Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell–rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Waldenström J. 1.  1950. Leber, Blutproteine und Nahrungseiweiss. Dtsch. Gesellsch. Verd. Stoffw. 15:113–19 [Google Scholar]
  2. Corrigan M, Hirschfield GM, Oo YH, Adams DH. 2.  2015. Autoimmune hepatitis: an approach to disease understanding and management. Br. Med. Bull. 114:181–91 [Google Scholar]
  3. Liberal R, Grant CR, Mieli-Vergani G, Vergani D. 3.  2013. Autoimmune hepatitis: a comprehensive review. J. Autoimmun. 41:126–39 [Google Scholar]
  4. Mieli-Vergani G, Vergani D. 4.  2011. Autoimmune hepatitis. Nat. Rev. Gastroenterol. Hepatol. 8:320–29 [Google Scholar]
  5. Dyson JK, Webb G, Hirschfield GM, Lohse A, Beuers U. 5.  et al. 2015. Unmet clinical need in autoimmune liver diseases. J. Hepatol. 62:208–18 [Google Scholar]
  6. van Gerven NM, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR. 6.  et al. 2014. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand. J. Gastroenterol. 49:1245–54 [Google Scholar]
  7. Gronbaek L, Vilstrup H, Jepsen P. 7.  2014. Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J. Hepatol. 60:612–17 [Google Scholar]
  8. Toda G, Zeniya M, Watanabe F, Imawari M, Kiyosawa K. 8.  et al. 1997. Present status of autoimmune hepatitis in Japan—correlating the characteristics with international criteria in an area with a high rate of HCV infection. Japanese National Study Group of Autoimmune Hepatitis. J. Hepatol. 26:1207–12 [Google Scholar]
  9. Jacobson DL, Gange SJ, Rose NR, Graham NM. 9.  1997. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 84:223–43 [Google Scholar]
  10. Cooper GS, Stroehla BC. 10.  2003. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2:119–25 [Google Scholar]
  11. Webb G, Rana A, Akhtar MZ, Ferguson JW, Neuberger JM. 11.  et al. 2016. Examining unmet need: international trends in transplantation for autoimmune liver disease. Hepatology 63:702A [Google Scholar]
  12. 12. Eur. Assoc. Study Liver. 2015. EASL clinical practice guidelines: autoimmune hepatitis. J. Hepatol. 63:971–1004 [Google Scholar]
  13. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G. 13.  et al. 2010. Diagnosis and management of autoimmune hepatitis. Hepatology 51:2193–213 [Google Scholar]
  14. Heneghan MA, Norris SM, O'Grady JG, Harrison PM, McFarlane IG. 14.  2001. Management and outcome of pregnancy in autoimmune hepatitis. Gut 48:97–102 [Google Scholar]
  15. Fontana RJ. 15.  2014. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology 146:914–28 [Google Scholar]
  16. Björnsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N. 16.  et al. 2010. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 51:2040–48 [Google Scholar]
  17. Dhaliwal HK, Hoeroldt BS, Dube AK, McFarlane E, Underwood JC. 17.  et al. 2015. Long-term prognostic significance of persisting histological activity despite biochemical remission in autoimmune hepatitis. Am. J. Gastroenterol. 110:993–99 [Google Scholar]
  18. Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG. 18.  et al. 1997. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 25:541–47 [Google Scholar]
  19. Zachou K, Gatselis N, Papadamou G, Rigopoulou EI, Dalekos GN. 19.  2011. Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naïve patients. J. Hepatol. 55:636–46 [Google Scholar]
  20. Weiler-Normann C, Schramm C, Quaas A, Wiegard C, Glaubke C. 20.  et al. 2013. Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J. Hepatol. 58:529–34 [Google Scholar]
  21. van Gerven NM, Verwer BJ, Witte BI, van Hoek B, Coenraad MJ. 21.  et al. 2013. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J. Hepatol. 58:141–47 [Google Scholar]
  22. Gautam M, Cheruvattath R, Balan V. 22.  2006. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl 12:1813–24 [Google Scholar]
  23. Montano-Loza AJ, Mason AL, Ma M, Bastiampillai RJ, Bain VG, Tandon P. 23.  2009. Risk factors for recurrence of autoimmune hepatitis after liver transplantation. Liver Transpl 15:1254–61 [Google Scholar]
  24. Calne RY, Sells RA, Pena JR, Davis DR, Millard PR. 24.  et al. 1969. Induction of immunological tolerance by porcine liver allografts. Nature 223:472–76 [Google Scholar]
  25. Simpson N, Cho YW, Cicciarelli JC, Selby RR, Fong TL. 25.  2006. Comparison of renal allograft outcomes in combined liver-kidney transplantation versus subsequent kidney transplantation in liver transplant recipients: analysis of UNOS database. Transplantation 82:1298–303 [Google Scholar]
  26. Navarro V, Herrine S, Katopes C, Colombe B, Spain CV. 26.  2006. The effect of HLA class I (A and B) and class II (DR) compatibility on liver transplantation outcomes: an analysis of the OPTN database. Liver Transpl 12:652–58 [Google Scholar]
  27. Devlin J, Doherty D, Thomson L, Wong T, Donaldson P. 27.  et al. 1998. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 27:926–33 [Google Scholar]
  28. Cantor HM, Dumont AE. 28.  1967. Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature 215:744–45 [Google Scholar]
  29. Carambia A, Freund B, Schwinge D, Heine M, Laschtowitz A. 29.  et al. 2014. TGF-beta-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells. J. Hepatol. 61:594–99 [Google Scholar]
  30. Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C. 30.  et al. 2015. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62:279–91 [Google Scholar]
  31. Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM. 31.  2004. Immunopathogenesis of schistosomiasis. Immunol. Rev. 201:156–67 [Google Scholar]
  32. Chang JJ, Lewin SR. 32.  2007. Immunopathogenesis of hepatitis B virus infection. Immunol. Cell Biol. 85:16–23 [Google Scholar]
  33. Crispe IN. 33.  2009. The liver as a lymphoid organ. Annu. Rev. Immunol. 27:147–63 [Google Scholar]
  34. Kubitz R, Droge C, Kluge S, Stross C, Walter N. 34.  et al. 2015. Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis. Clin. Rev. Allergy Immunol. 48:273–84 [Google Scholar]
  35. Jara P, Hierro L, Martinez-Fernandez P, Alvarez-Doforno R, Yanez F. 35.  et al. 2009. Recurrence of bile salt export pump deficiency after liver transplantation. N. Engl. J. Med. 361:1359–67 [Google Scholar]
  36. Klein I, Crispe IN. 36.  2006. Complete differentiation of CD8+ T cells activated locally within the transplanted liver. J. Exp. Med. 203:437–47 [Google Scholar]
  37. Derkow K, Loddenkemper C, Mintern J, Kruse N, Klugewitz K. 37.  et al. 2007. Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis. Hepatology 46:1155–65 [Google Scholar]
  38. Tay SS, Wong YC, Roediger B, Sierro F, Lu B. 38.  et al. 2014. Intrahepatic activation of naive CD4+ T cells by liver-resident phagocytic cells. J. Immunol. 193:2087–95 [Google Scholar]
  39. Hübscher SG. 39.  2014. Role of liver biopsy in autoimmune liver disease. Diagn. Histopathol. 20:109–18 [Google Scholar]
  40. Czaja AJ, Carpenter HA. 40.  1993. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology 105:1824–32 [Google Scholar]
  41. Miao Q, Bian Z, Tang R, Zhang H, Wang Q. 41.  et al. 2015. Emperipolesis mediated by CD8 T cells is a characteristic histopathologic feature of autoimmune hepatitis. Clin. Rev. Allergy Immunol. 48:226–35 [Google Scholar]
  42. Bach N, Thung SN, Schaffner F. 42.  1992. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis. Hepatology 15:572–77 [Google Scholar]
  43. De Luca-Johnson J, Wangensteen KJ, Hanson J, Krawitt E, Wilcox R. 43.  2016. Natural history of patients presenting with autoimmune hepatitis and coincident nonalcoholic fatty liver disease. Dig. Dis. Sci. 61:2710–20 [Google Scholar]
  44. Czaja AJ, Carpenter HA. 44.  2001. Autoimmune hepatitis with incidental histologic features of bile duct injury. Hepatology 34:659–65 [Google Scholar]
  45. Washington MK, Manns MP. 45.  2012. Autoimmune hepatitis. MacSween's Pathology of the Liver BC Portmann, LD Ferrell 467–90 Edinburgh, Scotl.: Churchill Livingstone, 6th ed.. [Google Scholar]
  46. Portmann B, Zen Y. 46.  2012. Inflammatory disease of the bile ducts-cholangiopathies: liver biopsy challenge and clinicopathological correlation. Histopathology 60:236–48 [Google Scholar]
  47. Norris S, Collins C, Doherty DG, Smith F, McEntee G. 47.  et al. 1998. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J. Hepatol. 28:84–90 [Google Scholar]
  48. Löhr HF, Schlaak JF, Gerken G, Fleischer B, Dienes HP. 48.  et al. 1994. Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver 14:161–66 [Google Scholar]
  49. Senaldi G, Portmann B, Mowat AP, Mieli-Vergani G, Vergani D. 49.  1992. Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis. Arch. Dis. Child. 67:1447–53 [Google Scholar]
  50. De Biasio MB, Periolo N, Avagnina A, Garcia de Davila MT, Ciocca M. 50.  et al. 2006. Liver infiltrating mononuclear cells in children with type 1 autoimmune hepatitis. J. Clin. Pathol. 59:417–23 [Google Scholar]
  51. Senaldi G, Portmann B, Mowat AP, Mieli-Vergani G, Vergani D. 51.  1992. Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis. Arch. Dis. Child. 67:1447–53 [Google Scholar]
  52. Yoshizawa K, Ota M, Katsuyama Y, Ichijo T, Inada H. 52.  et al. 1999. T cell repertoire in the liver of patients with autoimmune hepatitis. Hum. Immunol. 60:806–15 [Google Scholar]
  53. Arenz M, zum Büschenfelde K, Löhr HF. 53.  1998. Limited T cell receptor Vβ-chain repertoire of liver-infiltrating T cells in autoimmune hepatitis. J. Hepatol. 28:70–77 [Google Scholar]
  54. Purswani S, Reynolds G, Smith R, Davies S, Triantafyllou E. 54.  et al. 2014. B-cell subpopulations in the human liver are distinct from blood, can be expanded locally and vary among liver diseases. Immunology 143:70–71 [Google Scholar]
  55. Daniels JA, Torbenson M, Anders RA, Boitnott JK. 55.  2009. Immunostaining of plasma cells in primary biliary cirrhosis. Am. J. Clin. Pathol. 131:243–49 [Google Scholar]
  56. Vergani D, Alvarez F, Bianchi FB, Cancado EL, Mackay IR. 56.  et al. 2004. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J. Hepatol. 41:677–83 [Google Scholar]
  57. Deane KD, El-Gabalawy H. 57.  2014. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE. Nat. Rev. Rheumatol. 10:212–28 [Google Scholar]
  58. Leslie D, Lipsky P, Notkins AL. 58.  2001. Autoantibodies as predictors of disease. J. Clin. Invest. 108:1417–22 [Google Scholar]
  59. Csepregi A, Szodoray P, Zeher M. 59.  2002. Do autoantibodies predict autoimmune liver disease in primary Sjogren's syndrome? Data of 180 patients upon a 5 year follow-up. Scand. J. Immunol. 56:623–29 [Google Scholar]
  60. Kisand KE, Metskula K, Kisand KV, Kivik T, Gershwin ME, Uibo R. 60.  2001. The follow-up of asymptomatic persons with antibodies to pyruvate dehydrogenase in adult population samples. J. Gastroenterol. 36:248–54 [Google Scholar]
  61. Ahonen P, Miettinen A, Perheentupa J. 61.  1987. Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. J. Clin. Endocrinol. Metab. 64:494–500 [Google Scholar]
  62. Obermayer-Straub P, Strassburg CP, Manns MP. 62.  2000. Autoimmune polyglandular syndrome type 1. Clin. Rev. Allergy Immunol. 18:167–83 [Google Scholar]
  63. Zachou K, Rigopoulou E, Dalekos GN. 63.  2004. Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease. J. Autoimmune Dis. 1:2 [Google Scholar]
  64. Czaja AJ. 64.  1999. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J. Hepatol. 30:394–401 [Google Scholar]
  65. Jensen DM, McFarlane IG, Portmann BS, Eddleston AL, Williams R. 65.  1978. Detection of antibodies directed against a liver-specific membrane lipoprotein in patients with acute and chronic active hepatitis. N. Engl. J. Med. 299:1–7 [Google Scholar]
  66. Bottazzo GF, Florin-Christensen A, Fairfax A, Swana G, Doniach D, Groeschel-Stewart U. 66.  1976. Classification of smooth muscle autoantibodies detected by immunofluorescence. J. Clin. Pathol. 29:403–10 [Google Scholar]
  67. Loeper J, Descatoire V, Maurice M, Beaune P, Belghiti J. 67.  et al. 1993. Cytochromes P-450 in human hepatocyte plasma membrane: recognition by several autoantibodies. Gastroenterology 104:203–16 [Google Scholar]
  68. Vergani D, Mieli-Vergani G, Mondelli M, Portmann B, Eddleston AL. 68.  1987. Immunoglobulin on the surface of isolated hepatocytes is associated with antibody-dependent cell-mediated cytotoxicity and liver damage. Liver 7:307–15 [Google Scholar]
  69. Vergani GM, Vergani D, Jenkins PJ, Portmann B, Mowat AP. 69.  et al. 1979. Lymphocyte cytotoxicity to autologous hepatocytes in HBsAg-negative chronic active hepatitis. Clin. Exp. Immunol. 38:16–21 [Google Scholar]
  70. Cochrane AM, Moussouros A, Thomsom AD, Eddleston AL, Wiiliams R. 70.  1976. Antibody-dependent cell-mediated (K cell) cytotoxicity against isolated hepatocytes in chronic active hepatitis. Lancet 1:441–44 [Google Scholar]
  71. Manns M, Zanger U, Gerken G, Sullivan KF, Meyer zum Buschenfelde KH. 71.  et al. 1990. 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 12:127–32 [Google Scholar]
  72. Hardtke-Wolenski M, Fischer K, Noyan F, Schlue J, Falk CS. 72.  et al. 2013. Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4+ T cells. Hepatology 58:718–28 [Google Scholar]
  73. Butler RC. 73.  1984. Studies on experimental chronic active hepatitis in the rabbit. II. Immunological findings. Br. J. Exp. Pathol. 65:509–19 [Google Scholar]
  74. Webb GJ, Hirschfield GM. 74.  2016. Using GWAS to identify genetic predisposition in hepatic autoimmunity. J. Autoimmun. 66:25–39 [Google Scholar]
  75. Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P. 75.  et al. 2008. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLOS Genet 4:e1000024 [Google Scholar]
  76. Strettell MD, Donaldson PT, Thomson LJ, Santrach PJ, Moore SB. 76.  et al. 1997. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology 112:2028–35 [Google Scholar]
  77. Doherty DG, Donaldson PT, Underhill JA, Farrant JM, Duthie A. 77.  et al. 1994. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology 19:609–15 [Google Scholar]
  78. Czaja AJ, Strettell MD, Thomson LJ, Santrach PJ, Moore SB. 78.  et al. 1997. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 25:317–23 [Google Scholar]
  79. de Boer YS, van Gerven NMF, Zwiers A, Verwer BJ, van Hoek B. 79.  et al. 2014. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 147:443–52 [Google Scholar]
  80. Pando M, Larriba J, Fernandez GC, Fainboim H, Ciocca M. 80.  et al. 1999. Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 30:1374–80 [Google Scholar]
  81. Bittencourt PL, Goldberg AC, Cancado EL, Porta G, Carrilho FJ. 81.  et al. 1999. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am. J. Gastroenterol. 94:1906–13 [Google Scholar]
  82. Yoshizawa K, Ota M, Katsuyama Y, Ichijo T, Matsumoto A. 82.  et al. 2005. Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis. J. Hepatol. 42:578–84 [Google Scholar]
  83. Vazquez-Garcia MN, Alaez C, Olivo A, Debaz H, Perez-Luque E. 83.  et al. 1998. MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis. J. Hepatol. 28:985–90 [Google Scholar]
  84. Amarapurkar DN, Patel ND, Amarapurkar AD, Kankonkar SR. 84.  2003. HLA genotyping in type-I autoimmune hepatitis in Western India. J. Assoc. Phys. India 51:967–69 [Google Scholar]
  85. van Gerven NMF, de Boer YS, Zwiers A, Verwer BJ, Drenth JPH. 85.  et al. 2015. HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun 16:247–52 [Google Scholar]
  86. Kirstein MM, Metzler F, Geiger E, Heinrich E, Hallensleben M. 86.  et al. 2015. Prediction of short- and long-term outcome in patients with autoimmune hepatitis. Hepatology 62:1524–35 [Google Scholar]
  87. Ma Y, Bogdanos DP, Hussain MJ, Underhill J, Bansal S. 87.  et al. 2006. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology 130:868–82 [Google Scholar]
  88. Czaja AJ, Donaldson PT, Lohse AW. 88.  2002. Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis. Am. J. Gastroenterol. 97:413–19 [Google Scholar]
  89. Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR. 89.  et al. 2002. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 35:658–64 [Google Scholar]
  90. Gough SC, Simmonds MJ. 90.  2007. The HLA region and autoimmune disease: associations and mechanisms of action. Curr. Genom. 8:453–65 [Google Scholar]
  91. Gromme M, Neefjes J. 91.  2002. Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways. Mol. Immunol. 39:181–202 [Google Scholar]
  92. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z. 92.  et al. 2012. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486:554–58 [Google Scholar]
  93. Monshi MM, Faulkner L, Gibson A, Jenkins RE, Farrell J. 93.  et al. 2013. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology 57:727–39 [Google Scholar]
  94. Katayama H, Mori T, Seki Y, Anraku M, Iseki M. 94.  et al. 2014. Lnk prevents inflammatory CD8+ T-cell proliferation and contributes to intestinal homeostasis. Eur. J. Immunol. 44:1622–32 [Google Scholar]
  95. Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G. 95.  et al. 2010. Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am. J. Hum. Genet. 86:970–77 [Google Scholar]
  96. Konig IR. 96.  2011. Validation in genetic association studies. Brief Bioinform 12:253–58 [Google Scholar]
  97. Agarwal K, Czaja AJ, Jones DE, Donaldson PT. 97.  2000. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 31:49–53 [Google Scholar]
  98. Vogel A, Strassburg CP, Manns MP. 98.  2002. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology 35:126–31 [Google Scholar]
  99. Agarwal K, Czaja AJ, Donaldson PT. 99.  2007. A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis. Tissue Antigens 69:227–35 [Google Scholar]
  100. Czaja AJ, Cookson S, Constantini PK, Clare M, Underhill JA, Donaldson PT. 100.  1999. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology 117:645–52 [Google Scholar]
  101. Lu Q. 101.  2013. The critical importance of epigenetics in autoimmunity. J. Autoimmun. 41:1–5 [Google Scholar]
  102. Lleo A, Liao J, Invernizzi P, Zhao M, Bernuzzi F. 102.  et al. 2012. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology 55:153–60 [Google Scholar]
  103. Lleo A, Zhang W, Zhao M, Tan Y, Bernuzzi F. 103.  et al. 2015. DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis. Clin. Epigenet. 7:61 [Google Scholar]
  104. Qin B, Huang F, Liang Y, Yang Z, Zhong R. 104.  2013. Analysis of altered microRNA expression profiles in peripheral blood mononuclear cells from patients with primary biliary cirrhosis. J. Gastroenterol. Hepatol. 28:543–50 [Google Scholar]
  105. Worth A, Thrasher AJ, Gaspar HB. 105.  2006. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br. J. Haematol. 133:124–40 [Google Scholar]
  106. Sneller MC, Wang J, Dale JK, Strober W, Middelton LA. 106.  et al. 1997. Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89:1341–48 [Google Scholar]
  107. Pensati L, Costanzo A, Ianni A, Accapezzato D, Iorio R. 107.  et al. 1997. Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis. Gastroenterology 113:1384–89 [Google Scholar]
  108. Ogawa S, Sakaguchi K, Takaki A, Shiraga K, Sawayama T. 108.  et al. 2000. 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. 15:69–75 [Google Scholar]
  109. Chen YY, Jeffery HC, Hunter S, Bhogal R, Birtwistle J. 109.  et al. 2016. Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis. Hepatology 64:138–50 [Google Scholar]
  110. Cai P, Konig R, Boor PJ, Kondraganti S, Kaphalia BS. 110.  et al. 2008. Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice. Toxicol. Appl. Pharmacol. 228:68–75 [Google Scholar]
  111. Villaseñor J, Benoist C, Mathis D. 111.  2005. AIRE and APECED: molecular insights into an autoimmune disease. Immunol. Rev. 204:156–64 [Google Scholar]
  112. Peterson P, Org T, Rebane A. 112.  2008. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat. Rev. Immunol. 8:948–57 [Google Scholar]
  113. Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D. 113.  2015. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348:589–94 [Google Scholar]
  114. Obermayer-Straub P, Perheentupa J, Braun S, Kayser A, Barut A. 114.  et al. 2001. Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Gastroenterology 121:668–77 [Google Scholar]
  115. Kisand K, Bøe Wolff AS, Podkrajšek KT, Tserel L, Link M. 115.  et al. 2010. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207:299–308 [Google Scholar]
  116. Lankisch TO, Strassburg CP, Debray D, Manns MP, Jacquemin E. 116.  2005. Detection of autoimmune regulator gene mutations in children with type 2 autoimmune hepatitis and extrahepatic immune-mediated diseases. J. Pediatr. 146:839–42 [Google Scholar]
  117. Hardtke-Wolenski M, Taubert R, Noyan F, Sievers M, Dywicki J. 117.  et al. 2015. Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens. Hepatology 61:1295–305 [Google Scholar]
  118. Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T. 118.  et al. 2015. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975–87 [Google Scholar]
  119. Godfrey VL, Wilkinson JE, Russell LB. 119.  1991. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138:1379–87 [Google Scholar]
  120. Zhang W, Sharma R, Ju S-T, He X-S, Tao Y. 120.  et al. 2008. Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology 49:545–52 [Google Scholar]
  121. Tsuda M, Torgerson TR, Selmi C, Gambineri E, Carneiro-Sampaio M. 121.  et al. 2010. The spectrum of autoantibodies in IPEX syndrome is broad and includes anti-mitochondrial autoantibodies. J. Autoimmun. 35:265–68 [Google Scholar]
  122. Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J. 122.  et al. 2007. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204:57–63 [Google Scholar]
  123. Walker LS, Sansom DM. 123.  2011. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 11:852–63 [Google Scholar]
  124. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. 124.  1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–47 [Google Scholar]
  125. Klocke K, Sakaguchi S, Holmdahl R, Wing K. 125.  2016. Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. PNAS 113:E2383–92 [Google Scholar]
  126. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB. 126.  et al. 2014. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20:1410–16 [Google Scholar]
  127. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE. 127.  et al. 2014. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345:1623–27 [Google Scholar]
  128. Lee S, Moon JS, Lee CR, Kim HE, Baek SM. 128.  et al. 2016. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J. Allergy Clin. Immunol. 137:327–30 [Google Scholar]
  129. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K. 129.  et al. 2013. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210:1695–710 [Google Scholar]
  130. Graff JN, Puri S, Bifulco CB, Fox BA, Beer TM. 130.  2014. Sustained complete response to CTLA-4 blockade in a patient with metastatic, castration-resistant prostate cancer. Cancer Immunol. Res. 2:399–403 [Google Scholar]
  131. Kim KW, Ramaiya NH, Krajewski KM, Jagannathan JP, Tirumani SH. 131.  et al. 2013. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest. New Drugs 31:1071–77 [Google Scholar]
  132. Metushi IG, Hayes MA, Uetrecht J. 132.  2015. Treatment of PD-1−/− mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients. Hepatology 61:1332–42 [Google Scholar]
  133. Agarwal K, Jones DE, Daly AK, James OF, Vaidya B. 133.  et al. 2000. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J. Hepatol. 32:538–41 [Google Scholar]
  134. Webb GJ, Siminovitch KA, Hirschfield GM. 134.  2015. The immunogenetics of primary biliary cirrhosis: a comprehensive review. J. Autoimmun. 64:42–52 [Google Scholar]
  135. Webb G, Chen YY, Li KK, Neil D, Oo YH. 135.  et al. 2016. Single-gene association between GATA-2 and autoimmune hepatitis: a novel genetic insight highlighting immunologic pathways to disease. J. Hepatol. 64:1190–93 [Google Scholar]
  136. Gao X, Johnson KD, Chang YI, Boyer ME, Dewey CN. 136.  et al. 2013. Gata2 cis-element is required for hematopoietic stem cell generation in the mammalian embryo. J. Exp. Med. 210:2833–42 [Google Scholar]
  137. Dickinson RE, Milne P, Jardine L, Zandi S, Swierczek SI. 137.  et al. 2014. The evolution of cellular deficiency in GATA2 mutation. Blood 123:863–74 [Google Scholar]
  138. Fujinami RS, von Herrath MG, Christen U, Whitton JL. 138.  2006. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin. Microbiol. Rev. 19:80–94 [Google Scholar]
  139. Gregorio GV, Choudhuri K, Ma Y, Pensati P, Iorio R. 139.  et al. 2003. 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. 133:404–13 [Google Scholar]
  140. Gregorio GV, Choudhuri K, Ma Y, Vegnente A, Mieli-Vergani G, Vergani D. 140.  1999. Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection. J. Immunol. 162:1802–10 [Google Scholar]
  141. Clifford BD, Donahue D, Smith L, Cable E, Luttig B. 141.  et al. 1995. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 21:613–19 [Google Scholar]
  142. Nishiguchi S, Kuroki T, Ueda T, Fukuda K, Takeda T. 142.  et al. 1992. Detection of hepatitis C virus antibody in the absence of viral RNA in patients with autoimmune hepatitis. Ann. Intern. Med. 116:21–25 [Google Scholar]
  143. Garcia-Buey L, Garcia-Monzon C, Rodriguez S, Borque MJ, Garcia-Sanchez A. 143.  et al. 1995. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology 108:1770–77 [Google Scholar]
  144. Berardi S, Lodato F, Gramenzi A, D'Errico A, Lenzi M. 144.  et al. 2007. High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?. Gut 56:237–42 [Google Scholar]
  145. Fattovich G, Giustina G, Favarato S, Ruol A. 145.  1996. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J. Hepatol. 24:38–47 [Google Scholar]
  146. Huppertz HI, Treichel U, Gassel AM, Jeschke R, Meyer zum Buschenfelde KH. 146.  1995. Autoimmune hepatitis following hepatitis A virus infection. J. Hepatol. 23:204–8 [Google Scholar]
  147. Skoog SM, Rivard RE, Batts KP, Smith CI. 147.  2002. Autoimmune hepatitis preceded by acute hepatitis A infection. Am. J. Gastroenterol. 97:1568–69 [Google Scholar]
  148. Vento S, Garofano T, Di Perri G, Dolci L, Concia E, Bassetti D. 148.  1991. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet 337:1183–87 [Google Scholar]
  149. Vento S, Guella L, Mirandola F, Cainelli F, Di Perri G. 149.  et al. 1995. Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 346:608–9 [Google Scholar]
  150. Nobili V, Comparcola D, Sartorelli MR, Devito R, Marcellini M. 150.  2003. Autoimmune hepatitis type 1 after Epstein-Barr virus infection. Pediatr. Infect. Dis. J. 22:387 [Google Scholar]
  151. Castellote J, Guell E, Porta F. 151.  2001. Autoimmune hepatitis following cytomegalovirus infection. Med. Clin. Barc. 117:76 (in Spanish) [Google Scholar]
  152. Nagasaki F, Ueno Y, Mano Y, Igarashi T, Yahagi K. 152.  et al. 2005. A patient with clinical features of acute hepatitis E viral infection and autoimmune hepatitis. Tohoku J. Exp. Med. 206:173–79 [Google Scholar]
  153. Vieira CL, Baldaia C, Fatela N, Ramalho F, Cardoso C. 153.  2013. Case of acute hepatitis E with concomitant signs of autoimmunity. World J. Hepatol. 5:152–55 [Google Scholar]
  154. Fainboim L, Canero Velasco MC, Marcos CY, Ciocca M, Roy A. 154.  et al. 2001. Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis. Hepatology 33:1512–17 [Google Scholar]
  155. van Gerven NMF, van der Eijk AA, Pas SD, Zaaijer HL, de Boer YS. 155.  et al. 2016. Seroprevalence of hepatitis E virus in autoimmune hepatitis patients in the Netherlands. J. Gastrointest. Liver Dis. 25:9–13 [Google Scholar]
  156. Lohse AW, Gerken G, Mohr H, Lohr HF, Treichel U. 156.  et al. 1995. Relation between autoimmune liver diseases and viral hepatitis: clinical and serological characteristics in 859 patients. Z. Gastroenterol. 33:527–33 [Google Scholar]
  157. Liberal R, Mieli-Vergani G, Vergani D. 157.  2016. Contemporary issues and future directions in autoimmune hepatitis. Expert Rev. Gastroenterol. Hepatol. 10:1163–74 [Google Scholar]
  158. Vergani D, Mieli-Vergani G, Alberti A, Neuberger J, Eddleston AL. 158.  et al. 1980. Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. N. Engl. J. Med. 303:66–71 [Google Scholar]
  159. Neuberger J, Mieli-Vergani G, Tredger JM, Davis M, Williams R. 159.  1981. Oxidative metabolism of halothane in the production of altered hepatocyte membrane antigens in acute halothane-induced hepatic necrosis. Gut 22:669–72 [Google Scholar]
  160. Gut J, Christen U, Frey N, Koch V, Stoffler D. 160.  1995. Molecular mimicry in halothane hepatitis: biochemical and structural characterization of lipoylated autoantigens. Toxicology 97:199–224 [Google Scholar]
  161. Griffin JM, Gilbert KM, Lamps LW, Pumford NR. 161.  2000. CD4+ T-cell activation and induction of autoimmune hepatitis following trichloroethylene treatment in MRL+/+ mice. Toxicol. Sci. 57:345–52 [Google Scholar]
  162. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. 162.  2013. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 144:1419–25 [Google Scholar]
  163. Bourdi M, Tinel M, Beaune PH, Pessayre D. 163.  1994. Interactions of dihydralazine with cytochromes P4501A: a possible explanation for the appearance of anti-cytochrome P4501A2 autoantibodies. Mol. Pharmacol. 45:1287–95 [Google Scholar]
  164. Lecoeur S, Andre C, Beaune PH. 164.  1996. Tienilic acid-induced autoimmune hepatitis: anti-liver and -kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol. Pharmacol. 50:326–33 [Google Scholar]
  165. Lecoeur S, Bonierbale E, Challine D, Gautier JC, Valadon P. 165.  et al. 1994. Specificity of in vitro covalent binding of tienilic acid metabolites to human liver microsomes in relationship to the type of hepatotoxicity: comparison with two directly hepatotoxic drugs. Chem. Res. Toxicol. 7:434–42 [Google Scholar]
  166. Gough A, Chapman S, Wagstaff K, Emery P, Elias E. 166.  1996. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 312:169–72 [Google Scholar]
  167. Appleyard S, Saraswati R, Gorard DA. 167.  2010. Autoimmune hepatitis triggered by nitrofurantoin: a case series. J. Med. Case Rep. 4:311 [Google Scholar]
  168. Bei R, Budillon A, Reale MG, Capuano G, Pomponi D. 168.  et al. 1999. Cryptic epitopes on alpha-fetoprotein induce spontaneous immune responses in hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis patients. Cancer Res 59:5471–74 [Google Scholar]
  169. Laskin CA, Vidins E, Blendis LM, Soloninka CA. 169.  1990. Autoantibodies in alcoholic liver disease. Am. J. Med. 89:129–33 [Google Scholar]
  170. Wang Q, Yang F, Miao Q, Krawitt EL, Gershwin ME, Ma X. 170.  2016. The clinical phenotypes of autoimmune hepatitis: a comprehensive review. J. Autoimmun. 66:98–107 [Google Scholar]
  171. Zhu J, Paul WE. 171.  2008. CD4 T cells: fates, functions, and faults. Blood 112:1557–69 [Google Scholar]
  172. Palmer MT, Weaver CT. 172.  2010. Autoimmunity: increasing suspects in the CD4+ T cell lineup. Nat. Immunol. 11:36–40 [Google Scholar]
  173. Lohr H, Manns M, Kyriatsoulis A, Lohse AW, Trautwein C. 173.  et al. 1991. Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis. Clin. Exp. Immunol. 84:297–302 [Google Scholar]
  174. Wen L, Peakman M, Lobo-Yeo A, McFarlane BM, Mowat AP. 174.  et al. 1990. T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet 336:1527–30 [Google Scholar]
  175. Dienes HP, Hutteroth T, Hess G, Meuer SC. 175.  1987. Immunoelectron microscopic observations on the inflammatory infiltrates and HLA antigens in hepatitis B and non-A, non-B. Hepatology 7:1317–25 [Google Scholar]
  176. Franco A, Barnaba V, Natali P, Balsano C, Musca A, Balsano F. 176.  1988. Expression of class I and class II major histocompatibility complex antigens on human hepatocytes. Hepatology 8:449–54 [Google Scholar]
  177. Ballardini G, Mirakian R, Bianchi FB, Pisi E, Doniach D, Bottazzo GF. 177.  1984. Aberrant expression of HLA-DR antigens on bileduct epithelium in primary biliary cirrhosis: relevance to pathogenesis. Lancet 2:1009–13 [Google Scholar]
  178. Chapman RW, Kelly PM, Heryet A, Jewell DP, Fleming KA. 178.  1988. Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis. Gut 29:422–27 [Google Scholar]
  179. Herkel J, Jagemann B, Wiegard C, Lazaro JF, Lueth S. 179.  et al. 2003. MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocytes. Hepatology 37:1079–85 [Google Scholar]
  180. O'Leary JG, Zachary K, Misdraji J, Chung RT. 180.  2008. De novo autoimmune hepatitis during immune reconstitution in an HIV-infected patient receiving highly active antiretroviral therapy. Clin. Infect. Dis. 46:e12–14 [Google Scholar]
  181. Snowden JA, Heaton DC. 181.  1997. Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity. Br. J. Dermatol. 137:130–32 [Google Scholar]
  182. Neumeister P, Strunk D, Apfelbeck U, Sill H, Linkesch W. 182.  2000. Adoptive transfer of vitiligo after allogeneic bone marrow transplantation for non-Hodgkin's lymphoma. Lancet 355:1334–35 [Google Scholar]
  183. Granito A, Stanzani M, Muratori L, Bogdanos DP, Muratori P. 183.  et al. 2008. LKM1-positive type 2 autoimmune hepatitis following allogenic hematopoietic stem-cell transplantation. Am. J. Gastroenterol. 103:1313–14 [Google Scholar]
  184. Zwolak A, Surdacka A, Daniluk J. 184.  2016. Bcl-2 and Fas expression in peripheral blood leukocytes of patients with alcoholic and autoimmune liver disorders. Hum. Exp. Toxicol. 35:799–807 [Google Scholar]
  185. Yachida M, Kurokohchi K, Arima K, Nishioka M. 185.  1999. Increased bcl-2 expression in lymphocytes and its association with hepatocellular damage in patients with autoimmune hepatitis. Clin. Exp. Immunol. 116:140–45 [Google Scholar]
  186. Toyonaga T, Hino O, Sugai S, Wakasugi S, Abe K. 186.  et al. 1994. Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver. PNAS 91:614–18 [Google Scholar]
  187. Zhao L, Tang Y, You Z, Wang Q, Liang S. 187.  et al. 2011. Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLOS ONE 6:e18909 [Google Scholar]
  188. Lan RYZ, Salunga TL, Tsuneyama K, Lian Z-X, Yang G-X. 188.  et al. 2009. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J. Autoimmun. 32:43–51 [Google Scholar]
  189. Yang C-Y, Ma X, Tsuneyama K, Huang S, Takahashi T. 189.  et al. 2014. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy. Hepatology 59:1944–53 [Google Scholar]
  190. Longhi MS, Liberal R, Holder B, Robson SC, Ma Y. 190.  et al. 2012. Inhibition of interleukin-17 promotes differentiation of CD25 cells into stable T regulatory cells in patients with autoimmune hepatitis. Gastroenterology 142:1526–35 [Google Scholar]
  191. Gagliani N, Vesely MCA, Iseppon A, Brockmann L, Xu H. 191.  et al. 2015. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523:221–25 [Google Scholar]
  192. Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P. 192.  et al. 2010. A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 52:999–1007 [Google Scholar]
  193. Liberal R, Grant CR, Holder BS, Cardone J, Martínez-Llordella M. 193.  et al. 2015. In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression. Hepatology 62:863–75 [Google Scholar]
  194. Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G. 194.  et al. 2006. Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J. Immunol. 176:4484–91 [Google Scholar]
  195. Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. 195.  2004. Impairment of CD4+CD25+ regulatory T-cells in autoimmune liver disease. J. Hepatol. 41:31–37 [Google Scholar]
  196. Liberal R, Grant CR, Holder BS, Ma Y, Mieli-Vergani G. 196.  et al. 2012. The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway. Hepatology 56:677–86 [Google Scholar]
  197. Oo YH, Weston CJ, Lalor PF, Curbishley SM, Withers DR. 197.  et al. 2010. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J. Immunol. 184:2886–98 [Google Scholar]
  198. Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D. 198.  et al. 2012. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J. Hepatol. 57:125–32 [Google Scholar]
  199. Taubert R, Hardtke-Wolenski M, Noyan F, Wilms A, Baumann AK. 199.  et al. 2014. Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J. Hepatol. 61:1106–14 [Google Scholar]
  200. Behairy BE, El-Araby HA, Abd El Kader HH, Ehsan NA, Salem ME. 200.  et al. 2016. Assessment of intrahepatic regulatory T cells in children with autoimmune hepatitis. Ann. Hepatol. 15:682–90 [Google Scholar]
  201. Jeffery HC, Jeffery LE, Lutz P, Corrigan M, Webb GJ. 201.  et al. 2017. Low dose interleukin-2 promotes STAT5 phosphorylation, Treg survival and CTLA-4 dependent function in autoimmune liver diseases. Clin. Exp. Immunol. 188:394–411 [Google Scholar]
  202. Longhi MS, Ma Y, Mitry RR, Bogdanos DP, Heneghan M. 202.  et al. 2005. Effect of CD4+CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J. Autoimmun. 25:63–71 [Google Scholar]
  203. Grant CR, Liberal R, Holder BS, Cardone J, Ma Y. 203.  et al. 2014. Dysfunctional CD39POS regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology 59:1007–15 [Google Scholar]
  204. Daniel V, Trojan K, Opelz G. 204.  2016. Immunosuppressive drugs affect induction of IFNy+ Treg in vitro. Hum. Immunol. 77:146–52 [Google Scholar]
  205. Akimova T, Kamath BM, Goebel JW, Meyers KEC, Rand EB. 205.  et al. 2012. Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients. Am. J. Transpl. 12:3449–61 [Google Scholar]
  206. Verdonk RC, Haagsma EB, Jonker MR, Bok LIH, Zandvoort JH. 206.  et al. 2007. Effects of different immunosuppressive regimens on regulatory T-cells in noninflamed colon of liver transplant recipients. Inflamm. Bowel Dis. 13:703–9 [Google Scholar]
  207. Oo YH, Adams DH. 207.  2012. Regulatory T cells and autoimmune hepatitis: defective cells or a hostile environment?. J. Hepatol. 57:6–8 [Google Scholar]
  208. Oo YH, Banz V, Kavanagh D, Liaskou E, Withers DR. 208.  et al. 2012. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J. Hepatol. 57:1044–51 [Google Scholar]
  209. Tedesco D, Thapa M, Gumber S, Elrod EJ, Rahman K. 209.  et al. 2017. CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease. Hepatology 65:661–77 [Google Scholar]
  210. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G. 210.  et al. 2004. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199:1455–65 [Google Scholar]
  211. Longhi MS, Hussain MJ, Kwok WW, Mieli-Vergani G, Ma Y, Vergani D. 211.  2011. Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. Hepatology 53:536–47 [Google Scholar]
  212. Longhi MS, Meda F, Wang P, Samyn M, Mieli-Vergani G. 212.  et al. 2008. Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis. Hepatology 47:581–91 [Google Scholar]
  213. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F. 213.  et al. 2016. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54:139–48 [Google Scholar]
  214. Morita M, Fujino M, Jiang G, Kitazawa Y, Xie L. 214.  et al. 2010. PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft. Am. J. Transpl. 10:40–46 [Google Scholar]
  215. Kido M, Watanabe N, Okazaki T, Akamatsu T, Tanaka J. 215.  et al. 2008. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology 135:1333–43 [Google Scholar]
  216. Ichiki Y, Aoki CA, Bowlus CL, Shimoda S, Ishibashi H, Gershwin ME. 216.  2005. T cell immunity in autoimmune hepatitis. Autoimmun. Rev. 4:315–21 [Google Scholar]
  217. Hashimoto E, Lindor KD, Homburger HA, Dickson ER, Czaja AJ. 217.  et al. 1993. Immunohistochemical characterization of hepatic lymphocytes in primary biliary cirrhosis in comparison with primary sclerosing cholangitis and autoimmune chronic active hepatitis. Mayo Clin. Proc. 68:1049–55 [Google Scholar]
  218. Tordjmann T, Soulie A, Guettier C, Schmidt M, Berthou C. 218.  et al. 1998. Perforin and granzyme B lytic protein expression during chronic viral and autoimmune hepatitis. Liver 18:391–97 [Google Scholar]
  219. Fox CK, Furtwaengler A, Nepomuceno RR, Martinez OM, Krams SM. 219.  2001. Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. Liver 21:272–79 [Google Scholar]
  220. Longhi MS, Hussain MJ, Bogdanos DP, Quaglia A, Mieli-Vergani G. 220.  et al. 2007. Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology 46:472–84 [Google Scholar]
  221. Rajoriya N, Fergusson JR, Leithead JA, Klenerman P. 221.  2014. Gamma delta T-lymphocytes in hepatitis C and chronic liver disease. Front. Immunol. 5:400 [Google Scholar]
  222. Martins EB, Graham AK, Chapman RW, Fleming KA. 222.  1996. Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases. Hepatology 23:988–93 [Google Scholar]
  223. Wen L, Peakman M, Mieli-Vergani G, Vergani D. 223.  1992. Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease. Clin. Exp. Immunol. 89:78–82 [Google Scholar]
  224. Kasper HU, Ligum D, Cucus J, Stippel DL, Dienes HP, Drebber U. 224.  2009. Liver distribution of gammadelta-T-cells in patients with chronic hepatitis of different etiology. APMIS 117:779–85 [Google Scholar]
  225. Stinissen P, Vandevyver C, Medaer R, Vandegaer L, Nies J. 225.  et al. 1995. Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements. J. Immunol. 154:4883–94 [Google Scholar]
  226. Bank I, Duvdevani M, Livneh A. 226.  2003. Expansion of gammadelta T-cells in Behcet's disease: role of disease activity and microbial flora in oral ulcers. J. Lab. Clin. Med. 141:33–40 [Google Scholar]
  227. Marquardt N, Beziat V, Nystrom S, Hengst J, Ivarsson MA. 227.  et al. 2015. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J. Immunol. 194:2467–71 [Google Scholar]
  228. Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P. 228.  et al. 2016. Human liver-resident CD56bright/CD16neg NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J. Autoimmun. 66:40–50 [Google Scholar]
  229. Tian Z, Chen Y, Gao B. 229.  2013. Natural killer cells in liver disease. Hepatology 57:1654–62 [Google Scholar]
  230. Kaneda K, Kurioka N, Seki S, Wake K, Yamamoto S. 230.  1984. Pit cell-hepatocyte contact in autoimmune hepatitis. Hepatology 4:955–58 [Google Scholar]
  231. Dong Z, Wei H, Sun R, Hu Z, Gao B, Tian Z. 231.  2004. Involvement of natural killer cells in PolyI:C-induced liver injury. J. Hepatol. 41:966–73 [Google Scholar]
  232. Wang J, Sun R, Wei H, Dong Z, Gao B, Tian Z. 232.  2006. Poly I:C prevents T cell-mediated hepatitis via an NK-dependent mechanism. J. Hepatol. 44:446–54 [Google Scholar]
  233. Jiang W, Sun R, Wei H, Tian Z. 233.  2005. Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. PNAS 102:17077–82 [Google Scholar]
  234. Grant AJ, Goddard S, Ahmed-Choudhury J, Reynolds G, Jackson DG. 234.  et al. 2002. Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am. J. Pathol. 160:1445–55 [Google Scholar]
  235. Burak KW, Swain MG, Santodomingo-Garzon T, Lee SS, Urbanski SJ. 235.  et al. 2013. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy. Can. J. Gastroenterol. 27:273–80 [Google Scholar]
  236. Beland K, Marceau G, Labardy A, Bourbonnais S, Alvarez F. 236.  2015. Depletion of B cells induces remission of autoimmune hepatitis in mice through reduced antigen presentation and help to T cells. Hepatology 62:1511–23 [Google Scholar]
  237. Liu X, Jiang X, Liu R, Wang L, Qian T. 237.  et al. 2015. B cells expressing CD11b effectively inhibit CD4+ T-cell responses and ameliorate experimental autoimmune hepatitis in mice. Hepatology 62:1563–75 [Google Scholar]
  238. Huang R, Wu H, Liu Y, Yang C, Pan Z. 238.  et al. 2016. Increase of infiltrating monocytes in the livers of patients with chronic liver diseases. Discov. Med. 21:25–33 [Google Scholar]
  239. Longhi MS, Mitry RR, Samyn M, Scalori A, Hussain MJ. 239.  et al. 2009. Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells. Hepatology 50:130–42 [Google Scholar]
  240. Kurokohchi K, Masaki T, Himoto T, Deguchi A, Nakai S. 240.  et al. 2006. Usefulness of liver infiltrating CD86-positive mononuclear cells for diagnosis of autoimmune hepatitis. World J. Gastroenterol. 12:2523–29 [Google Scholar]
  241. Eipel C, Abshagen K, Vollmar B. 241.  2010. Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. World J. Gastroenterol. 16:6046–57 [Google Scholar]
  242. Grant AJ, Lalor PF, Hübscher SG, Briskin M, Adams DH. 242.  2001. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 33:1065–72 [Google Scholar]
  243. Warren A, Le Couteur DG, Fraser R, Bowen DG, McCaughan GW, Bertolino P. 243.  2006. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44:1182–90 [Google Scholar]
  244. John B, Crispe IN. 244.  2004. Passive and active mechanisms trap activated CD8+ T cells in the liver. J. Immunol. 172:5222–29 [Google Scholar]
  245. Bonder CS, Norman MU, Swain MG, Zbytnuik LD, Yamanouchi J. 245.  et al. 2005. Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1. Immunity 23:153–63 [Google Scholar]
  246. Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. 246.  2000. The liver as a site of T-cell apoptosis: graveyard, or killing field?. Immunol. Rev. 174:47–62 [Google Scholar]
  247. Buschenfelde KH, Kossling FK, Miescher PA. 247.  1972. Experimental chronic active hepatitis in rabbits following immunization with human liver proteins. Clin. Exp. Immunol. 11:99–108 [Google Scholar]
  248. Kuriki J, Murakami H, Kakumu S, Sakamoto N, Yokochi T. 248.  et al. 1983. Experimental autoimmune hepatitis in mice after immunization with syngeneic liver proteins together with the polysaccharide of Klebsiella pneumoniae. . Gastroenterology 84:596–603 [Google Scholar]
  249. Lohse AW, Manns M, Dienes HP, Meyer zum Büschenfelde KH, Cohen IR. 249.  1990. Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity. Hepatology 11:24–30 [Google Scholar]
  250. Tiegs G, Hentschel J, Wendel A. 250.  1992. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J. Clin. Invest. 90:196–203 [Google Scholar]
  251. Beldi G, Wu Y, Banz Y, Nowak M, Miller L. 251.  et al. 2008. Natural killer T cell dysfunction in CD39-null mice protects against concanavalin A-induced hepatitis. Hepatology 48:841–52 [Google Scholar]
  252. Mizuhara H, O'Neill E, Seki N, Ogawa T, Kusunoki C. 252.  et al. 1994. T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J. Exp. Med. 179:1529–37 [Google Scholar]
  253. Ferran C, Sheehan K, Dy M, Schreiber R, Merite S. 253.  et al. 1990. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation. Eur. J. Immunol. 20:509–15 [Google Scholar]
  254. Erhardt A, Biburger M, Papadopoulos T, Tiegs G. 254.  2007. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 45:475–85 [Google Scholar]
  255. Kwon HJ, Won YS, Park O, Feng D, Gao B. 255.  2014. Opposing effects of prednisolone treatment on T/NKT cell- and hepatotoxin-mediated hepatitis in mice. Hepatology 59:1094–106 [Google Scholar]
  256. Ye F, Yan S, Xu L, Jiang Z, Liu N. 256.  et al. 2009. Tr1 regulatory T cells induced by ConA pretreatment prevent mice from ConA-induced hepatitis. Immunol. Lett. 122:198–207 [Google Scholar]
  257. Gunther C, He GW, Kremer AE, Murphy JM, Petrie EJ. 257.  et al. 2016. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. J. Clin. Invest. 126:4346–60 [Google Scholar]
  258. Nagakawa J, Hishinuma I, Hirota K, Miyamoto K, Yamanaka T. 258.  et al. 1990. Involvement of tumor necrosis factor-alpha in the pathogenesis of activated macrophage-mediated hepatitis in mice. Gastroenterology 99:758–65 [Google Scholar]
  259. Su GL. 259.  2002. Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am. J. Physiol. Gastrointest. Liver Physiol. 283:G256–65 [Google Scholar]
  260. Gil-Farina I, Di Scala M, Salido E, Lopez-Franco E, Rodriguez-Garcia E. 260.  et al. 2016. Transient expression of transgenic IL-12 in mouse liver triggers unremitting inflammation mimicking human autoimmune hepatitis. J. Immunol. 197:2145–56 [Google Scholar]
  261. Tamaki S, Homma S, Enomoto Y, Komita H, Zeniya M. 261.  et al. 2005. Autoimmune hepatic inflammation by vaccination of mice with dendritic cells loaded with well-differentiated hepatocellular carcinoma cells and administration of interleukin-12. Clin. Immunol. 117:280–93 [Google Scholar]
  262. Dugan CM, MacDonald AE, Roth RA, Ganey PE. 262.  2010. A mouse model of severe halothane hepatitis based on human risk factors. J. Pharmacol. Exp. Ther. 333:364–72 [Google Scholar]
  263. You Q, Cheng L, Ju C. 263.  2010. Generation of T cell responses targeting the reactive metabolite of halothane in mice. Toxicol. Lett. 194:79–85 [Google Scholar]
  264. Gilbert KM. 264.  2010. Xenobiotic exposure and autoimmune hepatitis. Hepat. Res. Treat. 2010:248157 [Google Scholar]
  265. Ando K, Moriyama T, Guidotti LG, Wirth S, Schreiber RD. 265.  et al. 1993. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J. Exp. Med. 178:1541–54 [Google Scholar]
  266. Ito H, Ando K, Ishikawa T, Saito K, Takemura M. 266.  et al. 2009. Role of TNF-alpha produced by nonantigen-specific cells in a fulminant hepatitis mouse model. J. Immunol. 182:391–97 [Google Scholar]
  267. Ohta A, Sekimoto M, Sato M, Koda T, Nishimura S. 267.  et al. 2000. Indispensable role for TNF-alpha and IFN-gamma at the effector phase of liver injury mediated by Th1 cells specific to hepatitis B virus surface antigen. J. Immunol. 165:956–61 [Google Scholar]
  268. Holdener M, Hintermann E, Bayer M, Rhode A, Rodrigo E. 268.  et al. 2008. Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection. J. Exp. Med. 205:1409–22 [Google Scholar]
  269. Lapierre P, Djilali-Saiah I, Vitozzi S, Alvarez F. 269.  2004. A murine model of type 2 autoimmune hepatitis: xenoimmunization with human antigens. Hepatology 39:1066–74 [Google Scholar]
  270. Lapierre P, Béland K, Djilali-Saiah I, Alvarez F. 270.  2006. Type 2 autoimmune hepatitis murine model: the influence of genetic background in disease development. J. Autoimmun. 26:82–89 [Google Scholar]
  271. Lapierre P, Béland K, Yang R, Alvarez F. 271.  2012. Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance. Hepatology 57:217–27 [Google Scholar]
  272. Ehser J, Holdener M, Christen S, Bayer M, Pfeilschifter JM. 272.  et al. 2013. Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune hepatitis. J. Autoimmun. 42:39–49 [Google Scholar]
  273. Corse E, Gottschalk RA, Park JS, Sepulveda MA, Loke P. 273.  et al. 2013. Cutting edge: chronic inflammatory liver disease in mice expressing a CD28-specific ligand. J. Immunol. 190:526–30 [Google Scholar]
  274. Watanabe Y, Kawakami H, Kawamoto H, Ikemoto Y, Masuda K. 274.  et al. 1987. Effect of neonatal thymectomy on experimental autoimmune hepatitis in mice. Clin. Exp. Immunol. 67:105–13 [Google Scholar]
  275. Iwamoto S, Kido M, Aoki N, Nishiura H, Maruoka R. 275.  et al. 2013. TNF-alpha is essential in the induction of fatal autoimmune hepatitis in mice through upregulation of hepatic CCL20 expression. Clin. Immunol. 146:15–25 [Google Scholar]
  276. Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A. 276.  et al. 2002. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11:397–409 [Google Scholar]
  277. Rudner LA, Lin JT, Park IK, Cates JMM, Dyer DA. 277.  et al. 2003. Necroinflammatory liver disease in BALB/c background, TGF-1-deficient mice requires CD4+ T cells. J. Immunol. 170:4785–92 [Google Scholar]
  278. Gorham JD, Lin JT, Sung JL, Rudner LA, French MA. 278.  2001. Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis. J. Immunol. 166:6413–22 [Google Scholar]
  279. Oertelt S, Lian Z-X, Cheng C-M, Chuang Y-H, Padgett KA. 279.  et al. 2006. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J. Immunol. 177:1655–60 [Google Scholar]
  280. Bonito AJ, Aloman C, Fiel MI, Danzl NM, Cha S. 280.  et al. 2013. Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J. Clin. Invest. 123:3510–24 [Google Scholar]
  281. Lin JT, Kitzmiller TJ, Cates JM, Gorham JD. 281.  2005. MHC-independent genetic regulation of liver damage in a mouse model of autoimmune hepatocellular injury. Lab. Invest. 85:550–61 [Google Scholar]
  282. 282.  Deleted in proof
  283. Yuksel M, Xiao X, Tai N, Vijay GM, Gulden E. 283.  et al. 2016. The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model. Clin. Exp. Immunol. 186:164–76 [Google Scholar]
  284. Yuksel M, Wang Y, Tai N, Peng J, Guo J. 284.  et al. 2015. A novel “humanized mouse” model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology 62:1536–50 [Google Scholar]
  285. Braley-Mullen H, Sharp GC, Medling B, Tang H. 285.  1999. Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J. Autoimmun. 12:157–65 [Google Scholar]
  286. Goris A, Liston A. 286.  2012. The immunogenetic architecture of autoimmune disease. Cold Spring Harb. Perspect. Biol. 4:a007260 [Google Scholar]
  287. Pardoll DM. 287.  2012. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12:252–64 [Google Scholar]
  288. Aoki N, Kido M, Iwamoto S, Nishiura H, Maruoka R. 288.  et al. 2011. Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice. Gastroenterology 140:1322–33 [Google Scholar]
  289. Maruoka R, Aoki N, Kido M, Iwamoto S, Nishiura H. 289.  et al. 2013. Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis. Gastroenterology 145:209–20 [Google Scholar]
  290. Rose NR, Bona C. 290.  1993. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol. Today 14:426–30 [Google Scholar]
  291. Goodnow CC. 291.  2007. Multistep pathogenesis of autoimmune disease. Cell 130:25–35 [Google Scholar]
  292. Tang R, Wei Y, Li Y, Chen W, Chen H. 292.  et al. 2017. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut In press
  293. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA. 293.  et al. 2014. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat. Med. 20:1043–49 [Google Scholar]
  294. Clemente-Casares X, Blanco J, Ambalavanan P, Yamanouchi J, Singha S. 294.  et al. 2016. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530:434–40 [Google Scholar]
  295. Maldonado RA, LaMothe RA, Ferrari JD, Zhang AH, Rossi RJ. 295.  et al. 2015. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. PNAS 112:E156–65 [Google Scholar]
  296. Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X. 296.  et al. 2016. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:179–84 [Google Scholar]
  297. Lied GA, Berstad A. 297.  2010. Functional and clinical aspects of the B-cell-activating factor (BAFF): a narrative review. Scand. J. Immunol. 73:1–7 [Google Scholar]
  298. Klatzmann D, Abbas AK. 298.  2015. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat. Rev. Immunol. 15:283–94 [Google Scholar]
  299. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM. 299.  et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371:2189–99 [Google Scholar]
  300. Wong GW, Yeong T, Lawrence D, Yeoman AD, Verma S, Heneghan MA. 300.  2017. Concurrent extrahepatic autoimmunity in autoimmune hepatitis: implications for diagnosis, clinical course and long-term outcomes. Liver Int 37:449–57 [Google Scholar]
  301. Bittencourt PL, Farias AQ, Porta G, Cancado EL, Miura I. 301.  et al. 2008. Frequency of concurrent autoimmune disorders in patients with autoimmune hepatitis: effect of age, gender, and genetic background. J. Clin. Gastroenterol. 42:300–5 [Google Scholar]
  302. Werner M, Prytz H, Ohlsson B, Almer S, Björnsson E. 302.  et al. 2008. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand. J. Gastroenterol. 43:1232–40 [Google Scholar]
  303. Rodman JS, Deutsch DJ, Gutman SI. 303.  1976. Methyldopa hepatitis. A report of six cases and review of the literature. Am. J. Med. 60:941–48 [Google Scholar]
  304. Germano V, Picchianti Diamanti A, Baccano G, Natale E, Onetti Muda A. 304.  et al. 2005. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann. Rheum. Dis. 64:1519–20 [Google Scholar]
  305. Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. 305.  2010. Adalimumab-induced autoimmune hepatitis. J. Clin. Gastroenterol. 44:e20–22 [Google Scholar]
  306. Scully LJ, Clarke D, Barr RJ. 306.  1993. Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis. Dig. Dis. Sci. 38:744–51 [Google Scholar]
  307. Chapman MH, Kajihara M, Borges G, O'Beirne J, Patch D. 307.  et al. 2010. Severe, acute liver injury and khat leaves. N. Engl. J. Med. 362:1642–44 [Google Scholar]
  308. Schlaak JF, Lohr H, Gallati H, Meyer zum Buschenfelde KH, Fleischer B. 308.  1993. Analysis of the in vitro cytokine production by liver-infiltrating T cells of patients with autoimmune hepatitis. Clin. Exp. Immunol. 94:168–73 [Google Scholar]
  309. Chernavsky AC, Paladino N, Rubio AE, De Biasio MB, Periolo N. 309.  et al. 2004. Simultaneous expression of Th1 cytokines and IL-4 confers severe characteristics to type I autoimmune hepatitis in children. Hum. Immunol. 65:683–91 [Google Scholar]
  310. Lan RY, Cheng C, Lian Z-X, Tsuneyama K, Yang G-X. 310.  et al. 2006. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 43:729–37 [Google Scholar]
  311. Suzuki Y, Kobayashi M, Hosaka T, Someya T, Akuta N. 311.  et al. 2004. Peripheral CD8+/CD25+ lymphocytes may be implicated in hepatocellular injuries in patients with acute-onset autoimmune hepatitis. J. Gastroenterol. 39:649–53 [Google Scholar]
  312. Eggink HF, Houthoff HJ, Huitema S, Gips CH, Poppema S. 312.  1982. Cellular and humoral immune reactions in chronic active liver disease. I. Lymphocyte subsets in liver biopsies of patients with untreated idiopathic autoimmune hepatitis, chronic active hepatitis B and primary biliary cirrhosis. Clin. Exp. Immunol. 50:17–24 [Google Scholar]
  313. Ferrante A, Davidson GP, Beard LJ, Goh DH. 313.  1989. Alterations in function and subpopulations of peripheral blood mononuclear leukocytes in children with portal hypertension. Leukocyte subtypes and function in portal hypertension. Int. Arch. Allergy Appl. Immunol. 88:348–52 [Google Scholar]
  314. Czaja AJ, Sievers C, Zein NN. 314.  2000. Nature and behavior of serum cytokines in type 1 autoimmune hepatitis. Dig. Dis. Sci. 45:1028–35 [Google Scholar]
  315. Maggiore G, De Benedetti F, Massa M, Pignatti P, Martini A. 315.  1995. Circulating levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in children with autoimmune hepatitis. J. Pediatr. Gastroenterol. Nutr. 20:23–27 [Google Scholar]
  316. al-Wabel A, al-Janadi M, Raziuddin S. 316.  1993. Cytokine profile of viral and autoimmune chronic active hepatitis. J. Allergy Clin. Immunol. 92:902–8 [Google Scholar]
  317. Yasumi Y, Takikawa Y, Endo R, Suzuki K. 317.  2007. Interleukin-17 as a new marker of severity of acute hepatic injury. Hepatol. Res. 37:248–54 [Google Scholar]
  318. Landi A, Weismuller TJ, Lankisch TO, Santer DM, Tyrrell DL. 318.  et al. 2014. Differential serum levels of eosinophilic eotaxins in primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis. J. Interf. Cytokine Res. 34:204–14 [Google Scholar]
  319. Hussain MJ, Mustafa A, Gallati H, Mowat AP, Mieli-Vergani G, Vergani D. 319.  1994. Cellular expression of tumour necrosis factor-alpha and interferon-gamma in the liver biopsies of children with chronic liver disease. J. Hepatol. 21:816–21 [Google Scholar]
  320. Kamijo A, Yoshizawa K, Joshita S, Yoneda S, Umemura T. 320.  et al. 2011. Cytokine profiles affecting the pathogenesis of autoimmune hepatitis in Japanese patients. Hepatol. Res. 41:350–57 [Google Scholar]
  321. Hirschfield GM, Gershwin ME. 321.  2013. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu. Rev. Pathol. Mech. Dis. 8:303–30 [Google Scholar]
  322. Martini E, Abuaf N, Cavalli F, Durand V, Johanet C, Homberg JC. 322.  1988. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology 8:1662–66 [Google Scholar]
  323. Homberg JC, Andre C, Abuaf N. 323.  1984. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. Clin. Exp. Immunol. 55:561–70 [Google Scholar]
  324. Strassburg CP, Obermayer-Straub P, Alex B, Durazzo M, Rizzetto M. 324.  et al. 1996. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Gastroenterology 111:1576–86 [Google Scholar]
  325. Zauli D, Ghetti S, Grassi A, Descovich C, Cassani F. 325.  et al. 1997. Anti-neutrophil cytoplasmic antibodies in type 1 and 2 autoimmune hepatitis. Hepatology 25:1105–7 [Google Scholar]
  326. Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Buschenfelde KH. 326.  1987. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1:292–94 [Google Scholar]
  327. Wies I, Brunner S, Henninger J, Herkel J, Kanzler S. 327.  et al. 2000. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 355:1510–15 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error