Digestive Diseases and Sciences

, Volume 48, Issue 8, pp 1658–1664

Frequency and Significance of Antibodies to Chromatin in Autoimmune Hepatitis

  • Albert J. Czaja
  • Zakera Shums
  • Walter L. Binder
  • Stephen J. Lewis
  • Vicki J. Nelson
  • Gary L. Norman
Article

Abstract

Our aims were to determine the frequency and prognostic implications of antibodies to chromatin in autoimmune hepatitis. Three hundred seventy-one serum samples from 172 patients were tested by enzyme-linked immunosorbent assay. Sixty-seven patients (39%) had antibodies to chromatin. Percent positivity was greater in men than women (58% vs 34%, P = 0.008), and seropositivity was associated with higher serum levels of γ-globulin and immunoglobulin G. Antibodies to chromatin disappeared in 25 of 60 patients who were tested successively (42%), and they were more common in samples obtained during active than inactive disease (32% vs 19%, P = 0.01). Relapse after drug withdrawal occurred more often in seropositive patients (91% vs 66%, P = 0.002). We conclude that antibodies to chromatin occur commonly in autoimmune hepatitis, and they are associated with disease activity. Percent positivity is greater in men than women, and seropositivity identifies individuals who commonlyrelapse after drug withdrawal.

autoantibodies chromatin hepatitis autoimmunity 

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REFERENCES

  1. 1.
    Czaja AJ, Homburger HA: Autoantibodies in liver disease. Gastroenterology 120: 239–249, 2001Google Scholar
  2. 2.
    Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WGE, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston ALWF, Fainboim L, Heathcote J, Homberg J-C, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RNM, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Buschenfelde K-H, Mieli-Vergani G, Nakanuma Y, Nishioka M, Penner E, Porta G, Portmann BC, Reed WD, Rodes J, Schalm SW, Scheuer PJ, Schrumpf E, Seki T, Toda G, Tsuji T, Tygstrup N, Vergani D, Zeniya M: International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31: 929–938, 1999Google Scholar
  3. 3.
    Czaja AJ, Freese DK: Diagnosis and treatment of autoimmune hepatitis. Hepatology 36: 479–497, 2002Google Scholar
  4. 4.
    Czaja AJ: Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol 30: 394–401, 1999Google Scholar
  5. 5.
    Targan SR, Landers C, Vidrich A, Czaja AJ: High-titer antineutrophil cytoplasmic antibodies in type 1 autoimmune hepatitis. Gastroenterology 108: 1159–1166, 1995Google Scholar
  6. 6.
    Zauli D, Ghetti S, Grassi A, Descovich C, Cassani F, Ballardini G, Muratori L, Bianchi FB: Antineutrophil cytoplasmic antibodies in type 1 and type 2 autoimmune hepatitis. Hepatology 25: 1105–1107, 1997Google Scholar
  7. 7.
    Czaja AJ, Ming C, Shirai M, Nishioka M: Frequency and significance of antibodies to histones in autoimmune hepatitis. J Hepatol 23: 32–38, 1995Google Scholar
  8. 8.
    Chen M, Shirai M, Czaja AJ, Kurokohchi K, Arichi T, Arima K, Kodama T, Nishioka M: Characterization of antihistone antibodies in patients with type 1 autoimmune hepatitis. J Gastroenterol Hepatol 13: 483–489, 1998Google Scholar
  9. 9.
    Fritzler MJ: Autoantibodies: diagnostic fingerprints and etiologic perplexities. Clin Invest Med 20: 50–66, 1997Google Scholar
  10. 10.
    Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB: Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology 24: 1068–1073, 1996Google Scholar
  11. 11.
    Czaja AJ, Morshed SA, Parveen S, Nishioka M: Antibodies to single-stranded and double-stranded DNA in antinuclear antibody-positive type 1-autoimmune hepatitis. Hepatology 26: 567–572, 1997Google Scholar
  12. 12.
    McFarlane IG, Hegarty JE, McSorley CG, McFarlane BM, Williams R: Antibodies to liver-specific protein predict outcome of treatment withdrawal in autoimmune chronic active hepatitis. Lancet 2: 954–956, 1984Google Scholar
  13. 13.
    Czaja AJ, Pfeifer KD, Decker RH, Vallari AS: Frequency and significance of antibodies to asialoglycoprotein receptor in type 1 autoimmune hepatitis. Dig Dis Sci 41: 1733–1740, 1996Google Scholar
  14. 14.
    Czaja AJ, Donaldson PT, Lohse AW: Antibodies to soluble liver antigen/liver pancreas and HLA risk factors in type 1 autoimmune hepatitis. Am J Gastroenterol 97: 413–419, 2002Google Scholar
  15. 15.
    Baeres M, Herkel J, Czaja AJ, Wies I, Kanzler S, Cancado ELR, Porta G, Nishioka M, Simon T, Daehnrich C, Schlumberger W, Galle PR, Lohse AW: Establishment of standardized SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence and clinical characteristics. Gut 51: 259–264, 2002Google Scholar
  16. 16.
    Li L, Chen M, Huang DY, Nishioka M: Frequency and significance of antibodies to chromatin in autoimmune hepatitis type 1. J Gastroenterol Hepatol 15: 1176–1782, 2000Google Scholar
  17. 17.
    Doenecke D, Albig W, Bode C, Drabent B, Franke K, Gavenis K, Witt O: Histones: genetic diversity and tissue-specific gene expression. Histochem Cell Biol 107: 1–10, 1997Google Scholar
  18. 18.
    Rubin RL: Autoantibody specificity in drug-induced lupus and neutrophil-mediated metabolism of lupus-inducing drugs. Clin Biochem 25: 223–234, 1992Google Scholar
  19. 19.
    Mohan CH, Adams S, Stanik V, Datta SK: Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 177: 1367–1381, 1993Google Scholar
  20. 20.
    Amoura Z, Koutouzov S, Piette J-C: The role of nucleosomes in lupus. Curr Opin Rheumatol 12: 369–373, 2000Google Scholar
  21. 21.
    Amoura Z, Chabre H, Koutouzov S, Lotton C, Cabrespines A, Bach JF, Jacob L: Nucleosome-restricted antibodies are detected before anti-dsDNA and/or antiihistone antibodies in serum of MRL-Mp lpr/lpr and C / C mice and are present in kidney eluates. Arthritis Rheum 37: 1684–1688, 1994Google Scholar
  22. 22.
    Burlingame RW, Boey ML, Starkebaum G, Rubin RL: The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest 94: 184–192, 1994Google Scholar
  23. 23.
    Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johson PJ, Williams R: Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology 13: 701–706, 1991Google Scholar
  24. 24.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB: Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 105: 1502–1507, 1993Google Scholar
  25. 25.
    Czaja AJ, Nishioka M, Morshed SA, Hachiya T: Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis. Gastroenterology 107: 200–207, 1994Google Scholar
  26. 26.
    Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB: Antinuclear antibodies and patterns of nuclear immunofluorescence in type 1 autoimmune hepatitis. Dig Dis Sci 42: 1688–1696, 1997Google Scholar
  27. 27.
    Homburger HA, Cahen YD, Griffiths J, Jacob GL: Detection of antinuclear antibodies. Comparative evaluation of enzyme immunoassay and indirect immunofluorescence methods. Arch Pathol Lab Med 122: 993–999, 1998Google Scholar
  28. 28.
    Czaja AJ, Manns MP, Homburger HA: Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis. Gastroenterology 103: 1290–1295, 1992Google Scholar
  29. 29.
    Czaja AJ: Drug therapy in the management of type 1 autoimmune hepatitis. Drugs 57: 49–68, 1999Google Scholar
  30. 30.
    Summerskill WHJ, Korman MG, Ammon HV, Baggenstoss AH: Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared. Gut 16: 876–883, 1975Google Scholar
  31. 31.
    Czaja AJ, Wolf AM, Baggenstoss AH: Laboratory assessment of severe chronic active liver disease (CALD): correlation of serum transaminase and gamma globulin levels with histologic features. Gastroenterology 80: 687–692, 1981Google Scholar
  32. 32.
    Czaja AJ, Menon KVN, Carpenter HA: Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis. Hepatology 35: 890–897, 2002Google Scholar
  33. 33.
    Tan EM: Autoantibodies to nuclear antigens: their immunology and meaning. Adv Immunol 33: 167–240, 1982Google Scholar
  34. 34.
    Strettell MDJ, Donaldson PT, Thomson LJ, Santrach PJ, Moore SB, Czaja AJ, Williams R: Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology 112: 2028–2035, 1997Google Scholar
  35. 35.
    Czaja AJ, Strettell MDJ, Thomson LJ, Santrach PJ, Moore SB, Donaldson PT, Williams R: Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 25: 317–323, 1997Google Scholar
  36. 36.
    Czaja AJ, Santrach PJ, Moore SB: Shared genetic risk factors in autoimmune liver disease. Dig Dis Sci 46: 140–147, 2001Google Scholar
  37. 37.
    Hall S, Czaja AJ, Kaufman DK, Markowitz H, Ginsburg WW: How lupoid is lupoid hepatitis? J Rheumatol 13: 95–98, 1986Google Scholar
  38. 38.
    Wood JR, Czaja AJ, Beaver SJ, Hall S, Ginsburg WW, Kaufman DK, Markowitz H: Frequency and significance of antibody to double-stranded DNA in chronic active hepatitis. Hepatology 6: 976–980, 1986Google Scholar
  39. 39.
    Czaja AJ: Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol 96: 1224–1231, 2001Google Scholar
  40. 40.
    Parveen S, Morshed SA, Arima K, Nishioka M, Czaja AJ, Chow C, Ng H-S: Antibodies to Ro/La, Cenp-B, and snRNPs antigens in autoimmune hepatitis of North America versus Asia. Dig Dis Sci 43: 1322–1331, 1998Google Scholar
  41. 41.
    Walport MJ: Lupus, DNase and defective disposal of cellular debris. Nature Genet 25: 135–136, 2000Google Scholar
  42. 42.
    Doherty DG, Penzotti JE, Koelle DM, Kwok WW, Lybrand TP, Masewicz S, Nepom GT: Structural basis of specificity and degeneracy of T cell recognition: pluriallelic restriction of T cell responses to a peptide antigen involves both specific and promiscuous interactions between the T cell receptor, peptide, and HLA-DR. J Immunol 161: 3527–3535, 1998Google Scholar
  43. 43.
    Czaja AJ, Doherty DG, Donaldson PT: Genetic bases of autoimmune hepatitis. Dig Dis Sci 47: 2139–2150, 2002Google Scholar
  44. 44.
    Czaja AJ: Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol 30: 394–401, 1999Google Scholar
  45. 45.
    Czaja AJ, Donaldson PT: Gender effects and synergism with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol 97: 2051–2057, 2002Google Scholar
  46. 46.
    Whitacre CC, Reingold SC, O'Looney PA: A gender gap in autoimmunity. Science 283: 1277–1278, 1999Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Albert J. Czaja
    • 1
  • Zakera Shums
    • 2
  • Walter L. Binder
    • 2
  • Stephen J. Lewis
    • 2
  • Vicki J. Nelson
    • 2
  • Gary L. Norman
    • 2
  1. 1.Division of Gastroenterology and HepatologyMayo Clinic and Mayo FoundationMinnesota
  2. 2.INOVA Diagnostics, San DiegoCaliforniaUSA

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