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Review

Contemporary issues and future directions in autoimmune hepatitis

, &
Pages 1163-1174 | Received 09 Aug 2015, Accepted 19 May 2016, Published online: 03 Jun 2016

References

  • Waldenström J. Leber. Blutprotein und Nahrungseiweiss. Deutsch Gesellshaff Z Verdan Stoffwechselkr. 1950;15:113–119.
  • Johnson PJ, McFarlane IG. Meeting report: international autoimmune hepatitis group. Hepatology. 1993;18:998–1005.
  • Liberal R, Longhi MS, Mieli-Vergani G, et al. Pathogenesis of autoimmune hepatitis. Best Pract Res Clin Gastroenterol. 2011;25:653–664.
  • Boberg KM, Aadland E, Jahnsen J, et al. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998;33:99–103.
  • Hurlburt KJ, McMahon BJ, Deubner H, et al. Prevalence of autoimmune liver disease in alaska natives. Am J Gastroenterol. 2002;97:2402–2407.
  • Ngu JH, Bechly K, Chapman BA, et al. Population-based epidemiology study of autoimmune hepatitis: a disease of older women? J Gastroenterol Hepatol. 2010;25:1681–1686.
  • Gronbaek L, Vilstrup H, Jepsen P. Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J Hepatol. 2014;60:612–617.
  • Nishioka M, Morshed SA, McFarlane IG. Geographical variation in the frequency and characteristics of autoimmune liver diseases. In: Krawitt EL, Wiesner, RH, Nishioka, M, et al., editors. Autoimmune liver diseases. 2nd ed. Amesterdam:Elsevier; 1998. p.413–428.
  • Jimenez-Rivera C, Ling SC, Ahmed N, et al. Incidence and characteristics of autoimmune hepatitis. Pediatrics. 2015;136:e1237–e1248.
  • 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.
  • 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(2):443–452. e5.
  • Seki T, Ota M, Furuta S, et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology. 1992;103:1041–1047.
  • 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.
  • 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.
  • Elfaramawy AA, Elhossiny RM, Abbas AA, et al. HLA-DRB1 as a risk factor in children with autoimmune hepatitis and its relation to hepatitis A infection. Ital J Pediatr. 2010;36:73.
  • Agarwal K, Czaja AJ, Jones DE, et al. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology. 2000;31:49–53.
  • 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.
  • 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.
  • Webb GJ, Siminovitch KA, Hirschfield GM. The immunogenetics of primary biliary cirrhosis: a comprehensive review. J Autoimmun. 2015;64:42–52.
  • Webb GJ, Hirschfield GM. Using GWAS to identify genetic predisposition in hepatic autoimmunity. J Autoimmun. 2016;66:25–39.
  • Webb G, Chen YY, Li KK, et al. Single-gene association between GATA-2 and autoimmune hepatitis: A novel genetic insight highlighting immunologic pathways to disease. J Hepatol. 2016;64:1190–1193.
  • Gregorio GV, Choudhuri K, Ma Y, et al. 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. 1999;162:1802–1810.
  • Gregorio GV, Choudhuri K, Ma Y, et al. Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection. Clin Exp Immunol. 2003;133:404–413.
  • Lenzi M, Bellentani S, Saccoccio G, et al. Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population: a nested case-control study of the Dionysos cohort. Gut. 1999;45:435–441.
  • 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.
  • Bjornsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51:2040–2048.
  • Rodrigues S, Lopes S, Magro F, et al. Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: a single center report of 8 cases. World J Gastroenterol 2015;21:7584–7588.
  • Senaldi G, Portmann B, Mowat AP, et al. Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis. Arch Dis Child. 1992;67:1447–1453.
  • Lobo-Yeo A, Senaldi G, Portmann B, et al. Class I and class II major histocompatibility complex antigen expression on hepatocytes: a study in children with liver disease. Hepatology. 1990;12:224–232.
  • Senaldi G, Lobo-Yeo A, Mowat AP, et al. Class I and class II major histocompatibility complex antigens on hepatocytes: importance of the method of detection and expression in histologically normal and diseased livers. J Clin Pathol. 1991;44:107–114.
  • Ichiki Y, Aoki CA, Bowlus CL, et al. T cell immunity in autoimmune hepatitis. Autoimmun Rev. 2005;4:315–321.
  • Delneste Y, Charbonnier P, Herbault N, et al. Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages. Blood. 2003;101:143–150.
  • Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med. 2009;361:888–898.
  • Korn T, Bettelli E, Oukka M, et al. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517.
  • Harada K, Shimoda S, Sato Y, et al. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol. 2009;157:261–270.
  • Liberal R, Grant CR, Mieli-Vergani G, et al. PWE-281 different effector T cell responses may account for different patterns of liver injury in childhood autoimmune liver disease. Gut. 2012;61(Suppl 2):A412.
  • Zhao L, Tang Y, You Z, et al. Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One. 2011;6:e18909.
  • Liberal R, Grant CR, Longhi MS, et al. Regulatory T cells: mechanisms of suppression and impairment in autoimmune liver disease. IUBMB Life. 2015;67:88–97.
  • Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–532.
  • 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.
  • 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.
  • 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.
  • Liberal R, Grant CR, Holder BS, et al. 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. 2015;62(3):863–875.
  • Longhi MS, Hussain MJ, Mitry RR, et al. Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176:4484–4491.
  • 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.
  • Taubert R, Hardtke-Wolenski M, Noyan F, et al. Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J Hepatol. 2014;61:1106–1114.
  • Liberal R, Grant CR, Holder BS, et al. The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway. Hepatology. 2012;56:677–686.
  • Longhi MS, Mitry RR, Samyn M, et al. Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells. Hepatology. 2009;50:130–142.
  • Grant CR, Liberal R, Mieli-Vergani G, et al. Regulatory T-cells in autoimmune diseases: challenges, controversies and–yet–unanswered questions. Autoimmun Rev. 2015;14:105–116.
  • Grant CR, Liberal R, Holder BS, et al. Dysfunctional CD39 regulatory T cells and aberrant control of T helper type 17 cells in autoimmune hepatitis. Hepatology. 2014;59(3):1007–1015.
  • Lapierre P, Djilali-Saiah I, Vitozzi S, et al. A murine model of type 2 autoimmune hepatitis: xenoimmunization with human antigens. Hepatology. 2004;39:1066–1074.
  • Lapierre P, Beland K, Martin C, et al. Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis. Hepatology. 2010;51:1789–1798.
  • Lapierre P, Beland K, Yang R, et al. Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance. Hepatology. 2013;57:217–227.
  • Yuksel M, Wang Y, Tai N, et al. A novel “humanized mouse” model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology. 2015;62(5):1536–1550.
  • 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.
  • Buxbaum J, Qian P, Allen PM, et al. Hepatitis resulting from liver-specific expression and recognition of self-antigen. J Autoimmun. 2008;31:208–215.
  • 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.
  • Krawitt EL. Clinical features and management of autoimmune hepatitis. World J Gastroenterol. 2008;14:3301–3305.
  • Crapper RM, Bhathal PS, Mackay IR, et al. ‘Acute’ autoimmune hepatitis. Digestion. 1986;34:216–225.
  • Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology. 1997;25:541–547.
  • 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.
  • Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology. 1996;110:848–857.
  • Schramm C, Herkel J, Beuers U, et al. Pregnancy in autoimmune hepatitis: outcome and risk factors. Am J Gastroenterol. 2006;101:556–560.
  • Werner M, Prytz H, Ohlsson B, et al. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand J Gastroenterol. 2008;43:1232–1240.
  • Verma S, Gunuwan B, Mendler M, et al. Factors predicting relapse and poor outcome in type I autoimmune hepatitis: role of cirrhosis development, patterns of transaminases during remission and plasma cell activity in the liver biopsy. Am J Gastroenterol. 2004;99:1510–1516.
  • McFarlane IG. Definition and classification of autoimmune hepatitis. Semin Liver Dis. 2002;22:317–324.
  • European Association for the study of the L. EASL Clinical Practice Guidelines: autoimmune hepatitis. J Hepatol. 2015;63:971–1004.
  • Gassert DJ, Garcia H, Tanaka K, et al. Corticosteroid-responsive cryptogenic chronic hepatitis: evidence for seronegative autoimmune hepatitis. Dig Dis Sci. 2007;52:2433–2437.
  • Vergani D, Alvarez F, Bianchi FB, et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol. 2004;41:677–683.
  • Bogdanos DP, Invernizzi P, Mackay IR, et al. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008;14:3374–3387.
  • Bogdanos DP, Mieli-Vergani G, Vergani D. Autoantibodies and their antigens in autoimmune hepatitis. Semin Liver Dis. 2009;29:241–253.
  • Fusconi M, Cassani F, Zauli D, et al. Anti-actin antibodies: a new test for an old problem. J Immunol Methods. 1990;130:1–8.
  • Czaja AJ, Cassani F, Cataleta M, et al. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology. 1996;24:1068–1073.
  • Frenzel C, Herkel J, Luth S, et al. Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis. Am J Gastroenterol. 2006;101:2731–2736.
  • Granito A, Muratori L, Muratori P, et al. Antibodies to filamentous actin (F-actin) in type 1 autoimmune hepatitis. J Clin Pathol. 2006;59:280–284.
  • Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–2213.
  • Ma Y, Okamoto M, Thomas MG, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology. 2002;35:658–664.
  • Liberal R, Grant CR, Longhi MS, et al. Diagnostic criteria of autoimmune hepatitis. Autoimmun Rev. 2014;13:435–440.
  • Strassburg CP, Obermayer-Straub P, Alex B, et al. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Gastroenterology. 1996;111:1576–1586.
  • Philipp T, Durazzo M, Trautwein C, et al. Recognition of uridine diphosphate glucuronosyl transferases by LKM-3 antibodies in chronic hepatitis D. Lancet. 1994;344:578–581.
  • Czaja AJ, Carpenter HA. Histological findings in chronic hepatitis C with autoimmune features. Hepatology. 1997;26:459–466.
  • Vergani D, Longhi MS, Bogdanos DP, et al. Autoimmune hepatitis. Semin Immunopathol. 2009;31:421–435.
  • de Boer YS, van Nieuwkerk CM, Witte BI, et al. Assessment of the histopathological key features in autoimmune hepatitis. Histopathology. 2015;66:351–362.
  • Washington MK. Autoimmune liver disease: overlap and outliers. Mod Pathol. 2007;20(Suppl 1):S15–S30.
  • Stravitz RT, Lefkowitch JH, Fontana RJ, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology. 2011;53:517–526.
  • Krawitt EL. Autoimmune hepatitis. N Engl J Med. 2006;354:54–66.
  • Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis–update 2015. J Hepatol. 2015;62:S100–S111.
  • Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–176.
  • Lohse AW. Diagnostic criteria for autoimmune hepatitis: scores and more. Dig Dis. 2015;33(Suppl 2):47–52.
  • Qiu D, Wang Q, Wang H, et al. Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients. J Hepatol. 2011;54:340–347.
  • Muratori P, Granito A, Pappas G, et al., Validation of simplified diagnostic criteria for autoimmune hepatitis in Italian patients. Hepatology. 2009;49:1782–1783. author reply 1783.
  • Cook GC, Mulligan R, Sherlock S. Controlled prospective trial of corticosteroid therapy in active chronic hepatitis. Q J Med. 1971;40:159–185.
  • Soloway RD, Summerskill WH, Baggenstoss AH, et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology. 1972;63:820–833.
  • Murray-Lyon IM, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet. 1973;1:735–737.
  • Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med. 1995;333:958–963.
  • Lohse AW, Mieli-Vergani G. Autoimmune hepatitis. J Hepatol. 2011;55:171–182.
  • European Association for the Study of the Liver. Electronic address eee. EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol. 2015;63:971–1004.
  • Vergani D, Mieli-Vergani G. Pharmacological management of autoimmune hepatitis. Expert Opin Pharmacother. 2011;12:607–613.
  • Al-Chalabi T, Boccato S, Portmann BC, et al. Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre. J Hepatol. 2006;45:575–583.
  • Luth S, Herkel J, Kanzler S, et al. Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis. J Clin Gastroenterol. 2008;42:926–930.
  • Yeoman AD, Longhi MS, Heneghan MA. Review article: the modern management of autoimmune hepatitis. Aliment Pharmacol Ther. 2010;31:771–787.
  • Heneghan MA, McFarlane IG. Current and novel immunosuppressive therapy for autoimmune hepatitis. Hepatology. 2002;35:7–13.
  • Vierling JM. Autoimmune hepatitis and overlap syndromes: diagnosis and management. Clin Gastroenterol Hepatol. 2015;13:2088–2108.
  • Hennes EM, Oo YH, Schramm C, et al. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am J Gastroenterol. 2008;103:3063–3070.
  • Sharzehi K, Huang MA, Schreibman IR, et al. Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory or intolerant to conventional therapy. Can J Gastroenterol. 2010;24:588–592.
  • Nakamura K, Yoneda M, Yokohama S, et al. Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis. J Gastroenterol Hepatol. 1998;13:490–495.
  • Larsen FS, Vainer B, Eefsen M, et al. Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis. World J Gastroenterol. 2007;13:3232–3236.
  • Sebode M, Schramm SC. AIH: which alternative for difficult-to-treat patients? Dig Dis. 2015;33(Suppl 2):83–87.
  • Maggiore G, De Benedetti F, Massa M, et al. Circulating levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in children with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 1995;20:23–27.
  • 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.
  • Weiler-Normann C, Wiegard C, Schramm C, et al. A case of difficult-to-treat autoimmune hepatitis successfully managed by TNF-alpha blockade. Am J Gastroenterol. 2009;104:2877–2878.
  • Fujii K, Rokutanda R, Osugi Y, et al. Adult-onset Still’s disease complicated by autoimmune hepatitis: successful treatment with infliximab. Intern Med. 2012;51:1125–1128.
  • Weiler-Normann C, Schramm C, Quaas A, et al. Infliximab as a rescue-treatment in difficult-to-treat autoimmune hepatitis. J Hepatol. 2013;58(3):529–534.
  • Rosenblum H, Amital H. Anti-TNF therapy: safety aspects of taking the risk. Autoimmun Rev. 2011;10:563–568.
  • Efe C. Drug induced autoimmune hepatitis and TNF-alpha blocking agents: is there a real relationship? Autoimmun Rev. 2013;12(3):337–339.
  • Barth E, Clawson J. A case of autoimmune hepatitis treated with rituximab. Case Rep Gastroenterol. 2010;4:502–509.
  • Burak KW, Swain MG, Santodomingo-Garzon T, et al. Rituximab for refractory autoimmune hepatitis: final results of a phase 1 study. J Hepatol. 2011;54:S507.
  • Manns MP, Woynarowski M, Kreisel W, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010;139:1198–1206.
  • Woynarowski M, Nemeth A, Baruch Y, et al. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J Pediatr. 2013;163(1347–1353):e1341.
  • Hempfling W, Grunhage F, Dilger K, et al. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology. 2003;38:196–202.
  • Reich DJ, Fiel I, Guarrera JV, et al. Liver transplantation for autoimmune hepatitis. Hepatology. 2000;32:693–700.
  • Mottershead M, Neuberger J. Transplantation in autoimmune liver diseases. World J Gastroenterol. 2008;14:3388–3395.
  • Strassburg CP, Manns MP. Treatment of autoimmune hepatitis. Semin Liver Dis. 2009;29:273–285.
  • Liberal R, Grant CR, Mieli-Vergani G, et al. Autoimmune hepatitis: a comprehensive review. J Autoimmun. 2013;41:126–139.
  • Liberal R, Zen Y, Mieli-Vergani G, et al. Liver transplantation and autoimmune liver diseases. Liver Transpl. 2013;19(10):1065–1077.
  • Ichai P, Duclos-Vallee JC, Guettier C, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl. 2007;13:996–1003.
  • 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.
  • Potts JR, Verma S. Optimizing management in autoimmune hepatitis with liver failure at initial presentation. World J Gastroenterol. 2011;17:2070–2075.
  • Longhi MS, Meda F, Wang P, et al. Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis. Hepatology. 2008;47:581–591.
  • 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.
  • Longhi MS, Liberal R, Holder B, et al. Inhibition of interleukin-17 promotes differentiation of CD25(-) cells into stable T regulatory cells in patients with autoimmune hepatitis. Gastroenterology. 2012;142(1526–1535):e1526.
  • Longhi MS, Hussain MJ, Bogdanos DP, et al. Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology. 2007;46:472–484.
  • Longhi MS, Hussain MJ, Kwok WW, et al. Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. Hepatology. 2011;53:536–547.
  • Dooms H, Abbas AK. Revisiting the role of IL-2 in autoimmunity. Eur J Immunol. 2010;40:1538–1540.
  • Rosenberg SA, Lotze MT. Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Annu Rev Immunol. 1986;4:681–709.
  • Abrams D, Levy Y, Losso MH, et al.; Group I-ES, Committee SS. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361:1548–1559.
  • Setoguchi R, Hori S, Takahashi T, et al. Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201:723–735.
  • Fontenot JD, Rasmussen JP, Gavin MA, et al. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142–1151.
  • O’Gorman WE, Dooms H, Thorne SH, et al. The initial phase of an immune response functions to activate regulatory T cells. J Immunol. 2009;183:332–339.
  • Wing JB, Sakaguchi S. Multiple treg suppressive modules and their adaptability. Front Immunol. 2012;3:178.
  • Gasteiger G, Kastenmuller W. Foxp3+ regulatory T-cells and IL-2: the Moirai of T-cell fates? Front Immunol. 2012;3:179.
  • Chen YY, Jeffery HC, Hunter S, et al. Human intrahepatic tregs are functional, require IL-2 from effector cells for survival and are susceptible to fas ligand mediated apoptosis. Hepatology. 2016. doi:10.1002/hep.28517. [Epub ahead of print].
  • Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365:2055–2066.
  • Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365:2067–2077.

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