nuclear antigens (ANA). Their immunobiology and medicine. Adv Immunol 33: 167

    Google Scholar 

  59. Walker JG, Doniach D, Roitt IM (1965) Serological tests in the diagnosis of primary biliary cirrhosis. Lancet I: 827

    Google Scholar 

  60. van de Water J, Gershwin E, Leung P, Ansari A, Coppel RL (1988) The autoepitope of the 74 kDa mitochondrial autoantigen of primary biliary cirrhosis corresponds to the functional site of dihydrolipoamide acetyltransferase. J Exp Med 167: 1791

    Google Scholar 

  61. Weber P, Brenner J, Stechemesser E, Klein R, Weckenmann U, Klöppel G, Kirchhof M, Fintelmann V, Berg PA (1986) Characterization and clinical relevance of a new complement fixing antibody: anti-M8 in patients with primary biliary cirrhosis. Hepatology 6: 553

    Google Scholar 

  62. Wiedmann KH, Melms A, Berg PA (1983) Anti-actin antibodies of IgM and IgG class in chronic liver diseases detected by fluorometric immunoassay. Liver 3: 369

    Google Scholar 

  63. Yeaman SJ (1986) The mammalian 2-oxoacid dehydrogenase: a complex family. Trends Biochem Sci 11: 293

    Google Scholar 

  64. Yeaman SJ, Danner DJ, Mutimer DJ, Fussey SPM, James OFW, Bassendine MF (1988) Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens. Lancet I: 1067

    Google Scholar 

  65. Fussey SPM, Bassendine MF, Fittes D, Turner IB, James OFW, Yeaman SJ (1990) The Elalpha and beta-subunit of the pyruvate dehydrogenase complex are M2"d" and M2"e" autoantigens in primary biliary cirrhosis. Clin Sci (in press)

  66. James OFW, Yeaman SF, Bassendine MF (1989) Molecular aspects of the M2-autoantigen in primary biliary cirrhosis: what a difference a year makes. Hepatology 10: 247

    Google Scholar 

  67. Klein R, Berg PA (1990) Anti-M9 antibodies in sera from patients with primary biliary cirrhosis recognize an epitope of glycogen phosphorylase. Clin Exp Immunol (in press)

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Authors and Affiliations

  1. Department of Internal Medicine, University of Tübingen, D-7400, Tübingen, Federal Republic of Germany

    Peter A. Berg & Reinhild Klein

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Berg, P.A., Klein, R. Autoantibodies in primary biliary cirrhosis. Springer Semin Immunopathol 12, 85–99 (1990). https://doi.org/10.1007/BF00192685

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