Digestive Diseases and Sciences

, Volume 60, Issue 10, pp 2881–2900 | Cite as

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

  • Albert J. Czaja


Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.


Autoimmune hepatitis Idiopathic Explainable Genetic Pathogenesis 


Conflict of interest



  1. 1.
    Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–2213.PubMedCrossRefGoogle Scholar
  2. 2.
    Kogan J, Safadi R, Ashur Y, Shouval D, Ilan Y. Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients. J Clin Gastroenterol. 2002;35:75–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Burgart LJ, Batts KP, Ludwig J, Nikias GA, Czaja AJ. Recent-onset autoimmune hepatitis. Biopsy findings and clinical correlations. Am J Surg Pathol. 1995;19:699–708.PubMedCrossRefGoogle Scholar
  4. 4.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB, Homburger HA. The nature and prognosis of severe cryptogenic chronic active hepatitis. Gastroenterology. 1993;104:1755–1761.PubMedGoogle Scholar
  5. 5.
    Kaymakoglu S, Cakaloglu Y, Demir K, et al. Is severe cryptogenic chronic hepatitis similar to autoimmune hepatitis? J Hepatol. 1998;28:78–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Czaja AJ. Cryptogenic chronic hepatitis and its changing guise in adults. Dig Dis Sci. 2011;56:3421–3438.PubMedCrossRefGoogle Scholar
  7. 7.
    Nikias GA, Batts KP, Czaja AJ. The nature and prognostic implications of autoimmune hepatitis with an acute presentation. J Hepatol. 1994;21:866–871.PubMedCrossRefGoogle Scholar
  8. 8.
    Kessler WR, Cummings OW, Eckert G, et al. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol. 2004;2:625–631.PubMedCrossRefGoogle Scholar
  9. 9.
    Fujiwara K, Yasui S, Tawada A, et al. Autoimmune fulminant liver failure in adults: experience in a Japanese center. Hepatol Res. 2011;41:133–141.PubMedCrossRefGoogle Scholar
  10. 10.
    Stravitz RT, Lefkowitch JH, Fontana RJ, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology. 2011;53:517–526.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Czaja AJ. Acute and acute severe (fulminant) autoimmune hepatitis. Dig Dis Sci. 2013;58:897–914.PubMedCrossRefGoogle Scholar
  12. 12.
    Czaja AJ, Carpenter HA. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology. 1993;105:1824–1832.PubMedGoogle Scholar
  13. 13.
    Carpenter HA, Czaja AJ. The role of histologic evaluation in the diagnosis and management of autoimmune hepatitis and its variants. Clin Liver Dis. 2002;6:685–705.PubMedCrossRefGoogle Scholar
  14. 14.
    Singh R, Nair S, Farr G, Mason A, Perrillo R. Acute autoimmune hepatitis presenting with centrizonal liver disease: case report and review of the literature. Am J Gastroenterol. 2002;97:2670–2673.PubMedCrossRefGoogle Scholar
  15. 15.
    Okano N, Yamamoto K, Sakaguchi K, et al. Clinicopathological features of acute-onset autoimmune hepatitis. Hepatol Res. 2003;25:263–270.PubMedCrossRefGoogle Scholar
  16. 16.
    Misdraji J, Thiim M, Graeme-Cook FM. Autoimmune hepatitis with centrilobular necrosis. Am J Surg Pathol. 2004;28:471–478.PubMedCrossRefGoogle Scholar
  17. 17.
    Hofer H, Oesterreicher C, Wrba F, Ferenci P, Penner E. Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation. J Clin Pathol. 2006;59:246–249.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Feld JJ, Dinh H, Arenovich T, et al. Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome. Hepatology. 2005;42:53–62.PubMedCrossRefGoogle Scholar
  19. 19.
    Ludwig J, Czaja AJ, Dickson ER, LaRusso NF, Wiesner RH. Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations and terminology. Liver. 1984;4:105–116.PubMedCrossRefGoogle Scholar
  20. 20.
    Czaja AJ, Carpenter HA. Autoimmune hepatitis with incidental histologic features of bile duct injury. Hepatology. 2001;34:659–665.PubMedCrossRefGoogle Scholar
  21. 21.
    Czaja AJ, Muratori P, Muratori L, Carpenter HA, Bianchi FB. Diagnostic and therapeutic implications of bile duct injury in autoimmune hepatitis. Liver Int. 2004;24:322–329.PubMedCrossRefGoogle Scholar
  22. 22.
    Czaja AJ. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol. 1999;30:394–401.PubMedCrossRefGoogle Scholar
  23. 23.
    Czaja AJ. Autoantibody-negative autoimmune hepatitis. Dig Dis Sci. 2012;57:610–624.PubMedCrossRefGoogle Scholar
  24. 24.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Immunologic features and HLA associations in chronic viral hepatitis. Gastroenterology. 1995;108:157–164.PubMedCrossRefGoogle Scholar
  25. 25.
    Loria P, Lonardo A, Leonardi F, et al. Non-organ-specific autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates. Dig Dis Sci. 2003;48:2173–2181.PubMedCrossRefGoogle Scholar
  26. 26.
    Adams LA, Lindor KD, Angulo P. The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2004;99:1316–1320.PubMedCrossRefGoogle Scholar
  27. 27.
    Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56:958–976.PubMedCrossRefGoogle Scholar
  28. 28.
    Czaja AJ. Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig Dis Sci. 2011;56:545–554.PubMedCrossRefGoogle Scholar
  29. 29.
    Strettell MD, Donaldson PT, Thomson LJ, et al. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology. 1997;112:2028–2035.PubMedCrossRefGoogle Scholar
  30. 30.
    Czaja AJ. Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6:379–388.PubMedCrossRefGoogle Scholar
  31. 31.
    de Boer YS, van Gerven NM, Zwiers A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 2014;147:443 e445–452 e445.Google Scholar
  32. 32.
    van Gerven NM, de Boer YS, Zwiers A, et al. HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun. 2015. doi: 10.1038/gene.2014.82.PubMedGoogle Scholar
  33. 33.
    Czaja AJ. Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol. 2001;96:1224–1231.PubMedCrossRefGoogle Scholar
  34. 34.
    Czaja AJ. Autoimmune hepatitis. Part A: pathogenesis. Expert Rev Gastroenterol Hepatol. 2007;1:113–128.PubMedCrossRefGoogle Scholar
  35. 35.
    Vergani D, Mieli-Vergani G. Aetiopathogenesis of autoimmune hepatitis. World J Gastroenterol. 2008;14:3306–3312.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Longhi MS, Ma Y, Mieli-Vergani G, Vergani D. Aetiopathogenesis of autoimmune hepatitis. J Autoimmun. 2010;34:7–14.PubMedCrossRefGoogle Scholar
  37. 37.
    Liberal R, Longhi MS, Mieli-Vergani G, Vergani D. Pathogenesis of autoimmune hepatitis. Best Prac Res Clin Gastroenterol. 2011;25:653–664.CrossRefGoogle Scholar
  38. 38.
    Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–938.PubMedCrossRefGoogle Scholar
  39. 39.
    Bittencourt PL, Goldberg AC, Cancado EL, et al. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol. 1999;94:1906–1913.PubMedCrossRefGoogle Scholar
  40. 40.
    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;37:302–308.PubMedCrossRefGoogle Scholar
  41. 41.
    Czaja AJ. Autoimmune hepatitis in diverse ethnic populations and geographical regions. Expert Rev Gastroenterol Hepatol. 2013;7:365–385.PubMedCrossRefGoogle Scholar
  42. 42.
    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;30:1374–1380.PubMedCrossRefGoogle Scholar
  43. 43.
    Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis. Clin Liver Dis. 2002;6:727–737.PubMedCrossRefGoogle Scholar
  44. 44.
    Czaja AJ, Manns MP. The validity and importance of subtypes in autoimmune hepatitis: a point of view. Am J Gastroenterol. 1995;90:1206–1211.PubMedGoogle Scholar
  45. 45.
    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;7:1333–1339.PubMedCrossRefGoogle Scholar
  46. 46.
    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;103:1290–1295.PubMedGoogle Scholar
  47. 47.
    Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology. 1997;25:541–547.PubMedCrossRefGoogle Scholar
  48. 48.
    Targan SR, Landers C, Vidrich A, Czaja AJ. High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology. 1995;108:1159–1166.PubMedCrossRefGoogle Scholar
  49. 49.
    Zauli D, Ghetti S, Grassi A, et al. Anti-neutrophil cytoplasmic antibodies in type 1 and 2 autoimmune hepatitis. Hepatology. 1997;25:1105–1107.PubMedCrossRefGoogle Scholar
  50. 50.
    Martini E, Abuaf N, Cavalli F, et al. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology. 1988;8:1662–1666.PubMedCrossRefGoogle Scholar
  51. 51.
    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;16:892–898.PubMedCrossRefGoogle Scholar
  52. 52.
    Czaja AJ, Shums Z, Norman GL. Nonstandard antibodies as prognostic markers in autoimmune hepatitis. Autoimmunity. 2004;37:195–201.PubMedCrossRefGoogle Scholar
  53. 53.
    Djilali-Saiah I, Fakhfakh A, Louafi H, et al. HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis. J Hepatol. 2006;45:844–850.PubMedCrossRefGoogle Scholar
  54. 54.
    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;88:1370–1378.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Ma Y, Thomas MG, Okamoto M, et al. Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule. J Immunol. 2002;169:277–285.PubMedCrossRefGoogle Scholar
  56. 56.
    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;40:904–909.PubMedCrossRefGoogle Scholar
  57. 57.
    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;116:643–649.PubMedCrossRefGoogle Scholar
  58. 58.
    Muratori L, Sztul E, Muratori P, et al. Distinct epitopes on formiminotransferase cyclodeaminase induce autoimmune liver cytosol antibody type 1. Hepatology. 2001;34:494–501.PubMedCrossRefGoogle Scholar
  59. 59.
    Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis and management of autoimmune hepatitis. Gastroenterology. 2010;139:58–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Czaja AJ, Doherty DG, Donaldson PT. Genetic bases of autoimmune hepatitis. Dig Dis Sci. 2002;47:2139–2150.PubMedCrossRefGoogle Scholar
  61. 61.
    Seki T, Kiyosawa K, Inoko H, Ota M. Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients. Hepatology. 1990;12:1300–1304.PubMedCrossRefGoogle Scholar
  62. 62.
    Seki T, Ota M, Furuta S, et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology. 1992;103:1041–1047.PubMedGoogle Scholar
  63. 63.
    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;42:578–584.PubMedCrossRefGoogle Scholar
  64. 64.
    Yokosawa S, Yoshizawa K, Ota M, et al. A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1. Hepatology. 2007;45:384–390.PubMedCrossRefGoogle Scholar
  65. 65.
    Yoshizawa K, Umemura T, Ota M. Genetic background of autoimmune hepatitis in Japan. J Gastroenterol. 2011;46:42–47.PubMedCrossRefGoogle Scholar
  66. 66.
    Qiu DK, Ma X. Relationship between human leukocyte antigen-DRB1 and autoimmune hepatitis type I in Chinese patients. J Gastroenterol Hepatol. 2003;18:63–67.PubMedCrossRefGoogle Scholar
  67. 67.
    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;28:985–990.PubMedCrossRefGoogle Scholar
  68. 68.
    Lim YS, Oh HB, Choi SE, et al. Susceptibility to type 1 autoimmune hepatitis is associated with shared amino acid sequences at positions 70–74 of the HLA-DRB1 molecule. J Hepatol. 2008;48:133–139.PubMedCrossRefGoogle Scholar
  69. 69.
    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;41:146–150.PubMedCrossRefGoogle Scholar
  70. 70.
    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;62:165–169.PubMedCrossRefGoogle Scholar
  71. 71.
    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;27:1409–1416.PubMedCrossRefGoogle Scholar
  72. 72.
    Duarte-Rey C, Pardo AL, Rodriguez-Velosa Y, et al. HLA class II association with autoimmune hepatitis in Latin America: a meta-analysis. Autoimmun Rev. 2009;8:325–331.PubMedCrossRefGoogle Scholar
  73. 73.
    Goldberg AC, Bittencourt PL, Oliveira LC, et al. Autoimmune hepatitis in Brazil: an overview. Scand J Immunol. 2007;66:208–216.PubMedCrossRefGoogle Scholar
  74. 74.
    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;130:868–882.PubMedCrossRefGoogle Scholar
  75. 75.
    Czaja AJ, Kruger M, Santrach PJ, Moore SB, Manns MP. Genetic distinctions between types 1 and 2 autoimmune hepatitis. Am J Gastroenterol.. 1997;92:2197–2200.PubMedGoogle Scholar
  76. 76.
    Jurado A, Cardaba B, Jara P, et al. Autoimmune hepatitis type 2 and hepatitis C virus infection: study of HLA antigens. J Hepatol. 1997;26:983–991.PubMedCrossRefGoogle Scholar
  77. 77.
    Donaldson PT, Czaja AJ. Genetic effects on susceptibility, clinical expression, and treatment outcome of type 1 autoimmune hepatitis. Clin Liver Dis. 2002;6:707–725.PubMedCrossRefGoogle Scholar
  78. 78.
    Donaldson PT. Genetics in autoimmune hepatitis. Semin Liver Dis. 2002;22:353–364.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang P, Su H, Underhill J, et al. Autoantibody and human leukocyte antigen profiles in children with autoimmune liver disease and their first-degree relatives. J Pediatr Gastroenterol Nutr. 2014;58:457–462.PubMedCrossRefGoogle Scholar
  80. 80.
    Findor JA, Sorda JA, Daruich JR, Manero EF. Familial association in autoimmune liver disease. Medicina (B Aires). 2002;62:241–244.Google Scholar
  81. 81.
    van Gerven NM, Verwer BJ, Witte BI, et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol. 2014;49:1245–1254.PubMedCrossRefGoogle Scholar
  82. 82.
    Hardtke-Wolenski M, Fischer K, Noyan F, et al. Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4(+) T cells. Hepatology. 2013;58:718–728.PubMedCrossRefGoogle Scholar
  83. 83.
    Tang J, Zhou C, Zhang ZJ, Zheng SS. Association of polymorphisms in non-classic MHC genes with susceptibility to autoimmune hepatitis. Hepatobiliary Pancreat Dis Int. 2012;11:125–131.PubMedCrossRefGoogle Scholar
  84. 84.
    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;31:49–53.PubMedCrossRefGoogle Scholar
  85. 85.
    Djilali-Saiah I, Ouellette P, Caillat-Zucman S, et al. CTLA-4/CD 28 region polymorphisms in children from families with autoimmune hepatitis. Hum Immunol. 2001;62:1356–1362.PubMedCrossRefGoogle Scholar
  86. 86.
    Hiraide A, Imazeki F, Yokosuka O, et al. Fas polymorphisms influence susceptibility to autoimmune hepatitis. Am J Gastroenterol. 2005;100:1322–1329.PubMedCrossRefGoogle Scholar
  87. 87.
    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;69:227–235.PubMedCrossRefGoogle Scholar
  88. 88.
    Cookson S, Constantini PK, Clare M, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology. 1999;30:851–856.PubMedCrossRefGoogle Scholar
  89. 89.
    Czaja AJ, Cookson S, Constantini PK, et al. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology. 1999;117:645–652.PubMedCrossRefGoogle Scholar
  90. 90.
    Li S, Huang X, Zhong H, et al. Tumour necrosis factor alpha (TNF-alpha) genetic polymorphisms and the risk of autoimmune liver disease: a meta-analysis. J Genet. 2013;92:617–628.PubMedCrossRefGoogle Scholar
  91. 91.
    Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology. 2002;35:126–131.PubMedCrossRefGoogle Scholar
  92. 92.
    Fan L, Tu X, Zhu Y, et al. Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol. 2005;20:249–255.PubMedCrossRefGoogle Scholar
  93. 93.
    Migita K, Nakamura M, Abiru S, et al. Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population. PLoS One. 2013;8:e71382.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Paladino N, Flores AC, Fainboim H, et al. The most severe forms of type I autoimmune hepatitis are associated with genetically determined levels of TGF-beta1. Clin Immunol. 2010;134:305–312.PubMedCrossRefGoogle Scholar
  95. 95.
    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;11:2768–2772.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    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;35:24–28.PubMedCrossRefGoogle Scholar
  97. 97.
    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;98:1616–1620.PubMedGoogle Scholar
  98. 98.
    Schott E, Witt H, Pascu M, et al. Association of CTLA4 single nucleotide polymorphisms with viral but not autoimmune liver disease. Eur J Gastroenterol Hepatol. 2007;19:947–951.PubMedCrossRefGoogle Scholar
  99. 99.
    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;38:689–695.PubMedCrossRefGoogle Scholar
  100. 100.
    van Gerven NM, de Boer YS, Zwiers A, et al. Cytotoxic T lymphocyte antigen-4 +49A/G polymorphism does not affect susceptibility to autoimmune hepatitis. Liver Int. 2013;33:1039–1043.PubMedCrossRefGoogle Scholar
  101. 101.
    Mells GF, Kaser A, Karlsen TH. Novel insights into autoimmune liver diseases provided by genome-wide association studies. J Autoimmun. 2013;46:41–54.PubMedCrossRefGoogle Scholar
  102. 102.
    Lapierre P, Beland K, Djilali-Saiah I, Alvarez F. Type 2 autoimmune hepatitis murine model: the influence of genetic background in disease development. J Autoimmun. 2006;26:82–89.PubMedCrossRefGoogle Scholar
  103. 103.
    Li Y, He X, Schembri-King J, Jakes S, Hayashi J. Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation. J Immunol. 2000;164:5199–5206.PubMedCrossRefGoogle Scholar
  104. 104.
    Westra HJ, Peters MJ, Esko T, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45:1238–1243.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Blonska M, Lin X. NF-kappaB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res. 2011;21:55–70.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Agarwal K, Jones DE, Daly AK, et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol. 2000;32:538–541.PubMedCrossRefGoogle Scholar
  107. 107.
    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;135:1200–1206.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    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;33:1512–1517.PubMedCrossRefGoogle Scholar
  109. 109.
    Elfaramawy AA, Elhossiny RM, Abbas AA, Aziz HM. HLA-DRB1 as a risk factor in children with autoimmune hepatitis and its relation to hepatitis A infection. Ital J Pediatr. 2010;36:73.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    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;161:3527–3535.PubMedGoogle Scholar
  111. 111.
    Corper AL, Stratmann T, Apostolopoulos V, et al. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science. 2000;288:505–511.PubMedCrossRefGoogle Scholar
  112. 112.
    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;9:287–293.PubMedCrossRefGoogle Scholar
  113. 113.
    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;279:1166–1172.PubMedCrossRefGoogle Scholar
  114. 114.
    Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev. 2000;174:250–259.PubMedCrossRefGoogle Scholar
  115. 115.
    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;19:609–615.PubMedCrossRefGoogle Scholar
  116. 116.
    Garboczi DN, Ghosh P, Utz U, et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature. 1996;384:134–141.PubMedCrossRefGoogle Scholar
  117. 117.
    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;274:209–219.PubMedCrossRefGoogle Scholar
  118. 118.
    Oldstone MB. Molecular mimicry and immune-mediated diseases. FASEB J. 1998;12:1255–1265.PubMedGoogle Scholar
  119. 119.
    Christen U, Holdener M, Hintermann E. Cytochrome P450 2D6 as a model antigen. Dig Dis. 2010;28:80–85.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    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;12:127–132.PubMedCrossRefGoogle Scholar
  121. 121.
    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;84:297–302.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Lapierre P, Djilali-Saiah I, Vitozzi S, Alvarez F. A murine model of type 2 autoimmune hepatitis: xenoimmunization with human antigens. Hepatology. 2004;39:1066–1074.PubMedCrossRefGoogle Scholar
  123. 123.
    Holdener M, Hintermann E, Bayer M, et al. Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection. J Exp Med. 2008;205:1409–1422.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Gueguen P, Dalekos G, Nousbaum JB, et al. Double reactivity against actin and alpha-actinin defines a severe form of autoimmune hepatitis type 1. J Clin Immunol. 2006;26:495–505.PubMedCrossRefGoogle Scholar
  125. 125.
    Oikonomou KG, Zachou K, Dalekos GN. Alpha-actinin: a multidisciplinary protein with important role in B-cell driven autoimmunity. Autoimmun Rev. 2011;10:389–396.PubMedCrossRefGoogle Scholar
  126. 126.
    Zachou K, Oikonomou K, Renaudineau Y, et al. Anti-alpha actinin antibodies as new predictors of response to treatment in autoimmune hepatitis type 1. Aliment Pharmacol Ther. 2012;35:116–125.PubMedCrossRefGoogle Scholar
  127. 127.
    Treichel U, Poralla T, Hess G, Manns M, Meyer zum Buschenfelde KH. Autoantibodies to human asialoglycoprotein receptor in autoimmune-type chronic hepatitis. Hepatology. 1990;11:606–612.PubMedCrossRefGoogle Scholar
  128. 128.
    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;41:1733–1740.PubMedCrossRefGoogle Scholar
  129. 129.
    Rigopoulou EI, Roggenbuck D, Smyk DS, et al. Asialoglycoprotein receptor (ASGPR) as target autoantigen in liver autoimmunity: lost and found. Autoimmun Rev. 2012;12:260–269.PubMedCrossRefGoogle Scholar
  130. 130.
    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 with type-1 autoimmune hepatitis. Clin Exp Immunol. 2000;121:364–374.PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Volkmann M, Martin L, Baurle A, et al. Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis. Hepatology. 2001;33:591–596.PubMedCrossRefGoogle Scholar
  132. 132.
    Volkmann M, Luithle D, Zentgraf H, et al. SLA/LP/tRNP((Ser)Sec) antigen in autoimmune hepatitis: identification of the native protein in human hepatic cell extract. J Autoimmun. 2010;34:59–65.PubMedCrossRefGoogle Scholar
  133. 133.
    Obermayer-Straub P, Manns MP. Cytochrome P450 enzymes and UDP-glucuronosyltransferases as hepatocellular autoantigens. Mol Biol Rep. 1996;23:235–242.PubMedCrossRefGoogle Scholar
  134. 134.
    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;26:1054–1066.PubMedCrossRefGoogle Scholar
  135. 135.
    Preuss B, Berg C, Dengjel J, Stevanovic S, Klein R. Relevance of the inner mitochondrial membrane enzyme F1F0-ATPase as an autoantigen in autoimmune liver disorders. Liver Int. 2012;32:249–257.PubMedCrossRefGoogle Scholar
  136. 136.
    Song Q, Liu G, Hu S, et al. Novel autoimmune hepatitis-specific autoantigens identified using protein microarray technology. J Proteome Res. 2010;9:30–39.PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Wu L, Song G. Identification of new autoimmune hepatitis-specific autoantigens by using protein microarray technology. Methods Mol Biol. 2012;909:227–239.PubMedGoogle Scholar
  138. 138.
    Tahiri F, Le Naour F, Huguet S, et al. Identification of plasma membrane autoantigens in autoimmune hepatitis type 1 using a proteomics tool. Hepatology. 2008;47:937–948.PubMedCrossRefGoogle Scholar
  139. 139.
    Zingaretti C, Arigo M, Cardaci A, et al. Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis. Mol Cell Proteomics. 2012;11:1885–1897.PubMedCentralPubMedCrossRefGoogle Scholar
  140. 140.
    Yamamoto AM, Cresteil D, Boniface O, Clerc FF, 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.PubMedCrossRefGoogle Scholar
  141. 141.
    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;170:1481–1489.PubMedCrossRefGoogle Scholar
  142. 142.
    Mizutani T, Shinoda M, Tanaka Y, et al. Autoantibodies against CYP2D6 and other drug-metabolizing enzymes in autoimmune hepatitis type 2. Drug Metab Rev. 2005;37:235–252.PubMedCrossRefGoogle Scholar
  143. 143.
    Lunel F, Abuaf N, Frangeul L, et al. Liver/kidney microsome antibody type 1 and hepatitis C virus infection. Hepatology. 1992;16:630–636.PubMedCrossRefGoogle Scholar
  144. 144.
    Vento S, Garofano T, Di Perri G, et al. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet. 1991;337:1183–1187.PubMedCrossRefGoogle Scholar
  145. 145.
    Huppertz HI, Treichel U, Gassel AM, Jeschke R. Meyer zum Buschenfelde KH. Autoimmune hepatitis following hepatitis A virus infection. J Hepatol. 1995;23:204–208.PubMedCrossRefGoogle Scholar
  146. 146.
    Tanaka H, Tujioka H, Ueda H, et al. Autoimmune hepatitis triggered by acute hepatitis A. World J Gastroenterol. 2005;11:6069–6071.PubMedCentralPubMedCrossRefGoogle Scholar
  147. 147.
    Tabak F, Ozdemir F, Tabak O, et al. Autoimmune hepatitis induced by the prolonged hepatitis A virus infection. Ann Hepatol. 2008;7:177–179.PubMedGoogle Scholar
  148. 148.
    Laskus T, Slusarczyk J. Autoimmune chronic active hepatitis developing after acute type B hepatitis. Dig Dis Sci.. 1989;34:1294–1297.PubMedCrossRefGoogle Scholar
  149. 149.
    Magrin S, Craxi A, Fabiano C, et al. Hepatitis C virus replication in ‘autoimmune’ chronic hepatitis. J Hepatol. 1991;13:364–367.PubMedCrossRefGoogle Scholar
  150. 150.
    Magrin S, Craxi A, Fiorentino G, et al. Is autoimmune chronic active hepatitis a HCV-related disease? J Hepatol. 1991;13:56–60.PubMedCrossRefGoogle Scholar
  151. 151.
    Vento S, Cainelli F, Renzini C, Concia E. Autoimmune hepatitis type 2 induced by HCV and persisting after viral clearance. Lancet. 1997;350:1298–1299.PubMedCrossRefGoogle Scholar
  152. 152.
    Robertson DA, Zhang SL, Guy EC, Wright R. Persistent measles virus genome in autoimmune chronic active hepatitis. Lancet. 1987;2:9–11.PubMedCrossRefGoogle Scholar
  153. 153.
    Kalland KH, Endresen C, Haukenes G, Schrumpf E. Measles-specific nucleotide sequences and autoimmune chronic active hepatitis. Lancet. 1989;1:1390–1391.PubMedCrossRefGoogle Scholar
  154. 154.
    Al-Hamoudi WK. Severe autoimmune hepatitis triggered by varicella zoster infection. World J Gastroenterol. 2009;15:1004–1006.PubMedCentralPubMedCrossRefGoogle Scholar
  155. 155.
    Kojima K, Nagayama R, Hirama S, et al. Epstein–Barr virus infection resembling autoimmune hepatitis with lactate dehydrogenase and alkaline phosphatase anomaly. J Gastroenterol. 1999;34:706–712.PubMedCrossRefGoogle Scholar
  156. 156.
    Chiba T, Goto S, Yokosuka O, et al. Fatal chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis. Eur J Gastroenterol Hepatol. 2004;16:225–228.PubMedCrossRefGoogle Scholar
  157. 157.
    Sevilla J, del Carmen Escudero M, Jimenez R, et al. Severe systemic autoimmune disease associated with Epstein–Barr virus infection. J Pediatr Hematol Oncol. 2004;26:831–833.PubMedCrossRefGoogle Scholar
  158. 158.
    Czaja AJ, Carpenter HA, Santrach PJ, et al. Evidence against hepatitis viruses as important causes of severe autoimmune hepatitis in the United States. J Hepatol. 1993;18:342–352.PubMedCrossRefGoogle Scholar
  159. 159.
    Christen U, Hintermann E, Holdener M, von Herrath MG. Viral triggers for autoimmunity: is the ‘glass of molecular mimicry’ half full or half empty? J Autoimmun. 2010;34:38–44.PubMedCentralPubMedCrossRefGoogle Scholar
  160. 160.
    Vogel A, Manns MP, Strassburg CP. Autoimmunity and viruses. Clin Liver Dis. 2002;6:739–753.PubMedCrossRefGoogle Scholar
  161. 161.
    Czaja AJ. Autoimmune hepatitis and viral infection. Gastroenterol Clin North Am. 1994;23:547–566.PubMedGoogle Scholar
  162. 162.
    Vento S, Di Perri G, Garofano T, et al. Hazards of interferon therapy for HBV-seronegative chronic hepatitis. Lancet. 1989;2:926.PubMedCrossRefGoogle Scholar
  163. 163.
    Shindo M, Di Bisceglie AM, Hoofnagle JH. Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C. Gastroenterology. 1992;102:1406–1408.PubMedGoogle Scholar
  164. 164.
    Efe C, Heurgue-Berlot A, Ozaslan E, et al. Late autoimmune hepatitis after hepatitis C therapy. Eur J Gastroenterol Hepatol. 2013;25:1308–1311.PubMedCrossRefGoogle Scholar
  165. 165.
    Rosen A, Casciola-Rosen L. Autoantigens in systemic autoimmunity: critical partner in pathogenesis. J Intern Med. 2009;265:625–631.PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Fox CK, Furtwaengler A, Nepomuceno RR, Martinez OM, Krams SM. Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. Liver. 2001;21:272–279.PubMedCrossRefGoogle Scholar
  167. 167.
    Savill J, Dransfield I, Gregory C, Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2002;2:965–975.PubMedCrossRefGoogle Scholar
  168. 168.
    Bai J, Odin JA. Apoptosis and the liver: relation to autoimmunity and related conditions. Autoimmun Rev. 2003;2:36–42.PubMedCrossRefGoogle Scholar
  169. 169.
    Canbay A, Feldstein AE, Higuchi H, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38:1188–1198.PubMedCrossRefGoogle Scholar
  170. 170.
    A-Gonzalez N, Bensinger SJ, Hong C, et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009;31:245–258.PubMedCentralPubMedCrossRefGoogle Scholar
  171. 171.
    Kahraman A, Gerken G, Canbay A. Apoptosis in immune-mediated liver diseases. Dig Dis. 2010;28:144–149.PubMedCrossRefGoogle Scholar
  172. 172.
    Czaja AJ. Targeting apoptosis in autoimmune hepatitis. Dig Dis Sci. 2014;59:2890–2904.PubMedCrossRefGoogle Scholar
  173. 173.
    Czaja AJ. Autoantibodies in autoimmune liver disease. Adv Clin Chem. 2005;40:127–164.PubMedCrossRefGoogle Scholar
  174. 174.
    Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci. 2010;55:2144–2161.PubMedCrossRefGoogle Scholar
  175. 175.
    Zhang WC, Zhao FR, Chen J, Chen WX. Meta-analysis: diagnostic accuracy of antinuclear antibodies, smooth muscle antibodies and antibodies to a soluble liver antigen/liver pancreas in autoimmune hepatitis. PLoS One. 2014;9:e92267.PubMedCentralPubMedCrossRefGoogle Scholar
  176. 176.
    Bogdanos DP, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver. 2001;21:225–232.PubMedCrossRefGoogle Scholar
  177. 177.
    Bowen DG. Of mice and molecular mimicry: modeling autoimmune hepatitis. Hepatology. 2008;48:1013–1015.PubMedCrossRefGoogle Scholar
  178. 178.
    Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med. 1999;341:2068–2074.PubMedCrossRefGoogle Scholar
  179. 179.
    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;190:169–176.PubMedCentralPubMedCrossRefGoogle Scholar
  180. 180.
    Rose NR, Mackay IR. Molecular mimicry: a critical look at exemplary instances in human diseases. Cell Mol Life Sci.. 2000;57:542–551.PubMedCrossRefGoogle Scholar
  181. 181.
    Djilali-Saiah I, Lapierre P, Vittozi S, Alvarez F. DNA vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis. J Immunol. 2002;169:4889–4896.PubMedCrossRefGoogle Scholar
  182. 182.
    Hintermann E, Holdener M, Bayer M, et al. Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J Autoimmun. 2011;37:242–253.PubMedCrossRefGoogle Scholar
  183. 183.
    Ehser J, Holdener M, Christen S, et al. Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune hepatitis. J Autoimmun. 2013;42:39–49.PubMedCrossRefGoogle Scholar
  184. 184.
    Christen U, von Herrath MG. Induction, acceleration or prevention of autoimmunity by molecular mimicry. Mol Immunol. 2004;40:1113–1120.PubMedCrossRefGoogle Scholar
  185. 185.
    Bjornsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51:2040–2048.PubMedCrossRefGoogle Scholar
  186. 186.
    Bjornsson E, Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice. J Hepatol. 2009;50:511–517.PubMedCrossRefGoogle Scholar
  187. 187.
    Kaymakoglu S. Drug-induced hepatitis, drug-induced autoimmunity or classical autoimmune hepatitis: how can we differentiate? Turk J Gastroenterol. 2004;15:123–125.PubMedGoogle Scholar
  188. 188.
    Huang YS, Chern HD, Su WJ, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology.. 2003;37:924–930.PubMedCrossRefGoogle Scholar
  189. 189.
    Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol. 2006;62:423–429.PubMedCrossRefGoogle Scholar
  190. 190.
    Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132:272–281.PubMedCrossRefGoogle Scholar
  191. 191.
    Lucena MI, Andrade RJ, Martinez C, et al. Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology. 2008;48:588–596.PubMedCrossRefGoogle Scholar
  192. 192.
    Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Semin Liver Dis. 2009;29:400–411.PubMedCrossRefGoogle Scholar
  193. 193.
    Lucena MI, Garcia-Martin E, Andrade RJ, et al. Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology. 2010;52:303–312.PubMedCrossRefGoogle Scholar
  194. 194.
    Russmann S, Jetter A, Kullak-Ublick GA. Pharmacogenetics of drug-induced liver injury. Hepatology. 2010;52:748–761.PubMedCrossRefGoogle Scholar
  195. 195.
    Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002;6:755–774.PubMedCrossRefGoogle Scholar
  196. 196.
    Lecoeur S, Andre C, Beaune PH. Tienilic acid-induced autoimmune hepatitis: anti-liver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol Pharmacol. 1996;50:326–333.PubMedGoogle Scholar
  197. 197.
    Tay S, Le H, Ford KA, et al. Mechanistic studies of the cationic binding pocket of CYP2C9 in vitro and in silico: metabolism of nonionizable analogs of tienilic acid. Drug Metab Dispos. 2014;42:1955–1963.PubMedCrossRefGoogle Scholar
  198. 198.
    Obermayer-Straub P, Perheentupa J, Braun S, et al. Hepatic autoantigens in patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. Gastroenterology. 2001;121:668–677.PubMedCrossRefGoogle Scholar
  199. 199.
    Hardtke-Wolenski M, Taubert R, Noyan F, et al. Autoimmune hepatitis in a murine APS-1 model is directed against multiple autoantigens. Hepatology. 2014. doi: 10.1002/hep.27639.PubMedGoogle Scholar
  200. 200.
    Bourdi M, Tinel M, Beaune PH, Pessayre D. Interactions of dihydralazine with cytochromes P4501A: a possible explanation for the appearance of anti-cytochrome P4501A2 autoantibodies. Mol Pharmacol. 1994;45:1287–1295.PubMedGoogle Scholar
  201. 201.
    Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis. 2000;4:73–96, vi.Google Scholar
  202. 202.
    Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16:3041–3053.PubMedCentralPubMedCrossRefGoogle Scholar
  203. 203.
    Beaune PH, Bourdi M. Autoantibodies against cytochromes P-450 in drug-induced autoimmune hepatitis. Ann N Y Acad Sci. 1993;685:641–645.PubMedCrossRefGoogle Scholar
  204. 204.
    Dansette PM, Bonierbale E, Minoletti C, et al. Drug-induced immunotoxicity. Eur J Drug Metab Pharmacokinet. 1998;23:443–451.PubMedCrossRefGoogle Scholar
  205. 205.
    Liebler DC, Guengerich FP. Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov. 2005;4:410–420.PubMedCrossRefGoogle Scholar
  206. 206.
    Robin MA, Le Roy M, Descatoire V, Pessayre D. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis. J Hepatol. 1997;26:23–30.PubMedCrossRefGoogle Scholar
  207. 207.
    Heurgue-Berlot A, Bernard-Chabert B, Diebold MD, Thiefin G. Drug-induced autoimmune-like hepatitis: a case of chronic course after drug withdrawal. Dig Dis Sci. 2011;56:2504–2505.PubMedCrossRefGoogle Scholar
  208. 208.
    Rieder MJ, Shear NH, Kanee A, Tang BK, Spielberg SP. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther. 1991;49:13–17.PubMedCrossRefGoogle Scholar
  209. 209.
    Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol. 2008;21:84–92.PubMedCrossRefGoogle Scholar
  210. 210.
    Bourdi M, Larrey D, Nataf J, et al. Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine-induced hepatitis. J Clin Invest. 1990;85:1967–1973.PubMedCentralPubMedCrossRefGoogle Scholar
  211. 211.
    Beaune PH, Lecoeur S, Bourdi M, et al. Anti-cytochrome P450 autoantibodies in drug-induced disease. Eur J Haematol Suppl. 1996;60:89–92.PubMedGoogle Scholar
  212. 212.
    Proctor WR, Chakraborty M, Fullerton AM, et al. Thymic stromal lymphopoietin and interleukin-4 mediate the pathogenesis of halothane-induced liver injury in mice. Hepatology.. 2014;60:1741–1752.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Kurth MJ, Yokoi T, Gershwin ME. Halothane-induced hepatitis: paradigm or paradox for drug-induced liver injury. Hepatology. 2014;60:1473–1475.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Oo YH, Adams DH. The role of chemokines in the recruitment of lymphocytes to the liver. J Autoimmun. 2010;34:45–54.PubMedCrossRefGoogle Scholar
  215. 215.
    Czaja AJ. Review article: chemokines as orchestrators of autoimmune hepatitis and potential therapeutic targets. Aliment Pharmacol Ther. 2014;40:261–279.PubMedCrossRefGoogle Scholar
  216. 216.
    Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147:577 e571–594 e571.CrossRefGoogle Scholar
  217. 217.
    Wasmuth HE, Tacke F, Trautwein C. Chemokines in liver inflammation and fibrosis. Sem Liver Dis. 2010;30:215–225.CrossRefGoogle Scholar
  218. 218.
    Antonelli A, Ferrari SM, Giuggioli D, et al. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev. 2014;13:272–280.PubMedCrossRefGoogle Scholar
  219. 219.
    Lee EY, Lee ZH, Song YW. CXCL10 and autoimmune diseases. Autoimmun Rev. 2009;8:379–383.PubMedCrossRefGoogle Scholar
  220. 220.
    Lei Y, Takahama Y. XCL1 and XCR1 in the immune system. Microbes Infect. 2012;14:262–267.PubMedCrossRefGoogle Scholar
  221. 221.
    Nishioji K, Okanoue T, Itoh Y, et al. Increase of chemokine interferon-inducible protein-10 (IP-10) in the serum of patients with autoimmune liver diseases and increase of its mRNA expression in hepatocytes. Clin Exp Immunol. 2001;123:271–279.PubMedCentralPubMedCrossRefGoogle Scholar
  222. 222.
    Li YL, Liu N, Zhao DT, et al. Investigate circulating levels of chemokines and evaluate the correlation between these chemokines and liver function indicators in autoimmune hepatitis. Zhonghua Gan Zang Bing Za Zhi. 2013;21:299–303.PubMedGoogle Scholar
  223. 223.
    Ikeda A, Aoki N, Kido M, et al. Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice. Hepatology. 2014;60:224–236.PubMedCrossRefGoogle Scholar
  224. 224.
    Manousou P, Kolios G, Drygiannakis I, et al. CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid. Clin Exp Immunol. 2013;172:9–15.PubMedCentralPubMedCrossRefGoogle Scholar
  225. 225.
    Oo YH, Banz V, Kavanagh D, et al. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J Hepatol. 2012;57:1044–1051.PubMedCentralPubMedCrossRefGoogle Scholar
  226. 226.
    Garcia-Lopez MA, Sanchez-Madrid F, Rodriguez-Frade JM, et al. CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab Invest. 2001;81:409–418.PubMedCrossRefGoogle Scholar
  227. 227.
    Saeki C, Nakano M, Takahashi H, et al. Accumulation of functional regulatory T cells in actively inflamed liver in mouse dendritic cell-based autoimmune hepatic inflammation. Clin Immunol. 2010;135:156–166.PubMedCrossRefGoogle Scholar
  228. 228.
    Landi A, Weismuller TJ, Lankisch TO, et al. Differential serum levels of eosinophilic eotaxins in primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis. J Interferon Cytokine Res. 2014;34:204–214.PubMedCentralPubMedCrossRefGoogle Scholar
  229. 229.
    Kitaura M, Suzuki N, Imai T, et al. Molecular cloning of a novel human CC chemokine (Eotaxin-3) that is a functional ligand of CC chemokine receptor 3. J Biol Chem. 1999;274:27975–27980.PubMedCrossRefGoogle Scholar
  230. 230.
    Xu HB, Gong YP, Cheng J, Chu YW, Xiong SD. CXCL16 participates in pathogenesis of immunological liver injury by regulating T lymphocyte infiltration in liver tissue. World J Gastroenterol. 2005;11:4979–4985.PubMedCentralPubMedCrossRefGoogle Scholar
  231. 231.
    Hintermann E, Bayer M, Pfeilschifter JM, Luster AD, Christen U. CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. J Autoimmun. 2010;35:424–435.PubMedCrossRefGoogle Scholar
  232. 232.
    Yellin M, Paliienko I, Balanescu A, et al. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64:1730–1739.PubMedCrossRefGoogle Scholar
  233. 233.
    Berres ML, Koenen RR, Rueland A, et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J Clin Invest. 2010;120:4129–4140.PubMedCentralPubMedCrossRefGoogle Scholar
  234. 234.
    Costantini S, Raucci R, Colonna G, et al. Peptides targeting chemokine receptor CXCR4: structural behavior and biological binding studies. J Pept Sci. 2014. doi: 10.1002/psc.2614.
  235. 235.
    Crescioli C, Cosmi L, Borgogni E, et al. Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes. J Endocrinol. 2007;195:145–155.PubMedCrossRefGoogle Scholar
  236. 236.
    Lee JW, Bajwa PJ, Carson MJ, et al. Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice. Gastroenterology. 2007;133:108–123.PubMedCrossRefGoogle Scholar
  237. 237.
    Trivedi PJ, Adams DH. Mucosal immunity in liver autoimmunity: a comprehensive review. J Autoimmun.. 2013;46:97–111.PubMedCrossRefGoogle Scholar
  238. 238.
    Montano-Loza AJ, Czaja AJ. Cell mediators of autoimmune hepatitis and their therapeutic implications. Dig Dis Sci. (Epub ahead of print). doi: 10.1007/s10620-014-3473-z.
  239. 239.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.PubMedCrossRefGoogle Scholar
  240. 240.
    Mbongue J, Nicholas D, Firek A, Langridge W. The role of dendritic cells in tissue-specific autoimmunity. J Immunol Res. 2014;2014:857143.PubMedCentralPubMedCrossRefGoogle Scholar
  241. 241.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–1061.PubMedCrossRefGoogle Scholar
  242. 242.
    Karim M, Kingsley CI, Bushell AR, Sawitzki BS, Wood KJ. Alloantigen-induced CD25+ CD4+ regulatory T cells can develop in vivo from CD25− CD4+ precursors in a thymus-independent process. J Immunol. 2004;172:923–928.PubMedCrossRefGoogle Scholar
  243. 243.
    Komatsu N, Okamoto K, Sawa S, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20:62–68.PubMedCrossRefGoogle Scholar
  244. 244.
    Harris SG, Phipps RP. The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. Eur J Immunol. 2001;31:1098–1105.PubMedCrossRefGoogle Scholar
  245. 245.
    Marra F, Efsen E, Romanelli RG, et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology. 2000;119:466–478.PubMedCrossRefGoogle Scholar
  246. 246.
    Fletcher JM, Lonergan R, Costelloe L, et al. CD39+ Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol. 2009;183:7602–7610.PubMedCrossRefGoogle Scholar
  247. 247.
    Sebastiani S, Allavena P, Albanesi C, et al. Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol. 2001;166:996–1002.PubMedCrossRefGoogle Scholar
  248. 248.
    Longhi MS, Ma Y, Bogdanos DP, et al. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol. 2004;41:31–37.PubMedCrossRefGoogle Scholar
  249. 249.
    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;25:63–71.PubMedCrossRefGoogle Scholar
  250. 250.
    Kido M, Watanabe N, Okazaki T, et al. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology. 2008;135:1333–1343.PubMedCrossRefGoogle Scholar
  251. 251.
    Ferri S, Longhi MS, De Molo C, et al. A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology. 2010;52:999–1007.PubMedCrossRefGoogle Scholar
  252. 252.
    Peiseler M, Sebode M, Franke B, et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol. 2012;57:125–132.PubMedCrossRefGoogle Scholar
  253. 253.
    Longhi MS, Ma Y, Mieli-Vergani G, Vergani D. Regulatory T cells in autoimmune hepatitis. J Hepatol. 2012;57:932–933.PubMedCrossRefGoogle Scholar
  254. 254.
    Peiseler M, Sebode M, Schramm C, Herkel J. Reply to: “Regulatory T cells in autoimmune hepatitis”. J Hepatol.. 2012;57:933–934.CrossRefGoogle Scholar
  255. 255.
    Muratori L, Longhi MS. The interplay between regulatory and effector T cells in autoimmune hepatitis: implications for innovative treatment strategies. J Autoimmun. 2013;46:74–80.PubMedCrossRefGoogle Scholar
  256. 256.
    Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol. 2007;25:297–336.PubMedCrossRefGoogle Scholar
  257. 257.
    Swain MG. Hepatic NKT cells: friend or foe? Clin Sci. 2008;114:457–466.PubMedCrossRefGoogle Scholar
  258. 258.
    Santodomingo-Garzon T, Swain MG. Role of NKT cells in autoimmune liver disease. Autoimmun Rev. 2011;10:793–800.PubMedCrossRefGoogle Scholar
  259. 259.
    Mattner J. Natural killer T (NKT) cells in autoimmune hepatitis. Curr Opin Immunol. 2013;25:697–703.PubMedCentralPubMedCrossRefGoogle Scholar
  260. 260.
    Van Kaer L. NKT cells: T lymphocytes with innate effector functions. Curr Opin Immunol. 2007;19:354–364.PubMedCrossRefGoogle Scholar
  261. 261.
    Exley MA, Koziel MJ. To be or not to be NKT: natural killer T cells in the liver. Hepatology. 2004;40:1033–1040.PubMedCrossRefGoogle Scholar
  262. 262.
    Geissmann F, Cameron TO, Sidobre S, et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 2005;3:e113.PubMedCentralPubMedCrossRefGoogle Scholar
  263. 263.
    Johnston B, Kim CH, Soler D, Emoto M, Butcher EC. Differential chemokine responses and homing patterns of murine TCR alpha beta NKT cell subsets. J Immunol. 2003;171:2960–2969.PubMedCrossRefGoogle Scholar
  264. 264.
    Thomas SY, Hou R, Boyson JE, et al. CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. J Immunol. 2003;171:2571–2580.PubMedCrossRefGoogle Scholar
  265. 265.
    Kumar V. NKT-cell subsets: promoters and protectors in inflammatory liver disease. J Hepatol. 2013;59:618–620.PubMedCentralPubMedCrossRefGoogle Scholar
  266. 266.
    Zhou D, Mattner J, Cantu C 3rd, et al. Lysosomal glycosphingolipid recognition by NKT cells. Science. 2004;306:1786–1789.PubMedCrossRefGoogle Scholar
  267. 267.
    Lalazar G, Preston S, Zigmond E. Ben Yaacov A, Ilan Y. Glycolipids as immune modulatory tools. Mini Rev Med Chem. 2006;6:1249–1253.PubMedCrossRefGoogle Scholar
  268. 268.
    Girardi E, Maricic I, Wang J, et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat Immunol. 2012;13:851–856.PubMedCentralPubMedCrossRefGoogle Scholar
  269. 269.
    Swain MG. Natural killer T cells within the liver: conductors of the hepatic immune orchestra. Dig Dis. 2010;28:7–13.PubMedCrossRefGoogle Scholar
  270. 270.
    La Cava A, Van Kaer L. Fu Dong S. CD4+ CD25+ Tregs and NKT cells: regulators regulating regulators. Trends Immunol. 2006;27:322–327.PubMedCrossRefGoogle Scholar
  271. 271.
    Nakano M, Saeki C, Takahashi H, et al. Activated natural killer T cells producing interferon-gamma elicit promoting activity to murine dendritic cell-based autoimmune hepatic inflammation. Clin Exp Immunol. 2012;170:274–282.PubMedCentralPubMedCrossRefGoogle Scholar
  272. 272.
    Biburger M, Tiegs G. Alpha-galactosylceramide-induced liver injury in mice is mediated by TNF-alpha but independent of Kupffer cells. J Immunol. 2005;175:1540–1550.PubMedCrossRefGoogle Scholar
  273. 273.
    Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13:139–145.PubMedCrossRefGoogle Scholar
  274. 274.
    Sprengers D, Sille FC, Derkow K, et al. Critical role for CD1d-restricted invariant NKT cells in stimulating intrahepatic CD8 T-cell responses to liver antigen. Gastroenterology. 2008;134:2132–2143.PubMedCrossRefGoogle Scholar
  275. 275.
    Kaneko Y, Harada M, Kawano T, et al. Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis. J Exp Med. 2000;191:105–114.PubMedCentralPubMedCrossRefGoogle Scholar
  276. 276.
    Linsen L, Somers V, Stinissen P. Immunoregulation of autoimmunity by natural killer T cells. Hum Immunol. 2005;66:1193–1202.PubMedCrossRefGoogle Scholar
  277. 277.
    Nowak M, Stein-Streilein J. Invariant NKT cells and tolerance. Int Rev Immunol. 2007;26:95–119.PubMedCrossRefGoogle Scholar
  278. 278.
    Park O, Jeong WI, Wang L, et al. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology. 2009;49:1683–1694.PubMedCentralPubMedCrossRefGoogle Scholar
  279. 279.
    Berzins SP, Smyth MJ, Baxter AG. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol. 2011;11:131–142.PubMedCrossRefGoogle Scholar
  280. 280.
    Blomqvist M, Rhost S, Teneberg S, et al. Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur J Immunol. 2009;39:1726–1735.PubMedCentralPubMedCrossRefGoogle Scholar
  281. 281.
    Arrenberg P, Maricic I, Kumar V. Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice. Gastroenterology. 2011;140:646–655.PubMedCentralPubMedCrossRefGoogle Scholar
  282. 282.
    Halder RC, Aguilera C, Maricic I, Kumar V. Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. J Clin Invest. 2007;117:2302–2312.PubMedCentralPubMedCrossRefGoogle Scholar
  283. 283.
    Joshi SK, Lang ML. Fine tuning a well-oiled machine: influence of NK1.1 and NKG2D on NKT cell development and function. Int Immunopharmacol. 2013;17:260–266.PubMedCentralPubMedCrossRefGoogle Scholar
  284. 284.
    Zhu R, Diem S, Araujo LM, et al. The Pro-Th1 cytokine IL-12 enhances IL-4 production by invariant NKT cells: relevance for T cell-mediated hepatitis. J Immunol. 2007;178:5435–5442.PubMedCrossRefGoogle Scholar
  285. 285.
    Lee KA, Song YC, Kim GY, et al. Retinoic acid alleviates Con A-induced hepatitis and differentially regulates effector production in NKT cells. Eur J Immunol. 2012;42:1685–1694.PubMedCrossRefGoogle Scholar
  286. 286.
    Deng ZB, Zhuang X, Ju S, et al. Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells. J Immunol. 2013;190:3579–3589.PubMedCentralPubMedCrossRefGoogle Scholar
  287. 287.
    Kawamura T, Takeda K, Kaneda H, et al. NKG2A inhibits invariant NKT cell activation in hepatic injury. J Immunol. 2009;182:250–258.PubMedCentralPubMedCrossRefGoogle Scholar
  288. 288.
    Vilarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA. 2007;104:18187–18192.PubMedCentralPubMedCrossRefGoogle Scholar
  289. 289.
    Yoshiga Y, Goto D, Segawa S, et al. Activation of natural killer T cells by alpha-carba-GalCer (RCAI-56), a novel synthetic glycolipid ligand, suppresses murine collagen-induced arthritis. Clin Exp Immunol. 2011;164:236–247.PubMedCentralPubMedCrossRefGoogle Scholar
  290. 290.
    Yang JQ, Kim PJ, Singh RR. Brief treatment with iNKT cell ligand alpha-galactosylceramide confers a long-term protection against lupus. J Clin Immunol. 2012;32:106–113.PubMedCentralPubMedCrossRefGoogle Scholar
  291. 291.
    Kadri N, Blomqvist M, Cardell SL. Type II natural killer T cells: a new target for immunomodulation? Expert Rev Clin Immunol. 2008;4:615–627.PubMedCrossRefGoogle Scholar
  292. 292.
    Czaja AJ. Current and prospective pharmacotherapy for autoimmune hepatitis. Expert Opin Pharmacother. 2014;15:1715–1736.PubMedCrossRefGoogle Scholar
  293. 293.
    Aoki N, Kido M, Iwamoto S, et al. Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice. Gastroenterology. 2011;140:1322 e1321–1325 e1321.CrossRefGoogle Scholar
  294. 294.
    Maruoka R, Aoki N, Kido M, et al. Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis. Gastroenterology. 2013;145:209 e209–220 e209.CrossRefGoogle Scholar
  295. 295.
    Hammerich L, Tacke F. Role of gamma-delta T cells in liver inflammation and fibrosis. World J Gastrointest Pathophysiol. 2014;5:107–113.PubMedCentralPubMedGoogle Scholar
  296. 296.
    Holtmeier W, Kabelitz D. gammadelta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151–183.PubMedCrossRefGoogle Scholar
  297. 297.
    Born WK, Reardon CL, O’Brien RL. The function of gammadelta T cells in innate immunity. Curr Opin Immunol. 2006;18:31–38.PubMedCrossRefGoogle Scholar
  298. 298.
    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;22:191–217.PubMedCrossRefGoogle Scholar
  299. 299.
    Bonneville M, O’Brien RL, Born WK. Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol. 2010;10:467–478.PubMedCrossRefGoogle Scholar
  300. 300.
    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;89:78–82.PubMedCentralPubMedCrossRefGoogle Scholar
  301. 301.
    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;23:988–993.PubMedGoogle Scholar
  302. 302.
    Dong Z, Saikumar P, Weinberg JM, Venkatachalam MA. Internucleosomal DNA cleavage triggered by plasma membrane damage during necrotic cell death. Involvement of serine but not cysteine proteases. Am J Pathol. 1997;151:1205–1213.PubMedCentralPubMedGoogle Scholar
  303. 303.
    Canbay A, Friedman S, Gores GJ. Apoptosis: the nexus of liver injury and fibrosis. Hepatology. 2004;39:273–278.PubMedCrossRefGoogle Scholar
  304. 304.
    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;7:307–315.PubMedCrossRefGoogle Scholar
  305. 305.
    Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol. 2014;20:2515–2532.PubMedCentralPubMedCrossRefGoogle Scholar
  306. 306.
    Czaja AJ. Review article: prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther. 2014;39:385–406.PubMedCrossRefGoogle Scholar
  307. 307.
    Sanz-Cameno P, Medina J, Garcia-Buey L, et al. Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis. J Hepatol. 2002;37:723–729.PubMedCrossRefGoogle Scholar
  308. 308.
    Beyazit Y, Efe C, Tanoglu A, et al. Nitric oxide is a potential mediator of hepatic inflammation and fibrogenesis in autoimmune hepatitis. Scand J Gastroenterol. 2015;50:204–210.PubMedCrossRefGoogle Scholar
  309. 309.
    Pemberton PW, Aboutwerat A, Smith A, et al. Oxidant stress in type I autoimmune hepatitis: the link between necroinflammation and fibrogenesis? Biochim Biophys Acta. 2004;1689:182–189.PubMedCrossRefGoogle Scholar
  310. 310.
    Codoner-Franch P, Tavarez-Alonso S, Simo-Jorda R, et al. Vitamin D status is linked to biomarkers of oxidative stress, inflammation, and endothelial activation in obese children. J Pediatr. 2012;161:848–854.PubMedCrossRefGoogle Scholar
  311. 311.
    Asemi Z, Samimi M, Tabassi Z, Shakeri H, Esmaillzadeh A. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013;143:1432–1438.PubMedCrossRefGoogle Scholar
  312. 312.
    Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis.. 2007;66:1137–1142.PubMedCentralPubMedCrossRefGoogle Scholar
  313. 313.
    Smyk DS, Orfanidou T, Invernizzi P, Bogdanos DP, Lenzi M. Vitamin D in autoimmune liver disease. Clin Res Hepatol Gastroenterol. 2013;37:535–545.PubMedCrossRefGoogle Scholar
  314. 314.
    Petta S, Camma C, Scazzone C, et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51:1158–1167.PubMedCrossRefGoogle Scholar
  315. 315.
    Farnik H, Bojunga J, Berger A, et al. Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. Hepatology. 2013;58:1270–1276.PubMedCrossRefGoogle Scholar
  316. 316.
    Trepo E, Ouziel R, Pradat P, et al. Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease. J Hepatol. 2013;59:344–350.PubMedCrossRefGoogle Scholar
  317. 317.
    Dasarathy J, Periyalwar P, Allampati S, et al. Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease. Liver Int. 2014;34:e118–e127.PubMedCentralPubMedCrossRefGoogle Scholar
  318. 318.
    Wong GL, Chan HL, Chan HY, et al. Adverse effects of vitamin D deficiency on outcomes of patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2015;13:783–790.PubMedCrossRefGoogle Scholar
  319. 319.
    Efe C, Kav T, Aydin C, et al. Low serum vitamin D levels are associated with severe histological features and poor response to therapy in patients with autoimmune hepatitis. Dig Dis Sci. 2014;59:3035–3042.PubMedCrossRefGoogle Scholar
  320. 320.
    Beyazit Y, Kocak E, Tanoglu A, Kekilli M. Oxidative stress might play a role in low serum vitamin D associated liver fibrosis among patients with autoimmune hepatitis. Dig Dis Sci. (Epub ahead of print). doi: 10.1007/s10620-015-3526-y.
  321. 321.
    Masuoka HC, Guicciardi ME, Gores GJ. Caspase inhibitors for the treatment of hepatitis C. Clin Liver Dis. 2009;13:467–475.PubMedCentralPubMedCrossRefGoogle Scholar
  322. 322.
    Anstee QM, Concas D, Kudo H, et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J Hepatol. 2010;53:542–550.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Professor Emeritus of Medicine, Division of Gastroenterology and HepatologyMayo Clinic College of MedicineRochesterUSA

Personalised recommendations