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Semin Liver Dis 2014; 34(03): 285-296
DOI: 10.1055/s-0034-1383728
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Animal Models of Primary Biliary Cirrhosis

Jinjun Wang
1   Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California
2   College of Environmental Science and Engineering, Yangzhou University, Yangzhou, Jaingsu Province, China
,
Guo-Xiang Yang
1   Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California
,
Koichi Tsuneyama
3   Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
,
M. Eric Gershwin
1   Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California
,
William M. Ridgway
4   Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio
,
Patrick S.C. Leung
1   Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California
› Author Affiliations
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Publication History

Publication Date:
24 July 2014 (online)

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Abstract

Within the last decade, several mouse models that manifest characteristic features of primary biliary cirrhosis (PBC) with antimitochondrial antibodies (AMAs) and immune-mediated biliary duct pathology have been reported. Here, the authors discuss the current findings on two spontaneous (nonobese diabetic autoimmune biliary disease [NOD.ABD] and dominant negative transforming growth factor-β receptor II [dnTGFβRII]) and two induced (chemical xenobiotics and microbial immunization) models of PBC. These models exhibit the serological, immunological, and histopathological features of human PBC. From these animal models, it is evident that the etiology of PBC is multifactorial and requires both specific genetic predispositions and environmental insults (either xenobiotic chemicals or microbial), which lead to the breaking of tolerance and eventually liver pathology. Human PBC is likely orchestrated by multiple factors and hence no single model can fully mimic the immunopathophysiology of human PBC. Nevertheless, knowledge gained from these models has greatly advanced our understanding of the major immunological pathways as well as the etiology of PBC.

Keywords

antimitochondrial antibodies - cholangiocytes - dnTGFBRII - intrahepatic bile ducts - NOD.ABD - xenobiotics - microbial immunization
 

  • References

  • 1 Liu Y, Meyer C, Xu C , et al. Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol 2013; 304 (5) G449-G468
    CrossrefPubMedGoogle Scholar
  • 2 Gershwin ME, Ansari AA, Mackay IR , et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev 2000; 174: 210-225
    CrossrefPubMedGoogle Scholar
  • 3 Leung PS, Chuang DT, Wynn RM , et al. Autoantibodies to BCOADC-E2 in patients with primary biliary cirrhosis recognize a conformational epitope. Hepatology 1995; 22 (2) 505-513
    CrossrefPubMedGoogle Scholar
  • 4 Moteki S, Leung PS, Dickson ER , et al. Epitope mapping and reactivity of autoantibodies to the E2 component of 2-oxoglutarate dehydrogenase complex in primary biliary cirrhosis using recombinant 2-oxoglutarate dehydrogenase complex. Hepatology 1996; 23 (3) 436-444
    CrossrefPubMedGoogle Scholar
  • 5 Van de Water J, Ansari A, Prindiville T , et al. Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. J Exp Med 1995; 181 (2) 723-733
    CrossrefPubMedGoogle Scholar
  • 6 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
    PubMedGoogle Scholar
  • 7 You Z, Wang Q, Bian Z , et al. The immunopathology of liver granulomas in primary biliary cirrhosis. J Autoimmun 2012; 39 (3) 216-221
    CrossrefPubMedGoogle Scholar
  • 8 Ishibashi H, Shimoda S, Gershwin ME. The immune response to mitochondrial autoantigens. Semin Liver Dis 2005; 25 (3) 337-346
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Chuang YH, Ridgway WM, Ueno Y, Gershwin ME. Animal models of primary biliary cirrhosis. Clin Liver Dis 2008; 12 (2) 333-347 , ix ix
    CrossrefPubMedGoogle Scholar
  • 10 Gershwin ME, Mackay IR. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 2008; 47 (2) 737-745
    PubMedGoogle Scholar
  • 11 Leung PS, Coppel RL, Gershwin ME. Etiology of primary biliary cirrhosis: the search for the culprit. Semin Liver Dis 2005; 25 (3) 327-336
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Dhirapong A, Lleo A, Yang GX , et al. B cell depletion therapy exacerbates murine primary biliary cirrhosis. Hepatology 2011; 53 (2) 527-535
    CrossrefPubMedGoogle Scholar
  • 13 Lleo A, Bowlus CL, Yang GX , et al. Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 2010; 52 (3) 987-998
    CrossrefPubMedGoogle Scholar
  • 14 Oertelt S, Rieger R, Selmi C , et al. A sensitive bead assay for antimitochondrial antibodies: chipping away at AMA-negative primary biliary cirrhosis. Hepatology 2007; 45 (3) 659-665
    CrossrefPubMedGoogle Scholar
  • 15 Folci M, Meda F, Gershwin ME, Selmi C. Cutting-edge issues in primary biliary cirrhosis. Clin Rev Allergy Immunol 2012; 42 (3) 342-354
    CrossrefPubMedGoogle Scholar
  • 16 Ali F, Rowley M, Jayakrishnan B, Teuber S, Gershwin ME, Mackay IR. Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun 2011; 37 (2) 79-87
    CrossrefPubMedGoogle Scholar
  • 17 Jin Q, Moritoki Y, Lleo A , et al. Comparative analysis of portal cell infiltrates in antimitochondrial autoantibody-positive versus antimitochondrial autoantibody-negative primary biliary cirrhosis. Hepatology 2012; 55 (5) 1495-1506
    CrossrefPubMedGoogle Scholar
  • 18 Lleo A, Liao J, Invernizzi P , et al. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology 2012; 55 (1) 153-160
    CrossrefPubMedGoogle Scholar
  • 19 Persani L, Bonomi M, Lleo A , et al. Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis. J Autoimmun 2012; 38 (2-3) J193-J196
    CrossrefPubMedGoogle Scholar
  • 20 Rong G, Zhong R, Lleo A , et al. Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis. Hepatology 2011; 54 (1) 196-203
    CrossrefPubMedGoogle Scholar
  • 21 Takahashi T, Miura T, Nakamura J , et al. Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis. Hepatology 2012; 55 (3) 846-855
    CrossrefPubMedGoogle Scholar
  • 22 Wang Q, Selmi C, Zhou X , et al. Epigenetic considerations and the clinical reevaluation of the overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis. J Autoimmun 2013; 41: 140-145
    CrossrefPubMedGoogle Scholar
  • 23 Zhang W, Ono Y, Miyamura Y, Bowlus CL, Gershwin ME, Maverakis E. T cell clonal expansions detected in patients with primary biliary cirrhosis express CX3CR1. J Autoimmun 2011; 37 (2) 71-78
    CrossrefPubMedGoogle Scholar
  • 24 Kawata K, Tsuda M, Yang GX , et al. Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis. PLoS ONE 2013; 8 (9) e74225
    CrossrefPubMedGoogle Scholar
  • 25 Kawata K, Yang GX, Ando Y , et al. Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFβRII mice. Hepatology 2013; 58 (3) 1094-1104
    CrossrefPubMedGoogle Scholar
  • 26 Ando Y, Yang GX, Kenny TP , et al. Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse. J Autoimmun 2013; 41: 111-119
    CrossrefPubMedGoogle Scholar
  • 27 Dhirapong A, Yang GX, Nadler S , et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology 2013; 57 (2) 708-715
    CrossrefPubMedGoogle Scholar
  • 28 Kikutani H, Makino S. The murine autoimmune diabetes model: NOD and related strains. Adv Immunol 1992; 51: 285-322
    PubMedGoogle Scholar
  • 29 Chen YG, Scheuplein F, Osborne MA, Tsaih SW, Chapman HD, Serreze DV. Idd9/11 genetic locus regulates diabetogenic activity of CD4 T-cells in nonobese diabetic (NOD) mice. Diabetes 2008; 57 (12) 3273-3280
    CrossrefPubMedGoogle Scholar
  • 30 Fox CJ, Paterson AD, Mortin-Toth SM, Danska JS. Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis. Am J Hum Genet 2000; 67 (1) 67-81
    CrossrefPubMedGoogle Scholar
  • 31 Fraser HI, Dendrou CA, Healy B , et al. Nonobese diabetic congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene. J Immunol 2010; 184 (9) 5075-5084
    CrossrefPubMedGoogle Scholar
  • 32 Aoki CA, Borchers AT, Ridgway WM, Keen CL, Ansari AA, Gershwin ME. NOD mice and autoimmunity. Autoimmun Rev 2005; 4 (6) 373-379
    CrossrefPubMedGoogle Scholar
  • 33 Koarada S, Wu Y, Fertig N , et al. Genetic control of autoimmunity: protection from diabetes, but spontaneous autoimmune biliary disease in a nonobese diabetic congenic strain. J Immunol 2004; 173 (4) 2315-2323
    CrossrefPubMedGoogle Scholar
  • 34 Irie J, Wu Y, Wicker LS , et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006; 203 (5) 1209-1219
    CrossrefPubMedGoogle Scholar
  • 35 Yang GX, Wu Y, Tsukamoto H , et al. CD8 T cells mediate direct biliary ductule damage in nonobese diabetic autoimmune biliary disease. J Immunol 2011; 186 (2) 1259-1267
    CrossrefPubMedGoogle Scholar
  • 36 Taylor AW. Review of the activation of TGF-beta in immunity. J Leukoc Biol 2009; 85 (1) 29-33
    PubMedGoogle Scholar
  • 37 Yoshimura A, Wakabayashi Y, Mori T. Cellular and molecular basis for the regulation of inflammation by TGF-beta. J Biochem 2010; 147 (6) 781-792
    CrossrefPubMedGoogle Scholar
  • 38 Ebert EC, Panja A, Das KM , et al. Patients with inflammatory bowel disease may have a transforming growth factor-beta-, interleukin (IL)-2- or IL-10-deficient state induced by intrinsic neutralizing antibodies. Clin Exp Immunol 2009; 155 (1) 65-71
    CrossrefPubMedGoogle Scholar
  • 39 Kel JM, Girard-Madoux MJ, Reizis B, Clausen BE. TGF-beta is required to maintain the pool of immature Langerhans cells in the epidermis. J Immunol 2010; 185 (6) 3248-3255
    CrossrefPubMedGoogle Scholar
  • 40 Perruche S, Zhang P, Maruyama T, Bluestone JA, Saas P, Chen W. Lethal effect of CD3-specific antibody in mice deficient in TGF-beta1 by uncontrolled flu-like syndrome. J Immunol 2009; 183 (2) 953-961
    CrossrefPubMedGoogle Scholar
  • 41 Oertelt S, Lian ZX, Cheng CM , et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 2006; 177 (3) 1655-1660
    CrossrefPubMedGoogle Scholar
  • 42 Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000; 12 (2) 171-181
    CrossrefPubMedGoogle Scholar
  • 43 Chuang YH, Lian ZX, Yang GX , et al. Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 2008; 47 (2) 571-580
    PubMedGoogle Scholar
  • 44 Yang CY, Leung PS, Yang GX , et al. Epitope-specific anti-nuclear antibodies are expressed in a mouse model of primary biliary cirrhosis and are cytokine-dependent. Clin Exp Immunol 2012; 168 (3) 261-267
    CrossrefPubMedGoogle Scholar
  • 45 Invernizzi P, Crosignani A, Battezzati PM , et al. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Hepatology 1997; 25 (5) 1090-1095
    CrossrefPubMedGoogle Scholar
  • 46 Kim WR, Poterucha JJ, Jorgensen RA , et al. Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Outcomes of ursodeoxycholic acid therapy and liver transplantation. Hepatology 1997; 26 (1) 22-26
    PubMedGoogle Scholar
  • 47 Moritoki Y, Lian ZX, Lindor K , et al. B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice. Hepatology 2009; 50 (6) 1893-1903
    CrossrefPubMedGoogle Scholar
  • 48 Chuang YH, Lian ZX, Tsuneyama K , et al. Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun 2006; 26 (4) 232-240
    CrossrefPubMedGoogle Scholar
  • 49 Yoshida K, Yang GX, Zhang W , et al. Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology 2009; 50 (5) 1494-1500
    CrossrefPubMedGoogle Scholar
  • 50 Tsuda M, Zhang W, Yang GX , et al. Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice. Hepatology 2013; 57 (2) 806-816
    CrossrefPubMedGoogle Scholar
  • 51 Ando Y, Yang GX, Tsuda M , et al. The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17A deleted dominant negative form of transforming growth factor beta receptor type II mice. Hepatology 2012; 56 (4) 1418-1426
    CrossrefPubMedGoogle Scholar
  • 52 Nakamura A, Yamazaki K, Suzuki K, Sato S. Increased portal tract infiltration of mast cells and eosinophils in primary biliary cirrhosis. Am J Gastroenterol 1997; 92 (12) 2245-2249
    PubMedGoogle Scholar
  • 53 Lan RY, Cheng C, Lian ZX , et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006; 43 (4) 729-737
    CrossrefPubMedGoogle Scholar
  • 54 Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med 1995; 181 (5) 1835-1845
    CrossrefPubMedGoogle Scholar
  • 55 Shimoda S, Van de Water J, Ansari A , et al. Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest 1998; 102 (10) 1831-1840
    CrossrefPubMedGoogle Scholar
  • 56 Bogdanos DP, Baum H, Grasso A , et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol 2004; 40 (1) 31-39
    PubMedGoogle Scholar
  • 57 Bogdanos DP, Baum H, Okamoto M , et al. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology 2005; 42 (2) 458-465
    CrossrefPubMedGoogle Scholar
  • 58 Bogdanos DP, Baum H, Sharma UC , et al. Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis. J Hepatol 2002; 36 (1) 14-21
    CrossrefPubMedGoogle Scholar
  • 59 Bogdanos DP, Koutsoumpas A, Baum H, Vergani D. Borrelia Burgdorferi: a new self-mimicking trigger in primary biliary cirrhosis. Dig Liver Dis 2006; 38 (10) 781-782 , author reply 782–783
    CrossrefPubMedGoogle Scholar
  • 60 Shimoda S, Nakamura M, Shigematsu H , et al. Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis. Hepatology 2000; 31 (6) 1212-1216
    CrossrefPubMedGoogle Scholar
  • 61 Burroughs AK, Butler P, Sternberg MJ, Baum H. Molecular mimicry in liver disease. Nature 1992; 358 (6385) 377-378
    CrossrefPubMedGoogle Scholar
  • 62 Selmi C, Balkwill DL, Invernizzi P , et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 2003; 38 (5) 1250-1257
    CrossrefPubMedGoogle Scholar
  • 63 Abdulkarim AS, Petrovic LM, Kim WR, Angulo P, Lloyd RV, Lindor KD. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae?. J Hepatol 2004; 40 (3) 380-384
    CrossrefPubMedGoogle Scholar
  • 64 Kita H, Matsumura S, He XS , et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest 2002; 109 (9) 1231-1240
    CrossrefPubMedGoogle Scholar
  • 65 Liu H, Norman GL, Shums Z , et al. PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis. J Autoimmun 2010; 35 (4) 436-442
    CrossrefPubMedGoogle Scholar
  • 66 Wang J, Budamagunta MS, Voss JC , et al. Antimitochondrial antibody recognition and structural integrity of the inner lipoyl domain of the E2 subunit of pyruvate dehydrogenase complex. J Immunol 2013; 191 (5) 2126-2133
    CrossrefPubMedGoogle Scholar
  • 67 Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 2013; 8: 303-330
    CrossrefPubMedGoogle Scholar
  • 68 Benson GD, Kikuchi K, Miyakawa H, Tanaka A, Watnik MR, Gershwin ME. Serial analysis of antimitochondrial antibody in patients with primary biliary cirrhosis. Clin Dev Immunol 2004; 11 (2) 129-133
    CrossrefPubMedGoogle Scholar
  • 69 Long SA, Quan C, Van de Water J , et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol 2001; 167 (5) 2956-2963
    CrossrefPubMedGoogle Scholar
  • 70 Rieger R, Leung PS, Jeddeloh MR , et al. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun 2006; 27 (1) 7-16
    CrossrefPubMedGoogle Scholar
  • 71 Leung PS, Lam K, Kurth MJ, Coppel RL, Gershwin ME. Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?. Trends Mol Med 2012; 18 (10) 577-582
    CrossrefPubMedGoogle Scholar
  • 72 Naiyanetr P, Butler JD, Meng L , et al. Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity. J Autoimmun 2011; 37 (3) 209-216
    CrossrefPubMedGoogle Scholar
  • 73 Leung PS, Wang J, Naiyanetr P , et al. Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA. J Autoimmun 2013; 41: 79-86
    CrossrefPubMedGoogle Scholar
  • 74 Amano K, Leung PS, Rieger R , et al. Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol 2005; 174 (9) 5874-5883
    CrossrefPubMedGoogle Scholar
  • 75 Wakabayashi K, Lian ZX, Leung PS , et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 2008; 48 (2) 531-540
    CrossrefPubMedGoogle Scholar
  • 76 Wakabayashi K, Yoshida K, Leung PS , et al. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol 2009; 155 (3) 577-586
    CrossrefPubMedGoogle Scholar
  • 77 Selmi C, Leung PS, Sherr DH , et al. Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop. J Autoimmun 2012; 39 (4) 272-284
    CrossrefPubMedGoogle Scholar
  • 78 Bogdanos DP, Smyk DS, Rigopoulou EI , et al. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun 2012; 38 (2-3) J156-J169
    CrossrefPubMedGoogle Scholar
  • 79 Shoenfeld Y, Tincani A, Gershwin ME. Sex gender and autoimmunity. J Autoimmun 2012; 38 (2-3) J71-J73
    CrossrefPubMedGoogle Scholar
  • 80 Wu SJ, Yang YH, Tsuneyama K , et al. Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology 2011; 53 (3) 915-925
    CrossrefPubMedGoogle Scholar
  • 81 Lleo A, Invernizzi P, Gao B, Podda M, Gershwin ME. Definition of human autoimmunity—autoantibodies versus autoimmune disease. Autoimmun Rev 2010; 9 (5) A259-A266
    CrossrefPubMedGoogle Scholar
  • 82 Takeuchi M, Hamana K, Hiraishi A. Proposal of the genus Sphingomonas sensu stricto and three new genera, Sphingobium, Novosphingobium and Sphingopyxis, on the basis of phylogenetic and chemotaxonomic analyses. Int J Syst Evol Microbiol 2001; 51 (Pt 4) 1405-1417
    PubMedGoogle Scholar
  • 83 Padgett KA, Selmi C, Kenny TP , et al. Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun 2005; 24 (3) 209-219
    CrossrefPubMedGoogle Scholar
  • 84 Brodie EL, DeSantis TZ, Parker JP, Zubietta IX, Piceno YM, Andersen GL. Urban aerosols harbor diverse and dynamic bacterial populations. Proc Natl Acad Sci U S A 2007; 104 (1) 299-304
    CrossrefPubMedGoogle Scholar
  • 85 Cavicchioli R, Fegatella F, Ostrowski M, Eguchi M, Gottschal J. Sphingomonads from marine environments. J Ind Microbiol Biotechnol 1999; 23 (4-5) 268-272
    CrossrefPubMedGoogle Scholar
  • 86 Kaplan MM. Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis. Am J Gastroenterol 2004; 99 (11) 2147-2149
    CrossrefPubMedGoogle Scholar
  • 87 Olafsson S, Gudjonsson H, Selmi C , et al. Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives. Am J Gastroenterol 2004; 99 (11) 2143-2146
    CrossrefPubMedGoogle Scholar
  • 88 Kawahara K, Moll H, Knirel YA, Seydel U, Zähringer U. Structural analysis of two glycosphingolipids from the lipopolysaccharide-lacking bacterium Sphingomonas capsulata . Eur J Biochem 2000; 267 (6) 1837-1846
    CrossrefPubMedGoogle Scholar
  • 89 Kosako Y, Yabuuchi E, Naka T, Fujiwara N, Kobayashi K. Proposal of Sphingomonadaceae fam. nov., consisting of Sphingomonas Yabuuchi et al. 1990, Erythrobacter Shiba and Shimidu 1982, Erythromicrobium Yurkov et al. 1994, Porphyrobacter Fuerst et al. 1993, Zymomonas Kluyver and van Niel 1936, and Sandaracinobacter Yurkov et al. 1997, with the type genus Sphingomonas Yabuuchi et al. 1990. Microbiol Immunol 2000; 44 (7) 563-575
    CrossrefPubMedGoogle Scholar
  • 90 Kinjo Y, Wu D, Kim G , et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 2005; 434 (7032) 520-525
    CrossrefPubMedGoogle Scholar
  • 91 Mattner J, Debord KL, Ismail N , et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 2005; 434 (7032) 525-529
    CrossrefPubMedGoogle Scholar
  • 92 Mattner J, Savage PB, Leung P , et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 2008; 3 (5) 304-315
    CrossrefPubMedGoogle Scholar
  • 93 Lyons PA, Hancock WW, Denny P , et al. The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137. Immunity 2000; 13 (1) 107-115
    CrossrefPubMedGoogle Scholar
  • 94 Wicker LS, Leiter EH, Todd JA , et al. Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 1994; 43 (3) 500-504
    CrossrefPubMedGoogle Scholar
  • 95 Koarada S, Wu Y, Yim YS, Wakeland EW, Ridgway WM. Nonobese diabetic CD4 lymphocytosis maps outside the MHC locus on chromosome 17. Immunogenetics 2004; 56 (5) 333-337
    PubMedGoogle Scholar
  • 96 Podolin PL, Denny P, Armitage N , et al. Localization of two insulin-dependent diabetes (Idd) genes to the Idd10 region on mouse chromosome 3. Mamm Genome 1998; 9 (4) 283-286
    CrossrefPubMedGoogle Scholar
  • 97 Wang J, Yang GX, Zhang W , et al. Escherichia coli infection induces autoimmune cholangitis and antimitochondrial antibodies in . non-obese diabetic (NOD).B6 (Idd10/Idd18) mice. Clin Exp Immunol 2014; 175 (2) 192-201
    CrossrefPubMedGoogle Scholar
  • 98 Mohammed JP, Fusakio ME, Rainbow DB , et al. Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. J Immunol 2011; 187 (1) 337-349
    CrossrefPubMedGoogle Scholar
  • 99 Haruta I, Kikuchi K, Hashimoto E , et al. Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation. Lab Invest 2010; 90 (4) 577-588
    CrossrefPubMedGoogle Scholar
  • 100 Haruta I, Kikuchi K, Nakamura M , et al. Involvement of commensal bacteria may lead to dysregulated inflammatory and autoimmune responses in a mouse model for chronic nonsuppurative destructive cholangitis. J Clin Immunol 2012; 32 (5) 1026-1037
    CrossrefPubMedGoogle Scholar
  • 101 Gershwin ME, Leung PS, Ridgway WM, Coppel RL, Ansari AA. Reply: To PMID 22996325. Hepatology 2013; 58 (2) 830
    PubMedGoogle Scholar
  • 102 Lleo A, Oertelt-Prigione S, Bianchi I , et al. Y chromosome loss in male patients with primary biliary cirrhosis. J Autoimmun 2013; 41: 87-91
    CrossrefPubMedGoogle Scholar