Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000069.xml
Semin Liver Dis 2019; 39(04): 422-431
DOI: 10.1055/s-0039-1688751
DOI: 10.1055/s-0039-1688751
Review Article
The Contribution of B Cells in Autoimmune Liver Diseases
Sarah A. Taylor
1
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
,
David N. Assis
2
Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
,
Cara L. Mack
3
Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
› Author Affiliations
Further Information
Publication History
Publication Date:
21 June 2019 (online)
Abstract
Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.
-
References
- 1 Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. Control systems and decision making for antibody production. Nat Immunol 2010; 11 (08) 681-688
- 2 Cooper N, Arnold DM. The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases. Br J Haematol 2010; 149 (01) 3-13
- 3 Anolik JH, Looney RJ, Lund FE, Randall TD, Sanz I. Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets. Immunol Res 2009; 45 (2–3): 144-158
- 4 Bao Y, Cao X. The immune potential and immunopathology of cytokine-producing B cell subsets: a comprehensive review. J Autoimmun 2014; 55: 10-23
- 5 Lund FE. Cytokine-producing B lymphocytes-key regulators of immunity. Curr Opin Immunol 2008; 20 (03) 332-338
- 6 Bour-Jordan H, Bluestone JA. B cell depletion: a novel therapy for autoimmune diabetes?. J Clin Invest 2007; 117 (12) 3642-3645
- 7 Serreze DV, Chapman HD, Varnum DS. , et al. B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice. J Exp Med 1996; 184 (05) 2049-2053
- 8 Chan O, Shlomchik MJ. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 1998; 160 (01) 51-59
- 9 O'Neill SK, Shlomchik MJ, Glant TT, Cao Y, Doodes PD, Finnegan A. Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis. J Immunol 2005; 174 (06) 3781-3788
- 10 Luu VP, Vazquez MI, Zlotnik A. B cells participate in tolerance and autoimmunity through cytokine production. Autoimmunity 2014; 47 (01) 1-12
- 11 Vazquez MI, Catalan-Dibene J, Zlotnik A. B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine 2015; 74 (02) 318-326
- 12 Luo Z, Jegga AG, Bezerra JA. Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies. Hepatology 2018; 67 (02) 676-689
- 13 Burak KW, Swain MG, Santodomingo-Garzon T. , et al. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy. Can J Gastroenterol 2013; 27 (05) 273-280
- 14 D'Agostino D, Costaguta A, Álvarez F. Successful treatment of refractory autoimmune hepatitis with rituximab. Pediatrics 2013; 132 (02) e526-e530
- 15 Mieli-Vergani G, Vergani D, Czaja AJ. , et al. Autoimmune hepatitis. Nat Rev Dis Primers 2018; 4: 18017
- 16 Zachou K, Rigopoulou E, Dalekos GN. Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease. J Autoimmune Dis 2004; 1 (01) 2
- 17 Gregorio GV, McFarlane B, Bracken P, Vergani D, Mieli-Vergani G. Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease. Autoimmunity 2002; 35 (08) 515-519
- 18 Muratori L, Parola M, Ripalti A. , et al. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane. Gut 2000; 46 (04) 553-561
- 19 Löhr HF, Schlaak JF, Lohse AW. , et al. Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis. Hepatology 1996; 24 (06) 1416-1421
- 20 Arenz M, Pingel S, Schirmacher P, Meyer zum Büschenfelde KH, Löhr HF. T cell receptor Vbeta chain restriction and preferred CDR3 motifs of liver-kidney microsomal antigen (LKM-1)-reactive T cells from autoimmune hepatitis patients. Liver 2001; 21 (01) 18-25
- 21 Ma Y, Thomas MG, Okamoto M. , et al. Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule. J Immunol 2002; 169 (01) 277-285
- 22 Muratori L, Cataleta M, Muratori P, Lenzi M, Bianchi FB. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis. Gut 1998; 42 (05) 721-726
- 23 Ma CS, Deenick EK. Human T follicular helper (Tfh) cells and disease. Immunol Cell Biol 2014; 92 (01) 64-71
- 24 Abe K, Takahashi A, Imaizumi H. , et al. Interleukin-21 plays a critical role in the pathogenesis and severity of type I autoimmune hepatitis. Springerplus 2016; 5 (01) 777
- 25 Ma L, Qin J, Ji H, Zhao P, Jiang Y. Tfh and plasma cells are correlated with hypergammaglobulinaemia in patients with autoimmune hepatitis. Liver Int 2014; 34 (03) 405-415
- 26 Aoki N, Kido M, Iwamoto S. , et al. Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice. Gastroenterology 2011; 140 (04) 1322-1333 .e1, 5
- 27 Béland K, Marceau G, Labardy A, Bourbonnais S, Alvarez F. Depletion of B cells induces remission of autoimmune hepatitis in mice through reduced antigen presentation and help to T cells. Hepatology 2015; 62 (05) 1511-1523
- 28 Liu X, Jiang X, Liu R. , et al. B cells expressing CD11b effectively inhibit CD4+ T-cell responses and ameliorate experimental autoimmune hepatitis in mice. Hepatology 2015; 62 (05) 1563-1575
- 29 Hennig C, Ilginus C, Boztug K. , et al. High-content cytometry and transcriptomic biomarker profiling of human B-cell activation. J Allergy Clin Immunol 2014; 133 (01) 172-80 .e1, 10
- 30 Nishioji K, Okanoue T, Itoh Y. , et al. Increase of chemokine interferon-inducible protein-10 (IP-10) in the serum of patients with autoimmune liver diseases and increase of its mRNA expression in hepatocytes. Clin Exp Immunol 2001; 123 (02) 271-279
- 31 Nishikawa H, Enomoto H, Iwata Y. , et al. B-cell activating factor belonging to the tumor necrosis factor family and interferon-γ-inducible protein-10 in autoimmune hepatitis. Medicine (Baltimore) 2016; 95 (12) e3194
- 32 Lied GA, Berstad A. Functional and clinical aspects of the B-cell-activating factor (BAFF): a narrative review. Scand J Immunol 2011; 73 (01) 1-7
- 33 Moisini I, Davidson A. BAFF: a local and systemic target in autoimmune diseases. Clin Exp Immunol 2009; 158 (02) 155-163
- 34 Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015; 386 (10003): 1565-1575
- 35 Krams SM, Van de Water J, Coppel RL. , et al. Analysis of hepatic T lymphocyte and immunoglobulin deposits in patients with primary biliary cirrhosis. Hepatology 1990; 12 (02) 306-313
- 36 Tsuneyama K, Baba H, Morimoto Y, Tsunematsu T, Ogawa H. Primary biliary cholangitis: its pathological characteristics and immunopathological mechanisms. J Med Invest 2017; 64 (1.2): 7-13
- 37 Webb GJ, Siminovitch KA, Hirschfield GM. The immunogenetics of primary biliary cirrhosis: a comprehensive review. J Autoimmun 2015; 64: 42-52
- 38 Hollingsworth KG, Newton JL, Taylor R. , et al. Pilot study of peripheral muscle function in primary biliary cirrhosis: potential implications for fatigue pathogenesis. Clin Gastroenterol Hepatol 2008; 6 (09) 1041-1048
- 39 Khanna A, Jopson L, Howel D. , et al. Rituximab is ineffective for treatment of fatigue in primary biliary cholangitis: a phase 2 randomized controlled trial. Hepatology 2018; (e-pub ahead of print)
- 40 Tsuda M, Moritoki Y, Lian ZX. , et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 2012; 55 (02) 512-521
- 41 Moritoki Y, Tsuneyama K, Nakamura Y. , et al. Anti-drug antibodies against a novel humanized anti-CD20 antibody impair its therapeutic effect on primary biliary cholangitis in human CD20- and FcγR-expressing mice. Front Immunol 2018; 9: 2534
- 42 Bassendine MF, Jones DE, Yeaman SJ. Biochemistry and autoimmune response to the 2-oxoacid dehydrogenase complexes in primary biliary cirrhosis. Semin Liver Dis 1997; 17 (01) 49-60
- 43 Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 1987; 138 (10) 3525-3531
- 44 Tsuneyama K, Van de Water J, Leung PS. , et al. Abnormal expression of the E2 component of the pyruvate dehydrogenase complex on the luminal surface of biliary epithelium occurs before major histocompatibility complex class II and BB1/B7 expression. Hepatology 1995; 21 (04) 1031-1037
- 45 Nakamura M, Ishibashi H, Matsui M. , et al. Peripheral B lymphocyte repertoire to mitochondrial antigen in primary biliary cirrhosis--positive correlation between the disease activity and the frequency of circulating B lymphocytes specific for pyruvate dehydrogenase complex. Autoimmunity 1995; 21 (04) 253-262
- 46 Jansen PL, Ghallab A, Vartak N. , et al. The ascending pathophysiology of cholestatic liver disease. Hepatology 2017; 65 (02) 722-738
- 47 Chung BK, Guevel BT, Reynolds GM. , et al. Phenotyping and auto-antibody production by liver-infiltrating B cells in primary sclerosing cholangitis and primary biliary cholangitis. J Autoimmun 2017; 77: 45-54
- 48 Shimoda S, Miyakawa H, Nakamura M. , et al. CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis. J Autoimmun 2008; 31 (02) 110-115
- 49 Nakamura M, Kondo H, Mori T. , et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology 2007; 45 (01) 118-127
- 50 Nakamura M. Clinical significance of autoantibodies in primary biliary cirrhosis. Semin Liver Dis 2014; 34 (03) 334-340
- 51 Wesierska-Gadek J, Penner E, Battezzati PM. , et al. Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology 2006; 43 (05) 1135-1144
- 52 Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019; 69 (01) 394-419
- 53 Tan YG, Wang YQ, Zhang M. , et al. Clonal characteristics of circulating B lymphocyte repertoire in primary biliary cholangitis. J Immunol 2016; 197 (05) 1609-1620
- 54 Takahashi T, Miura T, Nakamura J. , et al. Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis. Hepatology 2012; 55 (03) 846-855
- 55 Bae HR, Leung PS, Tsuneyama K. , et al. Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology 2016; 64 (04) 1189-1201
- 56 Bae HR, Hodge DL, Yang GX. , et al. The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. Hepatology 2018; 67 (04) 1408-1419
- 57 Krams SM, Cao S, Hayashi M, Villanueva JC, Martinez OM. Elevations in IFN-gamma, IL-5, and IL-10 in patients with the autoimmune disease primary biliary cirrhosis: association with autoantibodies and soluble CD30. Clin Immunol Immunopathol 1996; 80 (3, Pt 1): 311-320
- 58 Li Y, Wang W, Tang L. , et al. Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+ lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis. Hepatology 2015; 61 (06) 1998-2007
- 59 Migita K, Ilyassova B, Kovzel EF. , et al. Serum BAFF and APRIL levels in patients with PBC. Clin Immunol 2010; 134 (02) 217-225
- 60 Zhang B, Hu M, Zhang P. , et al. BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis. Braz J Med Biol Res 2013; 46 (05) 433-439
- 61 Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet 2013; 382 (9904): 1587-1599
- 62 Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis - a comprehensive review. J Hepatol 2017; 67 (06) 1298-1323
- 63 Tabibian JH, O'Hara SP, Larusso NF. Primary sclerosing cholangitis: the gut-liver axis. Clin Gastroenterol Hepatol 2012; 10 (07) 819 , author reply 819–820
- 64 Tabibian JH, O'Hara SP, Lindor KD. Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroenterol 2014; 49 (08) 901-908
- 65 Chung BK, Henriksen EKK, Jørgensen KK, Karlsen TH, Hirschfield GM, Liaskou E. Gut and liver B cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease. Hepatol Commun 2018; 2 (08) 956-967
- 66 Sebode M, Weiler-Normann C, Liwinski T, Schramm C. Autoantibodies in autoimmune liver disease-clinical and diagnostic relevance. Front Immunol 2018; 9: 609
- 67 Marzorati S, Invernizzi P, Lleo A. Making sense of autoantibodies in cholestatic liver diseases. Clin Liver Dis 2016; 20 (01) 33-46
- 68 Lenzen H, Weismüller TJ, Negm AA. , et al. Antineutrophil cytoplasmic antibodies in bile are associated with disease activity in primary sclerosing cholangitis. Scand J Gastroenterol 2013; 48 (10) 1205-1212
- 69 Jendrek ST, Gotthardt D, Nitzsche T. , et al. Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis. Gut 2017; 66 (01) 137-144
- 70 Berglin L, Björkström NK, Bergquist A. Primary sclerosing cholangitis is associated with autoreactive IgA antibodies against biliary epithelial cells. Scand J Gastroenterol 2013; 48 (06) 719-728
- 71 Bezerra JA, Wells RG, Mack CL. , et al. Biliary atresia: clinical and research challenges for the 21st century. Hepatology 2018; (e-pub ahead of print)
- 72 Bednarek J, Traxinger B, Brigham D. , et al. Cytokine-producing B cells promote immune-mediated bile duct injury in murine biliary atresia. Hepatology 2018; 68 (05) 1890-1904
- 73 Bove KE, Sheridan R, Fei L. , et al. Hepatic hilar lymph node reactivity at Kasai portoenterostomy for biliary atresia: correlations with age, outcome, and histology of proximal biliary remnant. Pediatr Dev Pathol 2018; 21 (01) 29-40
- 74 Holladay SD, Smialowicz RJ. Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure. Environ Health Perspect 2000; 108 (Suppl. 03) 463-473
- 75 Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest 2007; 117 (03) 712-718
- 76 Hadchouel M, Hugon RN, Odievre M. Immunoglobulin deposits in the biliary remnants of extrahepatic biliary atresia: a study by immunoperoxidase staining in 128 infants. Histopathology 1981; 5 (02) 217-221
- 77 Mack CL, Tucker RM, Lu BR. , et al. Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia. Hepatology 2006; 44 (05) 1231-1239
- 78 Lu BR, Brindley SM, Tucker RM, Lambert CL, Mack CL. α-Enolase autoantibodies cross-reactive to viral proteins in a mouse model of biliary atresia. Gastroenterology 2010; 139 (05) 1753-1761
- 79 Pang SY, Dai YM, Zhang RZ. , et al. Autoimmune liver disease-related autoantibodies in patients with biliary atresia. World J Gastroenterol 2018; 24 (03) 387-396
- 80 Feldman AG, Tucker RM, Fenner EK, Pelanda R, Mack CL. B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia. PLoS One 2013; 8 (08) e73644
- 81 Jones D, Manns MP, Hexham M, Pedrosa MC, Vierling JM. AMBER- a novel phase 2/3 trial of ianalumab, a human anti-BAFF receptor antibody, in autoimmune hepatitis, NCT03217422. Hepatology 2018; 68: 1120A
- 82 Heidt S, Roelen DL, Eijsink C. , et al. Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clin Exp Immunol 2010; 159 (02) 199-207
- 83 Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis--update 2015. J Hepatol 2015; 62 (1, Suppl): S100-S111
- 84 European Association for the Study of the Liver. Autoimmune hepatitis. J Hepatol 2015; 63 (04) 971-1004
- 85 Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterol 2017; 23 (33) 6030-6048
- 86 Manns MP, Czaja AJ, Gorham JD. , et al; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51 (06) 2193-2213
- 87 Inductivo-Yu I, Adams A, Gish RG. , et al. Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin Gastroenterol Hepatol 2007; 5 (07) 799-802
- 88 Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G. Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5-year follow-up. J Hepatol 2009; 51 (01) 156-160
- 89 Mistilis SP, Vickers CR, Darroch MH, McCarthy SW. Cyclosporin, a new treatment for autoimmune chronic active hepatitis. Med J Aust 1985; 143 (10) 463-465
- 90 Person JL, McHutchison JG, Fong TL, Redeker AG. A case of cyclosporine-sensitive, steroid-resistant, autoimmune chronic active hepatitis. J Clin Gastroenterol 1993; 17 (04) 317-320
- 91 Sherman KE, Narkewicz M, Pinto PC. Cyclosporine in the management of corticosteroid-resistant type I autoimmune chronic active hepatitis. J Hepatol 1994; 21 (06) 1040-1047
- 92 Aqel BA, Machicao V, Rosser B, Satyanarayana R, Harnois DM, Dickson RC. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastroenterol 2004; 38 (09) 805-809
- 93 Larsen FS, Vainer B, Eefsen M, Bjerring PN, Adel Hansen B. Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis. World J Gastroenterol 2007; 13 (23) 3232-3236
- 94 Al Taii H, Hanouneh MA, Hanouneh I, Lopez R, Zein N, Alkhouri N. The use of tacrolimus in refractory autoimmune hepatitis in children and adults: a single center experience. Scand J Gastroenterol 2017; 52 (02) 157-158
- 95 Than NN, Wiegard C, Weiler-Normann C. , et al. Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on tacrolimus therapy. Scand J Gastroenterol 2016; 51 (03) 329-336
- 96 Chatrath H, Allen L, Boyer TD. Use of sirolimus in the treatment of refractory autoimmune hepatitis. Am J Med 2014; 127 (11) 1128-1131
- 97 Kurowski J, Melin-Aldana H, Bass L, Alonso EM, Ekong UD. Sirolimus as rescue therapy in pediatric autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2014; 58 (01) e4 –e6
- 98 Rubin JN, Te HS. Refractory autoimmune hepatitis: beyond standard therapy. Dig Dis Sci 2016; 61 (06) 1757-1762
- 99 Roberts SK, Kemp W. Salvage therapies for autoimmune hepatitis: a critical review. Semin Liver Dis 2017; 37 (04) 343-362
- 100 Bezerra JA, Spino C, Magee JC. , et al; Childhood Liver Disease Research and Education Network (ChiLDREN). Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA 2014; 311 (17) 1750-1759
- 101 Mack CL, Spino C, Moore J. A phase I/IIa trial of intravenous immunoglobulin (IVIG) therapy following portoenterostomy in infants with biliary atresia. J Ped Gastroenterol Nutr 2019; 68 (04) 495-501
- 102 Dörner T, Isenberg D, Jayne D, Wiendl H, Zillikens D, Burmester G. ; International Roundtable on B cells as Therapeutic Target for Intervention. Current status on B-cell depletion therapy in autoimmune diseases other than rheumatoid arthritis. Autoimmun Rev 2009; 9 (02) 82-89
- 103 Hofmann K, Clauder AK, Manz RA. Targeting B cells and plasma cells in autoimmune diseases. Front Immunol 2018; 9: 835
- 104 Trivedi PJ, Hirschfield GM. Treatment of autoimmune liver disease: current and future therapeutic options. Ther Adv Chronic Dis 2013; 4 (03) 119-141