Advertisement

Autoimmune Hepatitis

  • Albert J. Czaja
Chapter
Part of the Molecular Pathology Library book series (MPLB, volume 5)

Abstract

Autoimmune hepatitis is the result of an immune response that is misdirected against normal self-antigens or foreign antigens that resemble self-antigens [1–6]. Its onset requires multiple deficiencies in a highly complex and interactive counter-regulatory network, and it is the consequence of genetic factors [7], molecular mimicry [2, 8], cytokine imbalances [9], and imprecise (or promiscuous) targeting of activated immunocytes (Fig. 41.1) [10, 11]. Single disturbances in a highly coordinated interactive system can be disruptive, and subtle perturbations can magnify into a disease state as defects in counter-regulatory homeostatic mechanisms cascade [4]. These concepts are derived from “chaos theory,”[12] and they apply to autoimmune hepatitis

Keywords

Major Histocompatibility Complex Primary Biliary Cirrhosis Autoimmune Hepatitis Major Histocompatibility Complex Molecule Susceptibility Allele 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Czaja AJ. Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol. 2001;96(4):1224–31.PubMedGoogle Scholar
  2. 2.
    Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis. Clin Liver Dis. 2002;6(3):727–37.PubMedGoogle Scholar
  3. 3.
    Manns MP, Vogel A. Autoimmune hepatitis, from mechanisms to therapy. Hepatology. 2006;43(2 Suppl 1):S132–144.PubMedGoogle Scholar
  4. 4.
    Czaja AJ. Autoimmune hepatitis. Part A: pathogenesis. Expert Rev Gastroenterol Hepatol. 2007;1(1):113–28.PubMedGoogle Scholar
  5. 5.
    Lapierre P, Beland K, Alvarez F. Pathogenesis of autoimmune hepatitis: from break of tolerance to immune-mediated hepatocyte apoptosis. Transl Res. 2007;149(3):107–13.PubMedGoogle Scholar
  6. 6.
    Vergani D, Mieli-Vergani G. Aetiopathogenesis of autoimmune hepatitis. World J Gastroenterol. 2008;14(21):3306–12.PubMedGoogle Scholar
  7. 7.
    Czaja AJ. Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6(4):379–88.PubMedGoogle Scholar
  8. 8.
    Bogdanos DP, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver. 2001;21(4):225–32.PubMedGoogle Scholar
  9. 9.
    Czaja AJ, Sievers C, Zein NN. Nature and behavior of serum cytokines in type 1 autoimmune hepatitis. Dig Dis Sci. 2000;45(5):1028–35.PubMedGoogle Scholar
  10. 10.
    Chicz RM, Urban RG, Gorga JC, Vignali DA, Lane WS, Strominger JL. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J Exp Med. 1993;178(1):27–47.PubMedGoogle Scholar
  11. 11.
    Doherty DG, Penzotti JE, Koelle DM, et al. 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. 1998;161(7):3527–35.PubMedGoogle Scholar
  12. 12.
    Ghosh P, Sen S, Ray DS. Nonlinear dynamics of finite perturbation: collapse and revival of spatial patterns. Phys Rev E Stat Nonlin Soft Matter Phys. 2009;79(1 Pt 2):016206.PubMedGoogle Scholar
  13. 13.
    Czaja AJ. Autoimmune hepatitis and viral infection. Gastroenterol Clin North Am. 1994;23(3):547–66.PubMedGoogle Scholar
  14. 14.
    Vogel A, Manns MP, Strassburg CP. Autoimmunity and viruses. Clin Liver Dis. 2002;6(3):739–53.PubMedGoogle Scholar
  15. 15.
    Vento S, Garofano T, Di Perri G, Dolci L, Concia E, Bassetti D. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet. 1991;337(8751):1183–7.PubMedGoogle Scholar
  16. 16.
    Huppertz HI, Treichel U, Gassel AM, Jeschke R, Meyer zum Buschenfelde KH. Autoimmune hepatitis following hepatitis A virus infection. J Hepatol. 1995;23(2):204–8.PubMedGoogle Scholar
  17. 17.
    Tanaka H, Tujioka H, Ueda H, Hamagami H, Kida Y, Ichinose M. Autoimmune hepatitis triggered by acute hepatitis A. World J Gastroenterol. 2005;11(38):6069–71.PubMedGoogle Scholar
  18. 18.
    Tabak F, Ozdemir F, Tabak O, Erer B, Tahan V, Ozaras R. Autoimmune hepatitis induced by the prolonged hepatitis A virus infection. Ann Hepatol. 2008;7(2):177–9.PubMedGoogle Scholar
  19. 19.
    Kamiyama T, Nouchi T, Kojima S, Murata N, Ikeda T, Sato C. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol. 1997;92(4):703–4.PubMedGoogle Scholar
  20. 20.
    Borum ML. Fulminant exacerbation of autoimmune hepatitis after the use of ma huang. Am J Gastroenterol. 2001;96(5):1654–5.PubMedGoogle Scholar
  21. 21.
    Cohen SM, O’Connor AM, Hart J, Merel NH, Te HS. Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause. 2004;11(5):575–7.PubMedGoogle Scholar
  22. 22.
    Helfgott SM, Sandberg-Cook J, Zakim D, Nestler J. Diclofenac-associated hepatotoxicity. JAMA. 1990;264(20):2660–2.PubMedGoogle Scholar
  23. 23.
    Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ. 1996;312(7024):169–72.PubMedGoogle Scholar
  24. 24.
    Germano V, Picchianti Diamanti A, Baccano G, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis. 2005;64(10):1519–20.PubMedGoogle Scholar
  25. 25.
    Veerappan GR, Mulhall BP, Holtzmuller KC. Vaccination-induced autoimmune hepatitis. Dig Dis Sci. 2005;50(1):212–3.PubMedGoogle Scholar
  26. 26.
    Czaja AJ, Doherty DG, Donaldson PT. Genetic bases of autoimmune hepatitis. Dig Dis Sci. 2002;47(10):2139–50.PubMedGoogle Scholar
  27. 27.
    Czaja AJ. Diverse manifestations and evolving treatments of autoimmune hepatitis. Minerva Gastroenterol Dietol. 2005;51(4):313–33.PubMedGoogle Scholar
  28. 28.
    Verma S, Torbenson M, Thuluvath PJ. The impact of ethnicity on the natural history of autoimmune hepatitis. Hepatology. 2007;46(6):1828–35.PubMedGoogle Scholar
  29. 29.
    Nguyen GC, Thuluvath PJ. Racial disparity in liver disease: biological, cultural, or socioeconomic factors. Hepatology. 2008;47(3):1058–66.PubMedGoogle Scholar
  30. 30.
    Siegel AB, McBride RB, El-Serag HB, et al. Racial disparities in utilization of liver transplantation for hepatocellular carcinoma in the United States, 1998–2002. Am J Gastroenterol. 2008;103(1):120–7.PubMedGoogle Scholar
  31. 31.
    Czaja A, Bayraktar Y. Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment. World J Gastroenterol. 2009;15(19):2314–28.PubMedGoogle Scholar
  32. 32.
    Bogdanos DP, 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
  33. 33.
    Czaja AJ. Autoimmune hepatitis. Evolving concepts and treatment strategies. Dig Dis Sci. 1995;40(2):435–56.PubMedGoogle Scholar
  34. 34.
    McFarlane IG. Pathogenesis of autoimmune hepatitis. Biomed Pharmacother. 1999;53(5–6):255–63.PubMedGoogle Scholar
  35. 35.
    Czaja AJ. Autoantibodies in autoimmune liver disease. Adv Clin Chem. 2005;40:127–64.PubMedGoogle Scholar
  36. 36.
    Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008;14(21):3374–87.PubMedGoogle Scholar
  37. 37.
    Czaja AJ. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol. 1999;30(3):394–401.PubMedGoogle Scholar
  38. 38.
    Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989;44:93–151.PubMedGoogle Scholar
  39. 39.
    Jensen DM, McFarlane IG, Portmann BS, Eddleston AL, Williams R. Detection of antibodies directed against a liver-specific membrane lipoprotein in patients with acute and chronic active hepatitis. N Engl J Med. 1978;299(1):1–7.PubMedGoogle Scholar
  40. 40.
    Vergani D, Mieli-Vergani G, Mondelli M, Portmann B, Eddleston AL. Immunoglobulin on the surface of isolated hepatocytes is associated with antibody-dependent cell-mediated cytotoxicity and liver damage. Liver. 1987;7(6):307–15.PubMedGoogle Scholar
  41. 41.
    Oldstone MB. Molecular mimicry and immune-mediated diseases. FASEB J. 1998;12(13):1255–65.PubMedGoogle Scholar
  42. 42.
    Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med. 1999;341(27):2068–74.PubMedGoogle Scholar
  43. 43.
    Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995;80(5):695–705.PubMedGoogle Scholar
  44. 44.
    Zhao ZS, Granucci F, Yeh L, Schaffer PA, Cantor H. Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. Science. 1998;279(5355):1344–7.PubMedGoogle Scholar
  45. 45.
    Kammer AR, van der Burg SH, Grabscheid B, et al. Molecular mimicry of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T cell recognition. J Exp Med. 1999;190(2):169–76.PubMedGoogle Scholar
  46. 46.
    Czaja AJ, Manns MP. The validity and importance of subtypes in autoimmune hepatitis: a point of view. Am J Gastroenterol. 1995;90(8):1206–11.PubMedGoogle Scholar
  47. 47.
    Czaja AJ. Clinical features, differential diagnosis and treatment of autoimmune hepatitis in the elderly. Drugs Aging. 2008;25(3):219–39.PubMedGoogle Scholar
  48. 48.
    Homberg JC, 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):1333–9.PubMedGoogle Scholar
  49. 49.
    Abuaf N, Johanet C, Chretien P, et al. Characterization of the liver cytosol antigen type 1 reacting with autoantibodies in chronic active hepatitis. Hepatology. 1992;16(4):892–8.PubMedGoogle Scholar
  50. 50.
    Muratori P, Czaja AJ, Muratori L, et al. Evidence of a genetic basis for the different geographic occurrences of liver/kidney microsomal antibody type 1 in hepatitis C. Dig Dis Sci. 2007;52(1):179–84.PubMedGoogle Scholar
  51. 51.
    Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology. 1997;25(3):541–7.PubMedGoogle Scholar
  52. 52.
    Czaja AJ, Manns MP, Homburger HA. Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis. Gastroenterology. 1992;103(4):1290–5.PubMedGoogle Scholar
  53. 53.
    Reddy KR, Krawitt EL, Homberg JC, et al. Absence of anti-LKM-1 antibody in hepatitis C viral infection in the United States of America. J Viral Hepat. 1995;2(4):175–9.PubMedGoogle Scholar
  54. 54.
    Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33(3):544–53.PubMedGoogle Scholar
  55. 55.
    Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G. Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children – a five year follow-up. J Hepatol. 2009;51(1):156–60.PubMedGoogle Scholar
  56. 56.
    Czaja AJ, Kruger M, Santrach PJ, Moore SB, Manns MP. Genetic distinctions between types 1 and 2 autoimmune hepatitis. Am J Gastroenterol. 1997;92(12):2197–200.PubMedGoogle Scholar
  57. 57.
    Bittencourt PL, Goldberg AC, Cancado EL, et al. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol. 1999;94(7):1906–13.PubMedGoogle Scholar
  58. 58.
    Djilali-Saiah I, Fakhfakh A, Louafi H, Caillat-Zucman S, Debray D, Alvarez F. HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis. J Hepatol. 2006;45(6):844–50.PubMedGoogle Scholar
  59. 59.
    Alvarez F, Bernard O, Homberg JC, Kreibich G. Anti-liver-kidney microsome antibody recognizes a 50, 000 molecular weight protein of the endoplasmic reticulum. J Exp Med. 1985;161(5):1231–6.PubMedGoogle Scholar
  60. 60.
    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. 1998;168(2):801–6.Google Scholar
  61. 61.
    Manns MP, Johnson EF, Griffin KJ, Tan EM, Sullivan KF. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1. J Clin Invest. 1989;83(3):1066–72.PubMedGoogle Scholar
  62. 62.
    Manns MP, Griffin KJ, Sullivan KF, Johnson EF. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase. J Clin Invest. 1991;88(4):1370–8.PubMedGoogle Scholar
  63. 63.
    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):1481–9.PubMedGoogle Scholar
  64. 64.
    Lapierre P, Hajoui O, Homberg JC, Alvarez F. Formiminotrans­ferase cyclodeaminase is an organ-specific autoantigen recognized by sera of patients with autoimmune hepatitis. Gastroenterology. 1999;116(3):643–9.PubMedGoogle Scholar
  65. 65.
    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.PubMedGoogle Scholar
  66. 66.
    Renous R, Lapierre P, Djilali-Saiah I, Vitozzi S, Alvarez F. Characterization of the antigenicity of the formiminotransferase-cyclodeaminase in type 2 autoimmune hepatitis. Exp Cell Res. 2004;292(2):332–41.PubMedGoogle Scholar
  67. 67.
    Lapierre P, Djilali-Saiah I, Vitozzi S, Alvarez F. A murine model of type 2 autoimmune hepatitis: xenoimmunization with human antigens. Hepatology. 2004;39(4):1066–74.PubMedGoogle Scholar
  68. 68.
    Aaltonen J, Bjorses P, Sandkuijl L, Perheentupa J, Peltonen L. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet. 1994;8(1):83–7.PubMedGoogle Scholar
  69. 69.
    Nagamine K, Peterson P, Scott HS, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17(4):393–8.PubMedGoogle Scholar
  70. 70.
    Clemente MG, Obermayer-Straub P, Meloni A, et al. Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1997;82(5):1353–61.PubMedGoogle Scholar
  71. 71.
    Clemente MG, Meloni A, Obermayer-Straub P, Frau F, Manns MP, De Virgiliis S. Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1. Gastroenterology. 1998;114(2):324–8.PubMedGoogle Scholar
  72. 72.
    Obermayer-Straub P, Perheentupa J, Braun S, et al. Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Gastroenterology. 2001;121(3):668–77.PubMedGoogle Scholar
  73. 73.
    Vogel A, Liermann H, Harms A, Strassburg CP, Manns MP, Obermayer-Straub P. Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1. Hepatology. 2001;33(5):1047–52.PubMedGoogle Scholar
  74. 74.
    Czaja AJ, Norman GL. Autoantibodies in the diagnosis and management of liver disease. J Clin Gastroenterol. 2003;37(4):315–29.PubMedGoogle Scholar
  75. 75.
    Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev. 2000;174:250–9.PubMedGoogle Scholar
  76. 76.
    Brown JH, Jardetzky T, Saper MA, Samraoui B, Bjorkman PJ, Wiley DC. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988;332(6167):845–50.PubMedGoogle Scholar
  77. 77.
    Brown JH, Jardetzky TS, Gorga JC, et al. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993;364(6432):33–9.PubMedGoogle Scholar
  78. 78.
    Doherty DG, Donaldson PT, Underhill JA, et al. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology. 1994;19(3):609–15.PubMedGoogle Scholar
  79. 79.
    Donaldson PT, Czaja AJ. Genetic effects on susceptibility, clinical expression, and treatment outcome of type 1 autoimmune hepatitis. Clin Liver Dis. 2002;6(3):707–25.PubMedGoogle Scholar
  80. 80.
    Stern LJ, Brown JH, Jardetzky TS, et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994;368(6468):215–21.PubMedGoogle Scholar
  81. 81.
    Dessen A, Lawrence CM, Cupo S, Zaller DM, Wiley DC. X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity. 1997;7(4):473–81.PubMedGoogle Scholar
  82. 82.
    Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johnson PJ, Williams R. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology. 1991;13(4):701–6.PubMedGoogle Scholar
  83. 83.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology. 1993;105(5):1502–7.PubMedGoogle Scholar
  84. 84.
    Strettell MD, Donaldson PT, Thomson LJ, et al. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology. 1997;112(6):2028–35.PubMedGoogle Scholar
  85. 85.
    Czaja AJ, Strettell MD, Thomson LJ, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology. 1997;25(2):317–23.PubMedGoogle Scholar
  86. 86.
    Donaldson PT. Genetics in autoimmune hepatitis. Semin Liver Dis. 2002;22(4):353–64.PubMedGoogle Scholar
  87. 87.
    Seki T, Kiyosawa K, Inoko H, Ota M. Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients. Hepatology. 1990;12(6):1300–4.PubMedGoogle Scholar
  88. 88.
    Seki T, Ota M, Furuta S, et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenter­ology. 1992;103(3):1041–7.PubMedGoogle Scholar
  89. 89.
    Yoshizawa K, Ota M, Katsuyama Y, et al. Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis. J Hepatol. 2005;42(4):578–84.PubMedGoogle Scholar
  90. 90.
    Qiu DK, Ma X. Relationship between human leukocyte antigen-DRB1 and autoimmune hepatitis type I in Chinese patients. J Gastroenterol Hepatol. 2003;18(1):63–7.PubMedGoogle Scholar
  91. 91.
    Vazquez-Garcia MN, Alaez C, Olivo A, et al. MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis. J Hepatol. 1998;28(6):985–90.PubMedGoogle Scholar
  92. 92.
    Fainboim L, Marcos Y, Pando M, et al. Chronic active autoimmune hepatitis in children. Strong association with a particular HLA-DR6 (DRB1*1301) haplotype. Hum Immunol. 1994;41(2):146–50.PubMedGoogle Scholar
  93. 93.
    Pando M, Larriba J, Fernandez GC, et al. Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology. 1999;30(6):1374–80.PubMedGoogle Scholar
  94. 94.
    Goldberg AC, Bittencourt PL, Mougin B, et al. Analysis of HLA haplotypes in autoimmune hepatitis type 1: identifying the major susceptibility locus. Hum Immunol. 2001;62(2):165–9.PubMedGoogle Scholar
  95. 95.
    Czaja AJ, Souto EO, Bittencourt PL, et al. Clinical distinctions and pathogenic implications of type 1 autoimmune hepatitis in Brazil and the United States. J Hepatol. 2002;37(3):302–8.PubMedGoogle Scholar
  96. 96.
    Goldberg AC, Bittencourt PL, Oliveira LC, et al. Autoimmune hepatitis in Brazil: an overview. Scand J Immunol. 2007;66(2–3):208–16.PubMedGoogle Scholar
  97. 97.
    Fortes Mdel P, Machado IV, Gil G, et al. Genetic contribution of major histocompatibility complex class II region to type 1 autoimmune hepatitis susceptibility in Venezuela. Liver Int. 2007;27(10):1409–16.PubMedGoogle Scholar
  98. 98.
    Tapia-Conyer R, Santos JI, Cavalcanti AM, et al. Hepatitis A in Latin America: a changing epidemiologic pattern. Am J Trop Med Hyg. 1999;61(5):825–9.PubMedGoogle Scholar
  99. 99.
    Fainboim L. Canero Velasco MC, Marcos CY, et al. Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis. Hepatology. 2001;33(6):1512–7.PubMedGoogle Scholar
  100. 100.
    Czaja AJ, Santrach PJ, Moore SB. HLA-DQ associations in type 1 autoimmune hepatitis. Mayo Clin Proc. 1995;70(12):1154–60.PubMedGoogle Scholar
  101. 101.
    Czaja AJ, Carpenter HA, Moore SB. Clinical and HLA phenotypes of type 1 autoimmune hepatitis in North American patients outside DR3 and DR4. Liver Int. 2006;26(5):552–8.PubMedGoogle Scholar
  102. 102.
    Czaja AJ, Carpenter HA, Moore SB. HLA DRB1*13 as a risk factor for type 1 autoimmune hepatitis in North American patients. Dig Dis Sci. 2008;53(2):522–8.PubMedGoogle Scholar
  103. 103.
    Teufel A, Worns M, Weinmann A, et al. Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients. World J Gastroenterol. 2006;12(34):5513–6.PubMedGoogle Scholar
  104. 104.
    Amarapurkar DN, Patel ND, Amarapurkar AD, Kankonkar SR. HLA genotyping in type-I autoimmune hepatitis in Western India. J Assoc Physicians India. 2003;51:967–9.PubMedGoogle Scholar
  105. 105.
    Shankarkumar U, Amarapurkar DN, Kankonkar S. Human leukocyte antigen allele associations in type-1 autoimmune hepatitis patients from western India. J Gastroenterol Hepatol. 2005;20(2):193–7.PubMedGoogle Scholar
  106. 106.
    Muratori P, Czaja AJ, Muratori L, et al. Genetic distinctions between autoimmune hepatitis in Italy and North America. World J Gastroenterol. 2005;11(12):1862–6.PubMedGoogle Scholar
  107. 107.
    Huang HC, Wu JC, Huang YS, et al. Genetic distinctions and clinical characteristics of type 1 autoimmune hepatitis in Taiwan. Hepatogastroenterology. 2008;55(82–83):605–8.PubMedGoogle Scholar
  108. 108.
    Kosar Y, Kacar S, Sasmaz N, et al. Type 1 autoimmune hepatitis in Turkish patients: absence of association with HLA B8. J Clin Gastroenterol. 2002;35(2):185–90.PubMedGoogle Scholar
  109. 109.
    Little PF. Structure and function of the human genome. Genome Res. 2005;15(12):1759–66.PubMedGoogle Scholar
  110. 110.
    Honda M, Kawai H, Shirota Y, Yamashita T, Takamura T, Kaneko S. cDNA microarray analysis of autoimmune hepatitis, primary biliary cirrhosis and consecutive disease manifestation. J Autoimmun. 2005;25(2):133–40.PubMedGoogle Scholar
  111. 111.
    Yokosawa S, Yoshizawa K, Ota M, et al. A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1. Hepatology. 2007;45(2):384–90.PubMedGoogle Scholar
  112. 112.
    Buffet C, Homberg JC, Pelletier G, Turner K, Etienne JP. Chronic active hepatitis associated with liver-kidney microsomal antibody of an autoimmune type. Two familial cases. Dig Dis Sci. 1986;31(11):1273–6.PubMedGoogle Scholar
  113. 113.
    Hodges S, Lobo-Yeo A, Donaldson P, Tanner MS, Vergani D. Autoimmune chronic active hepatitis in a family. Gut. 1991;32(3):299–302.PubMedGoogle Scholar
  114. 114.
    Findor JA, Sorda JA, Daruich JR, Manero EF. Familial association in autoimmune liver disease. Medicina (B Aires). 2002;62(3):241–4.Google Scholar
  115. 115.
    Ma Y, Bogdanos DP, Hussain MJ, et al. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology. 2006;130(3):868–82.PubMedGoogle Scholar
  116. 116.
    Jurado A, Cardaba B, Jara P, et al. Autoimmune hepatitis type 2 and hepatitis C virus infection: study of HLA antigens. J Hepatol. 1997;26(5):983–91.PubMedGoogle Scholar
  117. 117.
    Djilali-Saiah I, Renous R, Caillat-Zucman S, Debray D, Alvarez F. Linkage disequilibrium between HLA class II region and autoimmune hepatitis in pediatric patients. J Hepatol. 2004;40(6):904–9.PubMedGoogle Scholar
  118. 118.
    Garcia KC, Degano M, Pease LR, et al. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science. 1998;279(5354):1166–72.PubMedGoogle Scholar
  119. 119.
    Penzotti JE, Doherty D, Lybrand TP, Nepom GT. A structural model for TCR recognition of the HLA class II shared epitope sequence implicated in susceptibility to rheumatoid arthritis. J Autoimmun. 1996;9(2):287–93.PubMedGoogle Scholar
  120. 120.
    Garboczi DN, Ghosh P, Utz U, Fan QR, Biddison WE, Wiley DC. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature. 1996;384(6605):134–41.PubMedGoogle Scholar
  121. 121.
    Garcia KC, Degano M, Stanfield RL, et al. An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science. 1996;274(5285):209–19.PubMedGoogle Scholar
  122. 122.
    Weyand CM, Hicok KC, Goronzy JJ. Nonrandom selection of T cell specificities in anti-HLA-DR responses. Sequence motifs of the responder HLA-DR allele influence T cell recruitment. J Immunol. 1991;147(1):70–8.PubMedGoogle Scholar
  123. 123.
    Yamanaka K, Kwok WW, Mickelson EM, Masewicz S, Nepom GT. T-cell receptor V beta selectivity in T-cell clones alloreactive to HLA-Dw14. Hum Immunol. 1992;33(1):57–64.PubMedGoogle Scholar
  124. 124.
    Manabe K, Hibberd ML, Donaldson PT, et al. T-cell receptor constant beta germline gene polymorphisms and susceptibility to autoimmune hepatitis. Gastroenterology. 1994;106(5):1321–5.PubMedGoogle Scholar
  125. 125.
    Arenz M, Meyer zum Buschenfelde KH, Lohr HF. Limited T cell receptor Vbeta-chain repertoire of liver-infiltrating T cells in autoimmune hepatitis. J Hepatol. 1998;28(1):70–7.PubMedGoogle Scholar
  126. 126.
    Hoshino Y, Enomoto N, Izumi N, Kurosaki M, Marumo F, Sato C. Limited usage of T-cell receptor beta chains and sequences of the complementarity determining region 3 of lymphocytes infiltrating in the liver of autoimmune hepatitis. Hepatology. 1995;22(1):142–7.PubMedGoogle Scholar
  127. 127.
    Loeper J, Descatoire V, Maurice M, et al. Presence of functional cytochrome P-450 on isolated rat hepatocyte plasma membrane. Hepatology. 1990;11(5):850–8.PubMedGoogle Scholar
  128. 128.
    Loeper J, Descatoire V, Maurice M, et al. Cytochromes P-450 in human hepatocyte plasma membrane: recognition by several autoantibodies. Gastroenterology. 1993;104(1):203–16.PubMedGoogle Scholar
  129. 129.
    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):127–32.PubMedGoogle Scholar
  130. 130.
    Lohr HF, Schlaak JF, Lohse AW, et al. Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis. Hepatology. 1996;24(6):1416–21.PubMedGoogle Scholar
  131. 131.
    Lohr H, Manns M, Kyriatsoulis A, et al. Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis. Clin Exp Immunol. 1991;84(2):297–302.PubMedGoogle Scholar
  132. 132.
    Lunel F, Abuaf N, Frangeul L, et al. Liver/kidney microsome antibody type 1 and hepatitis C virus infection. Hepatology. 1992;16(3):630–6.PubMedGoogle Scholar
  133. 133.
    Giostra F, Manzin A, Lenzi M, et al. Low hepatitis C viremia levels in patients with anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis. J Hepatol. 1996;25(4):433–8.PubMedGoogle Scholar
  134. 134.
    Gerotto M, Pontisso P, Giostra F, et al. Analysis of the hepatitis C virus genome in patients with anti-LKM-1 autoantibodies. J Hepatol. 1994;21(2):273–6.PubMedGoogle Scholar
  135. 135.
    Michitaka K, Durazzo M, Tillmann HL, Walker D, Philipp T, Manns MP. Analysis of hepatitis C virus genome in patients with autoimmune hepatitis type 2. Gastroenterology. 1994;106(6):1603–10.PubMedGoogle Scholar
  136. 136.
    Gregorio GV, 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):404–13.PubMedGoogle Scholar
  137. 137.
    Czaja AJ. Extrahepatic immunologic features of chronic viral hepatitis. Dig Dis. 1997;15(3):125–44.PubMedGoogle Scholar
  138. 138.
    Czaja AJ, Carpenter HA. Histological findings in chronic hepatitis C with autoimmune features. Hepatology. 1997;26(2):459–66.PubMedGoogle Scholar
  139. 139.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Genetic predispositions for immunological features in chronic liver diseases other than autoimmune hepatitis. J Hepatol. 1996;24(1):52–9.PubMedGoogle Scholar
  140. 140.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Immunologic features and HLA associations in chronic viral hepatitis. Gastroenterology. 1995;108(1):157–64.PubMedGoogle Scholar
  141. 141.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB, Taswell HF, Homburger HA. Evidence against hepatitis viruses as important causes of severe autoimmune hepatitis in the United States. J Hepatol. 1993;18(3):342–52.PubMedGoogle Scholar
  142. 142.
    Manns MP, 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):1054–66.PubMedGoogle Scholar
  143. 143.
    Aguilera I, Wichmann I, Sousa JM, et al. Antibodies against glutathione S-transferase T1 (GSTT1) in patients with de novo immune hepatitis following liver transplantation. Clin Exp Immunol. 2001;126(3):535–9.PubMedGoogle Scholar
  144. 144.
    Costa M, Rodriguez-Sanchez JL, Czaja AJ, Gelpi C. Isolation and characterization of cDNA encoding the antigenic protein of the human tRNP(Ser)Sec complex recognized by autoantibodies from patients withtype-1 autoimmune hepatitis. Clin Exp Immunol. 2000;121(2):364–74.PubMedGoogle Scholar
  145. 145.
    Spiess M. The asialoglycoprotein receptor: a model for endocytic transport receptors. Biochemistry. 1990;29(43):10009–18.PubMedGoogle Scholar
  146. 146.
    Treichel U, Poralla T, Hess G, Manns M, Meyer zum Buschenfelde KH. Autoantibodies to human asialoglycoprotein receptor in autoimmune-type chronic hepatitis. Hepatology. 1990;11(4):606–12.PubMedGoogle Scholar
  147. 147.
    Poralla T, Treichel U, Lohr H, Fleischer B. The asialoglycoprotein receptor as target structure in autoimmune liver diseases. Semin Liver Dis. 1991;11(3):215–22.PubMedGoogle Scholar
  148. 148.
    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. 1984;2(8409):954–6.PubMedGoogle Scholar
  149. 149.
    McFarlane BM, McSorley CG, Vergani D, McFarlane IG, Williams R. Serum autoantibodies reacting with the hepatic asialoglycoprotein receptor protein (hepatic lectin) in acute and chronic liver ­disorders. J Hepatol. 1986;3(2):196–205.PubMedGoogle Scholar
  150. 150.
    Czaja AJ, Pfeifer KD, Decker RH, Vallari AS. Frequency and ­significance of antibodies to asialoglycoprotein receptor in type 1 autoimmune hepatitis. Dig Dis Sci. 1996;41(9):1733–40.PubMedGoogle Scholar
  151. 151.
    Bluestone JA. Is CTLA-4 a master switch for peripheral T cell tolerance? J Immunol. 1997;158(5):1989–93.PubMedGoogle Scholar
  152. 152.
    Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7(4):445–50.PubMedGoogle Scholar
  153. 153.
    Scheipers P, Reiser H. Role of the CTLA-4 receptor in T cell ­activation and immunity. Physiologic function of the CTLA-4 receptor. Immunol Res. 1998;18(2):103–15.PubMedGoogle Scholar
  154. 154.
    McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol. 1999;77(1):1–10.PubMedGoogle Scholar
  155. 155.
    Agarwal K, Czaja AJ, Jones DE, Donaldson PT. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology. 2000;31(1):49–53.PubMedGoogle Scholar
  156. 156.
    Djilali-Saiah I, Ouellette P, Caillat-Zucman S, Debray D, Kohn JI, Alvarez F. CTLA-4/CD 28 region polymorphisms in children from families with autoimmune hepatitis. Hum Immunol. 2001;62(12):1356–62.PubMedGoogle Scholar
  157. 157.
    Agarwal K, Jones DE, Daly AK, et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol. 2000;32(4):538–41.PubMedGoogle Scholar
  158. 158.
    Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Lazaridis KN. Primary biliary cirrhosis is associated with a genetic variant in the 3′ flanking region of the CTLA4 gene. Gastroenterology. 2008;135(4):1200–6.PubMedGoogle Scholar
  159. 159.
    Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Petersen GM, Lazaridis KN. Interacting alleles of the coinhibitory immunoreceptor genes cytotoxic T-lymphocyte antigen 4 and programmed cell-death 1 influence risk and features of primary biliary cirrhosis. Hepatology. 2008;47(2):563–70.PubMedGoogle Scholar
  160. 160.
    Bittencourt PL, Palacios SA, Cancado EL, et al. Cytotoxic T ­lymphocyte antigen-4 gene polymorphisms do not confer susceptibility to autoimmune hepatitis types 1 and 2 in Brazil. Am J Gastroenterol. 2003;98(7):1616–20.PubMedGoogle Scholar
  161. 161.
    Umemura T, Ota M, Yoshizawa K, et al. Association of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with type 1 autoimmune hepatitis in Japanese. Hepatol Res. 2008;38(7):689–95.PubMedGoogle Scholar
  162. 162.
    Okumura A, Ishikawa T, Sato S, et al. Deficiency of forkhead box P3 and cytotoxic T-lymphocyte-associated antigen-4 gene expressions and impaired suppressor function of CD4(+)CD25(+) T cells in patients with autoimmune hepatitis. Hepatol Res. 2008;38(9):896–903.PubMedGoogle Scholar
  163. 163.
    Romagnani S. Induction of TH1 and TH2 responses: a key role for the ‘natural’ immune response? Immunol Today. 1992;13(10):379–81.PubMedGoogle Scholar
  164. 164.
    Peters M. Actions of cytokines on the immune response and viral interactions: an overview. Hepatology. 1996;23(4):909–16.PubMedGoogle Scholar
  165. 165.
    Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. 1995;16(1):34–8.PubMedGoogle Scholar
  166. 166.
    Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev. 1996;9(4):532–62.PubMedGoogle Scholar
  167. 167.
    Maggiore G, De Benedetti F, Massa M, Pignatti P, Martini A. Circulating levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in children with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 1995;20(1):23–7.PubMedGoogle Scholar
  168. 168.
    Kawashima H, Kato N, Ioi H, et al. mRNA expression of T-helper 1, T-helper 2 cytokines in autoimmune hepatitis in childhood. Pediatr Int. 2008;50(3):284–6.PubMedGoogle Scholar
  169. 169.
    Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology. 1992;103(1):264–74.PubMedGoogle Scholar
  170. 170.
    Wabel A, Janadi M, Raziuddin S. Cytokine profile of viral and autoimmune chronic active hepatitis. J Allergy Clin Immunol. 1993;92(6):902–8.Google Scholar
  171. 171.
    Lohr HF, Schlaak JF, Gerken G, Fleischer B, Dienes HP, Meyer zum Buschenfelde KH. Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver. 1994;14(3):161–6.PubMedGoogle Scholar
  172. 172.
    Fan LY, Tu XQ, Zhu Y, et al. Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. World J Gastroenterol. 2005;11(18):2768–72.PubMedGoogle Scholar
  173. 173.
    Cookson S, Constantini PK, Clare M, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology. 1999;30(4):851–6.PubMedGoogle Scholar
  174. 174.
    Czaja AJ, Cookson S, Constantini PK, Clare M, Underhill JA, Donaldson PT. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology. 1999;117(3):645–52.PubMedGoogle Scholar
  175. 175.
    Bayer EM, Herr W, Kanzler S, et al. Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity. J Hepatol. 1998;28(5):803–11.PubMedGoogle Scholar
  176. 176.
    Bittencourt PL, Palacios SA, Cancado EL, et al. Autoimmune hepatitis in Brazilian patients is not linked to tumor necrosis factor alpha polymorphisms at position −308. J Hepatol. 2001;35(1):24–8.PubMedGoogle Scholar
  177. 177.
    Montano-Loza AJ, Carpenter HA, Czaja AJ. Clinical significance of HLA DRB103-DRB104 in type 1 autoimmune hepatitis. Liver Int. 2006;26(10):1201–8.PubMedGoogle Scholar
  178. 178.
    Schreuder GM, Hurley CK, Marsh SG, et al. The HLA dictionary 2001: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens. Hum Immunol. 2001;62(8):826–49.PubMedGoogle Scholar
  179. 179.
    Moloney MM, Thomson LJ, Strettell MJ, Williams R, Donaldson PT. Human leukocyte antigen-C genes and susceptibility to primary sclerosing cholangitis. Hepatology. 1998;28(3):660–2.PubMedGoogle Scholar
  180. 180.
    Longhi MS, Hussain MJ, Mitry RR, et al. Functional study of CD4+ CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176(7):4484–91.PubMedGoogle Scholar
  181. 181.
    Longhi MS, Ma Y, Mitry RR, et al. Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun. 2005;25(1):63–71.PubMedGoogle Scholar
  182. 182.
    Lan RY, Cheng C, Lian ZX, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology. 2006;43(4):729–37.PubMedGoogle Scholar
  183. 183.
    Longhi MS, Meda F, Wang P, et al. Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis. Hepatology. 2008;47(2):581–91.PubMedGoogle Scholar
  184. 184.
    Zhang C, Zhang J, Tian Z. The regulatory effect of natural killer cells: do “NK-reg cells” exist? Cell Mol Immunol. 2006;3(4):241–54.PubMedGoogle Scholar
  185. 185.
    Lalazar G, Preston S, Zigmond E, Ben Yaacov A, Ilan Y. Glycolipids as immune modulatory tools. Mini Rev Med Chem. 2006;6(11):1249–53.PubMedGoogle Scholar
  186. 186.
    Takahashi H, Oikawa T, Amano K, et al. Intrahepatic NKT cell and soluble CD1d have a significant role in the immuno-pathogenesis­ of AIH but not PBC (abstract). Hepatology. 2006;44 suppl 1:227A–8A.Google Scholar
  187. 187.
    Bluestone JA, Cron RQ, Cotterman M, Houlden BA, Matis LA. Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4−, CD8− T lymphocytes. J Exp Med. 1988;168(5):1899–916.PubMedGoogle Scholar
  188. 188.
    Born WK, Reardon CL, O’Brien RL. The function of gammadelta T cells in innate immunity. Curr Opin Immunol. 2006;18(1):31–8.PubMedGoogle Scholar
  189. 189.
    Morita CT, Mariuzza RA, Brenner MB. Antigen recognition by human gamma delta T cells: pattern recognition by the adaptive immune ­system. Springer Semin Immunopathol. 2000;22(3):191–217.PubMedGoogle Scholar
  190. 190.
    Holtmeier W, Kabelitz D. gammadelta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151–83.PubMedGoogle Scholar
  191. 191.
    Strominger JL. The gamma delta T cell receptor and class Ib MHC-related proteins: enigmatic molecules of immune recognition. Cell. 1989;57(6):895–8.PubMedGoogle Scholar
  192. 192.
    Hayday AC. [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol. 2000;18:975–1026.PubMedGoogle Scholar
  193. 193.
    Thedrez A, Sabourin C, Gertner J, et al. Self/non-self discrimination by human gammadelta T cells: simple solutions for a complex issue? Immunol Rev. 2007;215:123–35.PubMedGoogle Scholar
  194. 194.
    Martins EB, Graham AK, Chapman RW, Fleming KA. Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases. Hepatology. 1996;23(5):988–93.PubMedGoogle Scholar
  195. 195.
    Wen L, Peakman M, Mieli-Vergani G, Vergani D. Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease. Clin Exp Immunol. 1992;89(1):78–82.PubMedGoogle Scholar
  196. 196.
    Wen L, Ma Y, Bogdanos DP, et al. Pediatric autoimmune liver diseases: the molecular basis of humoral and cellular immunity. Curr Mol Med. 2001;1(3):379–89.PubMedGoogle Scholar
  197. 197.
    Campbell DJ, Kim CH, Butcher EC. Chemokines in the systemic organization of immunity. Immunol Rev. 2003;195:58–71.PubMedGoogle Scholar
  198. 198.
    Heydtmann M, Lalor PF, Eksteen JA, Hubscher SG, Briskin M, Adams DH. CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J Immunol. 2005;174(2):1055–62.PubMedGoogle Scholar
  199. 199.
    Moreno C, Gustot T, Nicaise C, et al. CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice. Hepatology. 2005;42(4):854–62.PubMedGoogle Scholar
  200. 200.
    Ajuebor MN, Aspinall AI, Zhou F, et al. Lack of chemokine receptor CCR5 promotes murine fulminant liver failure by preventing the apoptosis of activated CD1d-restricted NKT cells. J Immunol. 2005;174(12):8027–37.PubMedGoogle Scholar
  201. 201.
    Fox CK, Furtwaengler A, Nepomuceno RR, Martinez OM, Krams SM. Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. Liver. 2001;21(4):272–9.PubMedGoogle Scholar
  202. 202.
    Bai J, Odin JA. Apoptosis and the liver: relation to autoimmunity and related conditions. Autoimmun Rev. 2003;2(1):36–42.PubMedGoogle Scholar
  203. 203.
    Ogawa S, Sakaguchi K, Takaki A, et al. Increase in CD95 (Fas/APO-1)-positive CD4+ and CD8+ T cells in peripheral blood derived from patients with autoimmune hepatitis or chronic hepatitis C with autoimmune phenomena. J Gastroenterol Hepatol. 2000;15(1):69–75.PubMedGoogle Scholar
  204. 204.
    Ichiki Y, Aoki CA, Bowlus CL, Shimoda S, Ishibashi H, Gershwin ME. T cell immunity in autoimmune hepatitis. Autoimmun Rev. 2005;4(5):315–21.PubMedGoogle Scholar
  205. 205.
    Hiraide A, Imazeki F, Yokosuka O, et al. Fas polymorphisms influence susceptibility to autoimmune hepatitis. Am J Gastroen­terol. 2005;100(6):1322–9.PubMedGoogle Scholar
  206. 206.
    Agarwal K, Czaja AJ, Donaldson PT. A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis. Tissue Antigens. 2007;69(3):227–35.PubMedGoogle Scholar
  207. 207.
    Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology. 2002;35(1):126–31.PubMedGoogle Scholar
  208. 208.
    Esteghamat F, Noorinayer B, Sanati MH, et al. C77G mutation in protein tyrosine phosphatase CD45 gene and autoimmune hepatitis. Hepatol Res. 2005;32(3):154–7.PubMedGoogle Scholar
  209. 209.
    Wang H, Mengsteab S, Tag CG, et al. Transforming growth factor-beta1 gene polymorphisms are associated with progression of liver fibrosis in Caucasians with chronic hepatitis C infection. World J Gastroenterol. 2005;11(13):1929–36.PubMedGoogle Scholar
  210. 210.
    Samon JB, Champhekar A, Minter LM, et al. Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells. Blood. 2008;112(5):1813–21.PubMedGoogle Scholar
  211. 211.
    Rudner LA, Lin JT, Park IK, et al. Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells. J Immunol. 2003;170(9):4785–92.PubMedGoogle Scholar
  212. 212.
    Czaja AJ, dos Santos RM, Porto A, Santrach PJ, Moore SB. Immune phenotype of chronic liver disease. Dig Dis Sci. 1998;43(9):2149–55.PubMedGoogle Scholar
  213. 213.
    Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97(8):2051–7.PubMedGoogle Scholar
  214. 214.
    Al-Chalabi T, Underhill JA, Portmann BC, McFarlane IG, Heneghan MA. Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis. J Hepatol. 2008;48(1):140–7.PubMedGoogle Scholar
  215. 215.
    Czaja AJ. Special clinical challenges in autoimmune hepatitis: the elderly, males, pregnancy, mild disease, fulminant onset, and non-Caucasians. Semin Liver Dis. 2009;29(3):315–30.Google Scholar
  216. 216.
    Whitacre CC, Reingold SC, O’Looney PA. A gender gap in autoimmunity. Science. 1999;283(5406):1277–8.PubMedGoogle Scholar
  217. 217.
    Heneghan MA, Norris SM, O’Grady JG, Harrison PM, McFarlane IG. Management and outcome of pregnancy in autoimmune hepatitis. Gut. 2001;48(1):97–102.PubMedGoogle Scholar
  218. 218.
    Buchel E, Van Steenbergen W, Nevens F, Fevery J. Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery. Am J Gastroenterol. 2002;97(12):3160–5.PubMedGoogle Scholar
  219. 219.
    Candia L, Marquez J, Espinoza LR. Autoimmune hepatitis and pregnancy: a rheumatologist’s dilemma. Semin Arthritis Rheum. 2005;35(1):49–56.PubMedGoogle Scholar
  220. 220.
    Miozzo M, Selmi C, Gentilin B, et al. Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis. Hepatology. 2007;46(2):456–62.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Mayo Clinic College of MedicineRochesterMinnesota

Personalised recommendations