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Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management

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Abstract

Autoimmune hepatitis is a consequence of perturbations in homeostatic mechanisms that maintain self-tolerance but are incompletely understood. The goals of this review are to describe key pathogenic pathways that have been under-evaluated or unassessed in autoimmune hepatitis, describe insights that may shape future therapies, and encourage investigational efforts. The T cell immunoglobulin mucin proteins constitute a family that modulates immune tolerance by limiting the survival of immune effector cells, clearing apoptotic bodies, and expanding the population of granulocytic myeloid-derived suppressor cells. Galectins influence immune cell migration, activation, proliferation, and survival, and T cell exhaustion can be induced and exploited as a possible management strategy. The programmed cell death-1 protein and its ligands comprise an antigen-independent inhibitory axis that can limit the performance of activated T cells by altering their metabolism, and epigenetic changes can silence pro-inflammatory genes or de-repress anti-inflammatory genes that affect disease severity. Changes in the intestinal microbiota and permeability of the intestinal mucosal barrier can be causative or consequential events that affect the occurrence and phenotype of immune-mediated disease, and they may help explain the female propensity for autoimmune hepatitis. Perturbations within these homeostatic mechanisms have been implicated in experimental models and limited clinical experiences, and they have been favorably manipulated by monoclonal antibodies, recombinant molecules, pharmacological agents or dietary supplements. In conclusion, pathogenic mechanisms that have been implicated in other systemic immune-mediated and liver diseases but under-evaluated or unassessed in autoimmune hepatitis warrant consideration and rigorous evaluation.

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References

  1. Liberal R, Longhi MS, Mieli-Vergani G, Vergani D. Pathogenesis of autoimmune hepatitis. Best Prac Res Clin Gastroenterol. 2011;25:653–664.

    Article  CAS  Google Scholar 

  2. Czaja AJ. Transitioning from idiopathic to explainable autoimmune hepatitis. Dig Dis Sci. 2015;60:2881–2900.

    Article  PubMed  CAS  Google Scholar 

  3. Bogdanos DP, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver. 2001;21:225–232.

    Article  PubMed  CAS  Google Scholar 

  4. Bowen DG. Of mice and molecular mimicry: modeling autoimmune hepatitis. Hepatology. 2008;48:1013–1015.

    Article  PubMed  Google Scholar 

  5. Hintermann E, Holdener M, Bayer M, et al. Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J Autoimmun. 2011;37:242–253.

    Article  PubMed  CAS  Google Scholar 

  6. Ehser J, Holdener M, Christen S, et al. Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune hepatitis. J Autoimmun. 2013;42:39–49.

    Article  PubMed  CAS  Google Scholar 

  7. Lohr H, Manns M, Kyriatsoulis A, et al. Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis. Clin Exp Immunol. 1991;84:297–302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Schlaak JF, Lohr H, Gallati H, Meyer zum Buschenfelde KH, Fleischer B. Analysis of the in vitro cytokine production by liver-infiltrating T cells of patients with autoimmune hepatitis. Clin Exp Immunol. 1993;94:168–173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Maggiore G, De Benedetti F, Massa M, Pignatti P, Martini A. Circulating levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in children with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 1995;20:23–27.

    Article  PubMed  CAS  Google Scholar 

  10. 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.

    Article  PubMed  CAS  Google Scholar 

  11. Czaja AJ, Sievers C, Zein NN. Nature and behavior of serum cytokines in type 1 autoimmune hepatitis. Dig Dis Sci. 2000;45:1028–1035.

    Article  PubMed  CAS  Google Scholar 

  12. Kamijo A, Yoshizawa K, Joshita S, et al. Cytokine profiles affecting the pathogenesis of autoimmune hepatitis in Japanese patients. Hepatol Res. 2011;41:350–357.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. Landi A, Weismuller TJ, Lankisch TO, et al. Differential serum levels of eosinophilic eotaxins in primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis. J Interferon Cytokine Res. 2014;34:204–214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Behfarjam F, Sanati MH, Nasseri Moghaddam S, et al. Role of Th1/Th2 cells and related cytokines in autoimmune hepatitis. Turk J Gastroenterol. 2017;28:110–114.

    Article  PubMed  Google Scholar 

  16. Czaja AJ. Review article: chemokines as orchestrators of autoimmune hepatitis and potential therapeutic targets. Aliment Pharmacol Ther. 2014;40:261–279.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. Longhi MS, Ma Y, Grant CR, et al. T-regs in autoimmune hepatitis-systemic lupus erythematosus/mixed connective tissue disease overlap syndrome are functionally defective and display a Th1 cytokine profile. J Autoimmun. 2013;41:146–151.

    Article  PubMed  CAS  Google Scholar 

  21. 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;62:863–875.

    Article  PubMed  CAS  Google Scholar 

  22. Migita K, Komori A, Kozuru H, et al. Circulating microRNA profiles in patients with type-1 autoimmune hepatitis. PLoS One. 2015;10:e0136908.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Czaja AJ. Emerging therapeutic biomarkers of autoimmune hepatitis and their impact on current and future management. Expert Rev Gastroenterol Hepatol. 2018;. https://doi.org/10.1080/17474124.2018.1453356.

    Article  PubMed  Google Scholar 

  24. Mataki N, Kikuchi K, Kawai T, et al. Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases. Am J Gastroenterol. 2007;102:302–312.

    Article  PubMed  CAS  Google Scholar 

  25. Oikawa T, Takahashi H, Ishikawa T, et al. Intrahepatic expression of the co-stimulatory molecules programmed death-1, and its ligands in autoimmune liver disease. Pathol Int. 2007;57:485–492.

    Article  PubMed  CAS  Google Scholar 

  26. Matsumoto K, Miyake Y, Matsushita H, et al. Anti-programmed cell death-1 antibody as a new serological marker for type 1 autoimmune hepatitis. J Gastroenterol Hepatol. 2014;29:110–115.

    Article  PubMed  CAS  Google Scholar 

  27. Miyake Y, Yamamoto K, Matsushita H, et al. Multicenter validation study of anti-programmed cell death-1 antibody as a serological marker for type 1 autoimmune hepatitis. Hepatol Res. 2014;44:1299–1307.

    Article  PubMed  CAS  Google Scholar 

  28. Aarslev K, Dige A, Greisen SR, et al. Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis. Scand J Gastroenterol. 2017;52:93–99.

    Article  PubMed  CAS  Google Scholar 

  29. Gronbaek H, Kreutzfeldt M, Kazankov K, et al. Single-centre experience of the macrophage activation marker soluble (s)CD163—associations with disease activity and treatment response in patients with autoimmune hepatitis. Aliment Pharmacol Ther. 2016;44:1062–1070.

    Article  PubMed  CAS  Google Scholar 

  30. Moller HJ. Soluble CD163. Scand J Clin Lab Invest. 2012;72:1–13.

    Article  PubMed  CAS  Google Scholar 

  31. Assis DN, Leng L, Du X, et al. The role of macrophage migration inhibitory factor in autoimmune liver disease. Hepatology. 2014;59:580–591.

    Article  PubMed  CAS  Google Scholar 

  32. Assis DN, Takahashi H, Leng L, et al. A macrophage migration inhibitory factor polymorphism is associated with autoimmune hepatitis severity in US and Japanese patients. Dig Dis Sci. 2016;61:3506–3512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Migita K, Abiru S, Maeda Y, et al. Elevated serum BAFF levels in patients with autoimmune hepatitis. Hum Immunol. 2007;68:586–591.

    Article  PubMed  CAS  Google Scholar 

  34. Nishikawa H, Enomoto H, Iwata Y, et al. B-cell activating factor belonging to the tumor necrosis factor family and interferon-gamma-Inducible protein-10 in autoimmune hepatitis. Medicine (Baltimore). 2016;95:e3194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Strettell MD, Donaldson PT, Thomson LJ, et al. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology. 1997;112:2028–2035.

    Article  PubMed  CAS  Google Scholar 

  36. Czaja AJ, Strettell MD, Thomson LJ, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology. 1997;25:317–323.

    Article  PubMed  CAS  Google Scholar 

  37. Yokosawa S, Yoshizawa K, Ota M, et al. A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1. Hepatology. 2007;45:384–390.

    Article  PubMed  CAS  Google Scholar 

  38. Mells GF, Kaser A, Karlsen TH. Novel insights into autoimmune liver diseases provided by genome-wide association studies. J Autoimmun. 2013;46:41–54.

    Article  PubMed  CAS  Google Scholar 

  39. de Boer YS, van Gerven NM, Zwiers A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 2014;147:443–452.

    Article  PubMed  CAS  Google Scholar 

  40. van Gerven NM, de Boer YS, Zwiers A, et al. HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun. 2015;16:247–252.

    Article  PubMed  CAS  Google Scholar 

  41. Umemura T, Joshita S, Hamano H, et al. Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients. J Hum Genet. 2017;62:963–967.

    Article  PubMed  CAS  Google Scholar 

  42. Fox CK, Furtwaengler A, Nepomuceno RR, Martinez OM, Krams SM. Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. Liver. 2001;21:272–279.

    Article  PubMed  CAS  Google Scholar 

  43. Bai J, Odin JA. Apoptosis and the liver: relation to autoimmunity and related conditions. Autoimmun Rev. 2003;2:36–42.

    Article  PubMed  Google Scholar 

  44. Czaja AJ. Targeting apoptosis in autoimmune hepatitis. Dig Dis Sci. 2014;59:2890–2904.

    Article  PubMed  CAS  Google Scholar 

  45. Sanz-Cameno P, Medina J, Garcia-Buey L, et al. Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis. J Hepatol. 2002;37:723–729.

    Article  PubMed  CAS  Google Scholar 

  46. Efe C, Kav T, Aydin C, et al. Low serum vitamin D levels are associated with severe histological features and poor response to therapy in patients with autoimmune hepatitis. Dig Dis Sci. 2014;59:3035–3042.

    Article  PubMed  CAS  Google Scholar 

  47. Beyazit Y, Kocak E, Tanoglu A, Kekilli M. Oxidative stress might play a role in low serum vitamin D associated liver fibrosis among patients with autoimmune hepatitis. Dig Dis Sci. 2015;60:1106–1108.

    Article  PubMed  Google Scholar 

  48. Beyazit Y, Efe C, Tanoglu A, et al. Nitric oxide is a potential mediator of hepatic inflammation and fibrogenesis in autoimmune hepatitis. Scand J Gastroenterol. 2015;50:204–210.

    Article  PubMed  CAS  Google Scholar 

  49. Czaja AJ. Nature and implications of oxidative and nitrosative stresses in autoimmune hepatitis. Dig Dis Sci. 2016;61:2784–2803.

    Article  PubMed  CAS  Google Scholar 

  50. Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol. 2004;40:646–652.

    Article  PubMed  CAS  Google Scholar 

  51. Czaja AJ. Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol. 2009;51:161–167.

    Article  PubMed  CAS  Google Scholar 

  52. Montano-Loza AJ, Thandassery RB, Czaja AJ. Targeting hepatic fibrosis in autoimmune hepatitis. Dig Dis Sci. 2016;61:3118–3139.

    Article  PubMed  CAS  Google Scholar 

  53. Wang J, Malik N, Yin M, et al. Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis. World J Gastroenterol. 2017;23:859–868.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Meyers JH, Sabatos CA, Chakravarti S, Kuchroo VK. The TIM gene family regulates autoimmune and allergic diseases. Trends Mol Med. 2005;11:362–369.

    Article  PubMed  CAS  Google Scholar 

  55. Zhu C, Anderson AC, Schubart A, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–1252.

    Article  PubMed  CAS  Google Scholar 

  56. Zhu C, Anderson AC, Kuchroo VK. TIM-3 and its regulatory role in immune responses. Curr Top Microbiol Immunol. 2011;350:1–15.

    PubMed  CAS  Google Scholar 

  57. Zhang Y, Ma CJ, Wang JM, et al. Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14 + monocytes. J Leukoc Biol. 2012;91:189–196.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8 + T cell exhaustion during chronic viral infection. Immunity. 2007;27:670–684.

    Article  PubMed  CAS  Google Scholar 

  59. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–499.

    Article  PubMed  CAS  Google Scholar 

  60. Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 2014;35:51–60.

    Article  PubMed  CAS  Google Scholar 

  61. McKinney EF, Lee JC, Jayne DR, Lyons PA, Smith KG. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature. 2015;523:612–616.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–499.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. McKinney EF, Smith KG. T-cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases. Immunol Cell Biol. 2016;94:935–942.

    Article  PubMed  CAS  Google Scholar 

  64. McKinney EF, Smith KG. T cell exhaustion and immune-mediated disease-the potential for therapeutic exhaustion. Curr Opin Immunol. 2016;43:74–80.

    Article  PubMed  CAS  Google Scholar 

  65. Catakovic K, Klieser E, Neureiter D, Geisberger R. T cell exhaustion: from pathophysiological basics to tumor immunotherapy. Cell Commun Signal. 2017;15:1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–242.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N. PD-1/PD-L and autoimmunity: a growing relationship. Cell Immunol. 2016;310:27–41.

    Article  PubMed  CAS  Google Scholar 

  69. Mann DA. Epigenetics in liver disease. Hepatology. 2014;60:1418–1425.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Jeffries MA, Sawalha AH. Autoimmune disease in the epigenetic era: how has epigenetics changed our understanding of disease and how can we expect the field to evolve? Expert Rev Clin Immunol. 2015;11:45–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Czaja AJ. Epigenetic changes and their implications in autoimmune hepatitis. Eur J Clin Invest. 2018;48:e12899.

    Article  CAS  Google Scholar 

  72. Lin R, Zhou L, Zhang J, Wang B. Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis. Int J Clin Exp Pathol. 2015;8:5153–5160.

    PubMed  PubMed Central  CAS  Google Scholar 

  73. 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;62:1536–1550.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Czaja AJ. Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis. World J Gastroenterol. 2016;22:9257–9278.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Kuchroo VK, Umetsu DT, DeKruyff RH, Freeman GJ. The TIM gene family: emerging roles in immunity and disease. Nat Rev Immunol. 2003;3:454–462.

    Article  PubMed  CAS  Google Scholar 

  76. Kuchroo VK, Meyers JH, Umetsu DT, DeKruyff RH. TIM family of genes in immunity and tolerance. Adv Immunol. 2006;91:227–249.

    Article  PubMed  CAS  Google Scholar 

  77. Chakravarti S, Sabatos CA, Xiao S, et al. Tim-2 regulates T helper type 2 responses and autoimmunity. J Exp Med. 2005;202:437–444.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Xiao S, Najafian N, Reddy J, et al. Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function. J Exp Med. 2007;204:1691–1702.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Cao E, Zang X, Ramagopal UA, et al. T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity. 2007;26:311–321.

    Article  PubMed  CAS  Google Scholar 

  80. Santiago C, Ballesteros A, Tami C, et al. Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity. 2007;26:299–310.

    Article  PubMed  CAS  Google Scholar 

  81. Kobayashi N, Karisola P, Pena-Cruz V, et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity. 2007;27:927–940.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Umetsu SE, Lee WL, McIntire JJ, et al. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nat Immunol. 2005;6:447–454.

    Article  PubMed  CAS  Google Scholar 

  83. Xiao S, Brooks CR, Zhu C, et al. Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice. Proc Natl Acad Sci U S A. 2012;109:12105–12110.

    Article  PubMed  PubMed Central  Google Scholar 

  84. DiLillo DJ, Matsushita T, Tedder TF. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N Y Acad Sci. 2010;1183:38–57.

    Article  PubMed  CAS  Google Scholar 

  85. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221–241.

    Article  PubMed  CAS  Google Scholar 

  86. Bouaziz JD, Le Buanec H, Saussine A, Bensussan A, Bagot M. IL-10 producing regulatory B cells in mice and humans: state of the art. Curr Mol Med. 2012;12:519–527.

    Article  PubMed  CAS  Google Scholar 

  87. Yang M, Rui K, Wang S, Lu L. Regulatory B cells in autoimmune diseases. Cell Mol Immunol. 2013;10:122–132.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Xiao S, Brooks CR, Sobel RA, Kuchroo VK. Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. J Immunol. 2015;194:1602–1608.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Gray M, Miles K, Salter D, Gray D, Savill J. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci U S A. 2007;104:14080–14085.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Miles K, Heaney J, Sibinska Z, et al. A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells. Proc Natl Acad Sci U S A. 2012;109:887–892.

    Article  PubMed  Google Scholar 

  91. Ueno T, Habicht A, Clarkson MR, et al. The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model. J Clin Invest. 2008;118:742–751.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Monney L, Sabatos CA, Gaglia JL, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–541.

    Article  PubMed  CAS  Google Scholar 

  93. Imaizumi T, Kumagai M, Sasaki N, et al. Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol. 2002;72:486–491.

    PubMed  CAS  Google Scholar 

  94. Dardalhon V, Anderson AC, Karman J, et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b + Ly-6G + myeloid cells. J Immunol. 2010;185:1383–1392.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008;181:5791–5802.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Movahedi K, Guilliams M, Van den Bossche J, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008;111:4233–4244.

    Article  PubMed  CAS  Google Scholar 

  97. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–174.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Fridlender ZG, Sun J, Mishalian I, et al. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One. 2012;7:e31524.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Deniset JF, Kubes P. Recent advances in understanding neutrophils. F1000Res. 2016;5:2912.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Wright GJ, Cherwinski H, Foster-Cuevas M, et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J Immunol. 2003;171:3034–3046.

    Article  PubMed  CAS  Google Scholar 

  101. Fischer MA, Davies ML, Reider IE, et al. CD11b(+), Ly6G(+) cells produce type I interferon and exhibit tissue protective properties following peripheral virus infection. PLoS Pathog. 2011;7:e1002374.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol. 2010;184:3106–3116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Nakayama M, Akiba H, Takeda K, et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009;113:3821–3830.

    Article  PubMed  CAS  Google Scholar 

  104. Meyers JH, Chakravarti S, Schlesinger D, et al. TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation. Nat Immunol. 2005;6:455–464.

    Article  PubMed  CAS  Google Scholar 

  105. John S, Mishra R. Galectin-9: From cell biology to complex disease dynamics. J Biosci. 2016;41:507–534.

    Article  PubMed  CAS  Google Scholar 

  106. Golden-Mason L, Rosen HR. Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology. 2017;66:271–279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Vaitaitis GM, Wagner DH Jr. Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity. PLoS One. 2012;7:e38708.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Morgan R, Gao G, Pawling J, et al. N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J Immunol. 2004;173:7200–7208.

    Article  PubMed  CAS  Google Scholar 

  109. Grigorian A, Lee SU, Tian W, et al. Control of T Cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J Biol Chem. 2007;282:20027–20035.

    Article  PubMed  CAS  Google Scholar 

  110. Marth JD, Grewal PK. Mammalian glycosylation in immunity. Nat Rev Immunol. 2008;8:874–887.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Bacigalupo ML, Manzi M, Rabinovich GA, Troncoso MF. Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma. World J Gastroenterol. 2013;19:8831–8849.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Yang RY, Hsu DK, Liu FT. Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci U S A. 1996;93:6737–6742.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Demetriou M, Granovsky M, Quaggin S, Dennis JW. Negative regulation of T-cell activation and autoimmunity by Mgat5N-glycosylation. Nature. 2001;409:733–739.

    Article  PubMed  CAS  Google Scholar 

  114. Lv K, Zhang Y, Zhang M, Zhong M, Suo Q. Galectin-9 ameliorates Con A-induced hepatitis by inducing CD4(+)CD25(low/int) effector T-Cell apoptosis and increasing regulatory T cell number. PLoS One. 2012;7:e48379.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Tadokoro T, Morishita A, Sakamoto T, et al. Galectin9 ameliorates fulminant liver injury. Mol Med Rep. 2017;16:36–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Kashio Y, Nakamura K, Abedin MJ, et al. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J Immunol. 2003;170:3631–3636.

    Article  PubMed  CAS  Google Scholar 

  117. Su EW, Bi S, Kane LP. Galectin-9 regulates T helper cell function independently of Tim-3. Glycobiology. 2011;21:1258–1265.

    Article  PubMed  CAS  Google Scholar 

  118. Seki M, Oomizu S, Sakata KM, et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127:78–88.

    Article  PubMed  CAS  Google Scholar 

  119. Sehrawat S, Suryawanshi A, Hirashima M, Rouse BT. Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: shifting the balance toward regulators. J Immunol. 2009;182:3191–3201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Wiersma VR, de Bruyn M, Helfrich W, Bremer E. Therapeutic potential of Galectin-9 in human disease. Med Res Rev. 2013;33:E102–E126.

    Article  PubMed  CAS  Google Scholar 

  121. Mengshol JA, Golden-Mason L, Arikawa T, et al. A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One. 2010;5:e9504.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Rosen HR. Emerging concepts in immunity to hepatitis C virus infection. J Clin Invest. 2013;123:4121–4130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Tang ZH, Liang S, Potter J, et al. Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease. J Immunol. 2013;190:1788–1796.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Markwick LJ, Riva A, Ryan JM, et al. Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis. Gastroenterology. 2015;148:590–602.

    Article  PubMed  CAS  Google Scholar 

  125. Montano-Loza AJ, Czaja AJ. Cell mediators of autoimmune hepatitis and their therapeutic implications. Dig Dis Sci. 2014;60:1528–1542.

    Article  PubMed  CAS  Google Scholar 

  126. Czaja AJ. Evolving paradigm for treatment of autoimmune hepatitis. Expert Rev Clin Immunol. 2017;13:781–798.

    Article  PubMed  CAS  Google Scholar 

  127. Zajac AJ, Blattman JN, Murali-Krishna K, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998;188:2205–2213.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003;77:4911–4927.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Davoodzadeh Gholami M, Kardar GA, Saeedi Y, et al. Exhaustion of T lymphocytes in the tumor microenvironment: significance and effective mechanisms. Cell Immunol 2017;322:1–14.

    Article  PubMed  CAS  Google Scholar 

  130. Brooks DG, McGavern DB, Oldstone MB. Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection. J Clin Invest. 2006;116:1675–1685.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015;6:7–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A. 2009;106:8623–8628.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Kahan SM, Wherry EJ, Zajac AJ. T cell exhaustion during persistent viral infections. Virology. 2015;479–480:180–193.

    Article  PubMed  CAS  Google Scholar 

  134. Bellon M, Nicot C. Telomere dynamics in immune senescence and exhaustion triggered by chronic viral infection. Viruses. 2017;9:289.

    Article  PubMed Central  Google Scholar 

  135. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–687.

    Article  PubMed  CAS  Google Scholar 

  136. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–245.

    Article  PubMed  CAS  Google Scholar 

  137. Wei F, Zhong S, Ma Z, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A. 2013;110:E2480–E2489.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8 + T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.

    Article  PubMed  CAS  Google Scholar 

  139. Crawford A, Angelosanto JM, Kao C, et al. Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection. Immunity. 2014;40:289–302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Lang KS, Recher M, Navarini AA, et al. Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation. Eur J Immunol. 2005;35:738–745.

    Article  PubMed  CAS  Google Scholar 

  141. Im SJ, Hashimoto M, Gerner MY, et al. Defining CD8 + T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537:417–421.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Blackburn SD, Shin H, Freeman GJ, Wherry EJ. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A. 2008;105:15016–15021.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Intlekofer AM, Takemoto N, Wherry EJ, et al. Effector and memory CD8 + T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005;6:1236–1244.

    Article  PubMed  CAS  Google Scholar 

  144. Paley MA, Kroy DC, Odorizzi PM, et al. Progenitor and terminal subsets of CD8 + T cells cooperate to contain chronic viral infection. Science. 2012;338:1220–1225.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Matloubian M, Concepcion RJ, Ahmed R. CD4 + T cells are required to sustain CD8 + cytotoxic T-cell responses during chronic viral infection. J Virol. 1994;68:8056–8063.

    PubMed  PubMed Central  CAS  Google Scholar 

  146. Parrish-Novak J, Dillon SR, Nelson A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57–63.

    Article  PubMed  CAS  Google Scholar 

  147. Parrish-Novak J, Foster DC, Holly RD, Clegg CH. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukoc Biol. 2002;72:856–863.

    PubMed  CAS  Google Scholar 

  148. Li Y, Bleakley M, Yee C. IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J Immunol. 2005;175:2261–2269.

    Article  PubMed  CAS  Google Scholar 

  149. Johnson LD, Jameson SC. Immunology. A chronic need for IL-21. Science. 2009;324:1525–1526.

    Article  PubMed  CAS  Google Scholar 

  150. Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science. 2009;324:1569–1572.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Yi JS, Du M, Zajac AJ. A vital role for interleukin-21 in the control of a chronic viral infection. Science. 2009;324:1572–1576.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Wilkins AL, Yang W, Yang JJ. Structural biology of the cell adhesion protein CD2: from molecular recognition to protein folding and design. Curr Protein Pept Sci. 2003;4:367–373.

    Article  PubMed  CAS  Google Scholar 

  153. Bolduan S, Koppensteiner H, Businger R, et al. T cells with low CD2 levels express reduced restriction factors and are preferentially infected in therapy naive chronic HIV-1 patients. J Int AIDS Soc. 2017;20:21865.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Harcharik S, Bernardo S, Moskalenko M, et al. Defining the role of CD2 in disease progression and overall survival among patients with completely resected stage-II to -III cutaneous melanoma. J Am Acad Dermatol. 2014;70:1036–1044.

    Article  PubMed  Google Scholar 

  155. Brooks DG, Ha SJ, Elsaesser H, et al. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc Natl Acad Sci U S A. 2008;105:20428–20433.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Tinoco R, Alcalde V, Yang Y, Sauer K, Zuniga EI. Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8 + T cell deletion and viral persistence in vivo. Immunity. 2009;31:145–157.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Garidou L, Heydari S, Gossa S, McGavern DB. Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection. J Virol. 2012;86:7060–7071.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Boettler T, Cheng Y, Ehrhardt K, von Herrath M. TGF-beta blockade does not improve control of an established persistent viral infection. Viral Immunol. 2012;25:232–238.

    PubMed  PubMed Central  CAS  Google Scholar 

  159. Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012;5:ra46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015–3029.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365–1369.

    Article  PubMed  CAS  Google Scholar 

  162. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–268.

    Article  PubMed  CAS  Google Scholar 

  164. Chen CL, Pan QZ, Zhao JJ, et al. PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma. Oncoimmunology. 2016;5:e1176653.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193:839–846.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A. 2003;100:5336–5341.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Frauwirth KA, Thompson CB. Regulation of T lymphocyte metabolism. J Immunol. 2004;172:4661–4665.

    Article  PubMed  CAS  Google Scholar 

  168. Chang CH, Curtis JD, Maggi LB Jr, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013;153:1239–1251.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Tkachev V, Goodell S, Opipari AW, et al. Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol. 2015;194:5789–5800.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Patsoukis N, Bardhan K, Chatterjee P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Michalek RD, Gerriets VA, Jacobs SR, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4 + T cell subsets. J Immunol. 2011;186:3299–3303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Nielsen C, Ohm-Laursen L, Barington T, Husby S, Lillevang ST. Alternative splice variants of the human PD-1 gene. Cell Immunol. 2005;235:109–116.

    Article  PubMed  CAS  Google Scholar 

  173. Wan B, Nie H, Liu A, et al. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol. 2006;177:8844–8850.

    Article  PubMed  CAS  Google Scholar 

  174. Bird A. Perceptions of epigenetics. Nature. 2007;447:396–398.

    Article  PubMed  CAS  Google Scholar 

  175. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23:781–783.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Javierre BM, Hernando H, Ballestar E. Environmental triggers and epigenetic deregulation in autoimmune disease. Discov Med. 2011;12:535–545.

    PubMed  Google Scholar 

  177. Meda F, Folci M, Baccarelli A, Selmi C. The epigenetics of autoimmunity. Cell Mol Immunol. 2011;8:226–236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Heyn H, Moran S, Hernando-Herraez I, et al. DNA methylation contributes to natural human variation. Genome Res. 2013;23:1363–1372.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Canas CA, Canas F, Bonilla-Abadia F, Ospina FE, Tobon GJ. Epigenetics changes associated to environmental triggers in autoimmunity. Autoimmunity. 2016;49:1–11.

    Article  PubMed  CAS  Google Scholar 

  180. Issa JP. Aging and epigenetic drift: a vicious cycle. J Clin Invest. 2014;124:24–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Dozmorov MG, Coit P, Maksimowicz-McKinnon K, Sawalha AH. Age-associated DNA methylation changes in naive CD4 + T cells suggest an evolving autoimmune epigenotype in aging T cells. Epigenomics. 2017;9:429–445.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Maegawa S, Gough SM, Watanabe-Okochi N, et al. Age-related epigenetic drift in the pathogenesis of MDS and AML. Genome Res. 2014;24:580–591.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803.

    Article  PubMed  CAS  Google Scholar 

  184. Fang F, Balch C, Schilder J, et al. A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer. 2010;116:4043–4053.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Konkankit VV, Kim W, Koya RC, et al. Decitabine immunosensitizes human gliomas to NY-ESO-1 specific T lymphocyte targeting through the Fas/Fas ligand pathway. J Transl Med. 2011;9:192.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Scandura JM, Roboz GJ, Moh M, et al. Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. Blood. 2011;118:1472–1480.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.

    Article  PubMed  CAS  Google Scholar 

  188. Zeng W, Dai H, Yan M, et al. Decitabine-induced changes in human myelodysplastic syndrome cell line SKM-1 are mediated by FOXO3A activation. J Immunol Res. 2017;2017:4302320.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Szyf M. Epigenetic therapeutics in autoimmune disease. Clin Rev Allergy Immunol. 2010;39:62–77.

    Article  PubMed  CAS  Google Scholar 

  190. Radic M, Muller S. Epigenetics of autoantigens: new opportunities for therapy of autoimmune diseases. Genet Epigenet. 2013;5:63–70.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Tough DF, Prinjha RK. Immune disease-associated variants in gene enhancers point to BET epigenetic mechanisms for therapeutic intervention. Epigenomics. 2017;9:573–584.

    Article  PubMed  CAS  Google Scholar 

  192. Somers EC, Richardson BC. Environmental exposures, epigenetic changes and the risk of lupus. Lupus. 2014;23:568–576.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Relle M, Foehr B, Schwarting A. Epigenetic aspects of systemic lupus erythematosus. Rheumatol Ther. 2015;2:33–46.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Liu Y, Aryee MJ, Padyukov L, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31:142–147.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Lian X, Xiao R, Hu X, et al. DNA demethylation of CD40 l in CD4 + T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum. 2012;64:2338–2345.

    Article  PubMed  CAS  Google Scholar 

  196. Lleo A, Zhang W, Zhao M, et al. DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis. Clin Epigenetics. 2015;7:61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Murphy SK, Yang H, Moylan CA, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145:1076–1087.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Cedar H, Bergman Y. Programming of DNA methylation patterns. Annu Rev Biochem. 2012;81:97–117.

    Article  PubMed  CAS  Google Scholar 

  199. Javierre BM, Fernandez AF, Richter J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010;20:170–179.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 1998;18:6538–6547.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Hendrich B, Abbott C, McQueen H, et al. Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mamm Genome. 1999;10:906–912.

    Article  PubMed  CAS  Google Scholar 

  202. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–935.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Ito S, Shen L, Dai Q, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333:1300–1303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Guo JU, Su Y, Zhong C, Ming GL, Song H. Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell Cycle. 2011;10:2662–2668.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502:472–479.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Gunther K, Rust M, Leers J, et al. Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. Nucleic Acids Res. 2013;41:3010–3021.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Baubec T, Ivanek R, Lienert F, Schubeler D. Methylation-dependent and -independent genomic targeting principles of the MBD protein family. Cell. 2013;153:480–492.

    Article  PubMed  CAS  Google Scholar 

  208. Menafra R, Stunnenberg HG. MBD2 and MBD3: elusive functions and mechanisms. Front Genet. 2014;5:428.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28:1057–1068.

    Article  PubMed  CAS  Google Scholar 

  210. Baubec T, Colombo DF, Wirbelauer C, et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature. 2015;520:243–247.

    Article  PubMed  CAS  Google Scholar 

  211. Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature. 1997;389:251–260.

    Article  PubMed  CAS  Google Scholar 

  212. Osley MA, Fleming AB, Kao CF. Histone ubiquitylation and the regulation of transcription. Results Probl Cell Differ. 2006;41:47–75.

    Article  PubMed  CAS  Google Scholar 

  213. Wysocka J, Allis CD, Coonrod S. Histone arginine methylation and its dynamic regulation. Front Biosci. 2006;11:344–355.

    Article  PubMed  CAS  Google Scholar 

  214. Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell. 2012;48:491–507.

    Article  PubMed  CAS  Google Scholar 

  215. Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Annu Rev Biochem. 2001;70:81–120.

    Article  PubMed  CAS  Google Scholar 

  216. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–749.

    Article  PubMed  PubMed Central  Google Scholar 

  217. Thiagalingam S, Cheng KH, Lee HJ, et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann N Y Acad Sci. 2003;983:84–100.

    Article  PubMed  CAS  Google Scholar 

  218. Knight JS, Zhao W, Luo W, et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest. 2013;123:2981–2993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Kondo Y, Shen L, Cheng AS, et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet. 2008;40:741–750.

    Article  PubMed  CAS  Google Scholar 

  220. Fisher L, Fisher A. Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease. Clin Gastroenterol Hepatol. 2007;5:513–520.

    Article  PubMed  CAS  Google Scholar 

  221. Miroliaee A, Nasiri-Toosi M, Khalilzadeh O, et al. Disturbances of parathyroid hormone-vitamin D axis in non-cholestatic chronic liver disease: a cross-sectional study. Hepatol Int. 2010;4:634–640.

    Article  PubMed  PubMed Central  Google Scholar 

  222. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689S–1696S.

    Article  PubMed  CAS  Google Scholar 

  223. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005;289:F8–F28.

    Article  PubMed  CAS  Google Scholar 

  224. Kim S, Shevde NK, Pike JW. 1,25-dihydroxyvitamin D3 stimulates cyclic vitamin D receptor/retinoid X receptor DNA-binding, co-activator recruitment, and histone acetylation in intact osteoblasts. J Bone Miner Res. 2005;20:305–317.

    Article  PubMed  CAS  Google Scholar 

  225. Ramagopalan SV, Heger A, Berlanga AJ, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010;20:1352–1360.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology. 2002;35:126–131.

    Article  PubMed  CAS  Google Scholar 

  227. Fan L, Tu X, Zhu Y, et al. Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol. 2005;20:249–255.

    Article  PubMed  CAS  Google Scholar 

  228. Ohyama Y, Yamasaki T. Eight cytochrome P450s catalyze vitamin D metabolism. Front Biosci. 2004;9:3007–3018.

    Article  PubMed  CAS  Google Scholar 

  229. Zhang Y, Leung DY, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. 2012;188:2127–2135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Luong KV, Nguyen LT. The role of vitamin D in autoimmune hepatitis. J Clin Med Res. 2013;5:407–415.

    PubMed  PubMed Central  Google Scholar 

  231. Farh KK, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518:337–343.

    Article  PubMed  CAS  Google Scholar 

  232. Whyte WA, Orlando DA, Hnisz D, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153:307–319.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Hnisz D, Abraham BJ, Lee TI, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155:934–947.

    Article  PubMed  CAS  Google Scholar 

  234. Parker SC, Stitzel ML, Taylor DL, et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A. 2013;110:17921–17926.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Di Croce L, Raker VA, Corsaro M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002;295:1079–1082.

    Article  PubMed  Google Scholar 

  236. Vire E, Brenner C, Deplus R, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–874.

    Article  PubMed  CAS  Google Scholar 

  237. Zoetendal EG, Vaughan EE, de Vos WM. A microbial world within us. Mol Microbiol. 2006;59:1639–1650.

    Article  PubMed  CAS  Google Scholar 

  238. Booijink CC, Zoetendal EG, Kleerebezem M, de Vos WM. Microbial communities in the human small intestine: coupling diversity to metagenomics. Future Microbiol. 2007;2:285–295.

    Article  PubMed  CAS  Google Scholar 

  239. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–230.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  240. Mariat D, Firmesse O, Levenez F, et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 2009;9:123.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  241. Claesson MJ, Cusack S, O’Sullivan O, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A. 2011;108:4586–4591.

    Article  PubMed  Google Scholar 

  242. Jalanka-Tuovinen J, Salonen A, Nikkila J, et al. Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms. PLoS One. 2011;6:e23035.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  243. Miller GE, Engen PA, Gillevet PM, et al. Lower neighborhood socioeconomic status associated with reduced diversity of the colonic microbiota in healthy adults. PLoS One. 2016;11:e0148952.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Power SE, O’Toole PW, Stanton C, Ross RP, Fitzgerald GF. Intestinal microbiota, diet and health. Br J Nutr. 2014;111:387–402.

    Article  PubMed  CAS  Google Scholar 

  245. Wen L, Ley RE, Volchkov PY, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455:1109–1113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  246. Mejia-Leon ME, Barca AM. Diet, microbiota and immune system in type 1 diabetes development and evolution. Nutrients. 2015;7:9171–9184.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  247. Miyake S, Kim S, Suda W, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to clostridia XIVa and IV clusters. PLoS One. 2015;10:e0137429.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Rogier R, Koenders MI, Abdollahi-Roodsaz S. Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune arthritis. J Immunol Res. 2015;2015:527696.

    Article  PubMed  PubMed Central  Google Scholar 

  249. Sokol H, Seksik P, Rigottier-Gois L, et al. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis. 2006;12:106–111.

    Article  PubMed  Google Scholar 

  250. Miyake Y, Yamamoto K. Role of gut microbiota in liver diseases. Hepatol Res. 2013;43:139–146.

    Article  PubMed  CAS  Google Scholar 

  251. Henao-Mejia J, Elinav E, Thaiss CA, Licona-Limon P, Flavell RA. Role of the intestinal microbiome in liver disease. J Autoimmun. 2013;46:66–73.

    Article  PubMed  CAS  Google Scholar 

  252. Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139:323–334.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  253. Csak T, Ganz M, Pespisa J, et al. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology. 2011;54:133–144.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  254. Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–185.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  255. Mueller T, Beutler C, Pico AH, et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int. 2011;31:1574–1588.

    Article  PubMed  CAS  Google Scholar 

  256. Wang AP, Migita K, Ito M, et al. Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis. J Autoimmun. 2005;25:85–91.

    Article  PubMed  CAS  Google Scholar 

  257. Kikuchi K, Lian ZX, Yang GX, et al. Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. Gastroenterology. 2005;128:304–312.

    Article  PubMed  CAS  Google Scholar 

  258. Honda Y, Yamagiwa S, Matsuda Y, et al. Altered expression of TLR homolog RP105 on monocytes hypersensitive to LPS in patients with primary biliary cirrhosis. J Hepatol. 2007;47:404–411.

    Article  PubMed  CAS  Google Scholar 

  259. Tabibian JH, O’Hara SP, Trussoni CE, et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology. 2016;63:185–196.

    Article  PubMed  CAS  Google Scholar 

  260. Shimoda S, Harada K, Niiro H, et al. Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis. Hepatology. 2011;53:1270–1281.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Shimoda S, Hisamoto S, Harada K, et al. Natural killer cells regulate T cell immune responses in primary biliary cirrhosis. Hepatology. 2015;62:1817–1827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  262. Turley SJ, Lee JW, Dutton-Swain N, Mathis D, Benoist C. Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc Natl Acad Sci U S A. 2005;102:17729–17733.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  263. Chan CC, Hwang SJ, Lee FY, et al. Prognostic value of plasma endotoxin levels in patients with cirrhosis. Scand J Gastroenterol. 1997;32:942–946.

    Article  PubMed  CAS  Google Scholar 

  264. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology. 2005;41:422–433.

    Article  PubMed  CAS  Google Scholar 

  265. Czaja AJ. Review article: next-generation transformative advances in the pathogenesis and management of autoimmune hepatitis. Aliment Pharmacol Ther. 2017;46:920–937.

    Article  PubMed  CAS  Google Scholar 

  266. Yurkovetskiy L, Burrows M, Khan AA, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39:400–412.

    Article  PubMed  CAS  Google Scholar 

  267. Markle JG, Frank DN, Mortin-Toth S, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339:1084–1088.

    Article  PubMed  CAS  Google Scholar 

  268. Markle JG, Frank DN, Adeli K, von Bergen M, Danska JS. Microbiome manipulation modifies sex-specific risk for autoimmunity. Gut Microbes. 2014;5:485–493.

    Article  PubMed  Google Scholar 

  269. de Souza AJ, Oriss TB, O’Malley KJ, Ray A, Kane LP. T cell Ig and mucin 1 (TIM-1) is expressed on in vivo-activated T cells and provides a costimulatory signal for T cell activation. Proc Natl Acad Sci U S A. 2005;102:17113–17118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  270. Miller GT, Hochman PS, Meier W, et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med. 1993;178:211–222.

    Article  PubMed  CAS  Google Scholar 

  271. Majeau GR, Meier W, Jimmo B, Kioussis D, Hochman PS. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J Immunol. 1994;152:2753–2767.

    PubMed  CAS  Google Scholar 

  272. da Silva AJ, Brickelmaier M, Majeau GR, et al. Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. J Immunol. 2002;168:4462–4471.

    Article  PubMed  Google Scholar 

  273. Chamian F, Lowes MA, Lin SL, et al. Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci U S A. 2005;102:2075–2080.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  274. Weaver TA, Charafeddine AH, Agarwal A, et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med. 2009;15:746–749.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  275. Rigby MR, Harris KM, Pinckney A, et al. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest. 2015;125:3285–3296.

    Article  PubMed  PubMed Central  Google Scholar 

  276. Kuchen S, Robbins R, Sims GP, et al. Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4 + T cell-B cell collaboration. J Immunol. 2007;179:5886–5896.

    Article  PubMed  CAS  Google Scholar 

  277. Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009;78:273–304.

    Article  PubMed  CAS  Google Scholar 

  278. Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513:124–128.

    Article  PubMed  CAS  Google Scholar 

  279. Bandukwala HS, Gagnon J, Togher S, et al. Selective inhibition of CD4 + T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc Natl Acad Sci U S A. 2012;109:14532–14537.

    Article  PubMed  PubMed Central  Google Scholar 

  280. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54:728–736.

    Article  PubMed  CAS  Google Scholar 

  281. Balada E, Ordi-Ros J, Serrano-Acedo S, Martinez-Lostao L, Vilardell-Tarres M. Transcript overexpression of the MBD2 and MBD4 genes in CD4 + T cells from systemic lupus erythematosus patients. J Leukoc Biol. 2007;81:1609–1616.

    Article  PubMed  CAS  Google Scholar 

  282. Campbell PM, Bovenzi V, Szyf M. Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo. Carcinogenesis. 2004;25:499–507.

    Article  PubMed  CAS  Google Scholar 

  283. Peeters JG, Vervoort SJ, Tan SC, et al. Inhibition of super-enhancer activity in autoinflammatory site-derived T cells reduces disease-associated gene expression. Cell Rep. 2015;12:1986–1996.

    Article  PubMed  CAS  Google Scholar 

  284. Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468:1119–1123.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  285. Detich N, Hamm S, Just G, Knox JD, Szyf M. The methyl donor S-adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-adenosylmethionine. J Biol Chem. 2003;278:20812–20820.

    Article  PubMed  CAS  Google Scholar 

  286. Reiter FP, Hohenester S, Nagel JM, et al. 1,25-(OH)(2)-vitamin D(3) prevents activation of hepatic stellate cells in vitro and ameliorates inflammatory liver damage but not fibrosis in the Abcb4(-/-) model. Biochem Biophys Res Commun. 2015;459:227–233.

    Article  PubMed  CAS  Google Scholar 

  287. Abramovitch S, Sharvit E, Weisman Y, et al. Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2015;308:G112–G120.

    Article  PubMed  CAS  Google Scholar 

  288. Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500:232–236.

    Article  PubMed  CAS  Google Scholar 

  289. Lopez P, Gonzalez-Rodriguez I, Sanchez B, et al. Interaction of Bifidobacterium bifidum LMG13195 with HT29 cells influences regulatory-T-cell-associated chemokine receptor expression. Appl Environ Microbiol. 2012;78:2850–2857.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  290. Dolpady J, Sorini C, Di Pietro C, et al. Oral probiotic VSL#3 prevents autoimmune diabetes by modulating microbiota and promoting indoleamine 2,3-dioxygenase-enriched tolerogenic intestinal environment. J Diabetes Res. 2016;2016:7569431.

    Article  PubMed  CAS  Google Scholar 

  291. Pawar RD, Ramanjaneyulu A, Kulkarni OP, et al. Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J Am Soc Nephrol. 2007;18:1721–1731.

    Article  PubMed  CAS  Google Scholar 

  292. Scaldaferri F, Lopetuso LR, Petito V, et al. Gelatin tannate ameliorates acute colitis in mice by reinforcing mucus layer and modulating gut microbiota composition: Emerging role for ‘gut barrier protectors’ in IBD? United Eur Gastroenterol J. 2014;2:113–122.

    Article  Google Scholar 

  293. Stone M, Fortin PR, Pacheco-Tena C, Inman RD. Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. J Rheumatol. 2003;30:2112–2122.

    PubMed  CAS  Google Scholar 

  294. Tabibian JH, Weeding E, Jorgensen RA, et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis—a pilot study. Aliment Pharmacol Ther. 2013;37:604–612.

    Article  PubMed  CAS  Google Scholar 

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  1. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA

    Albert J. Czaja

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AJC researched, designed, and wrote this article. The tables are original, constructed by AJC, fully referenced, and developed solely for this review. The figure was drawn by AJC, and it has never been published previously. The review article is original, current, comprehensive, and previously unpublished.

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Czaja, A.J. Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management. Dig Dis Sci 63, 1706–1725 (2018). https://doi.org/10.1007/s10620-018-5072-x

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