THE PATHOGENESIS OF AUTOIMMUNITY IN A MURINE MODEL OF PRIMARY BILIARY CIRRHOSIS

Summary

Principal Investigator: M Eric Gershwin
Abstract: rimary biliary cirrhosis (PBC) is an enigmatic, liver specific, autoimmune disease characterized by antimito- chondrial antibodies and progressive destruction of intrahepatic bile ducts. There has not been an animal model of PBC and studies are dependent on human clinical specimens, a problem compounded by the cryptic nature of disease onset that prevents identification of patients in early stages. In other autoimmune diseases, the dissection of the immune process has been facilitated by informative animal models. We propose a consortium approach utilizing the strengths of three campuses to study two novel murine models of autoimmune biliary disease, the NOD.c3c4 congenic mouse with B6/B10 derived regions on chromosomes 3 and 4 as well as a new strain, called 2445. Line 2445 has significantly reduced B6/B10 ntervals on chromosome 3 and 4 compared to NOD.c3c4, which will facilitate positional cloning of genes ntegral to disease. Both strains of mice develop progressive portal tract lymphocytic infiltrates, granulomas, anti-mitochondrial antibodies and terminal biliary disease. Our objectives are to perform a detailed ontogenetic analysis of the immune system to define the kinetics by which specific lineages contribute to disease process utilizing NOD.c3c4, strain 2445, and controls. The studies to be performed are those which mirror human PBC, including analysis of the innate, humoral and cellular immune systems, including liver lymphoid subpopulations and immunohistochemistry to identify the developmental stage each component contributes to disease pathogenesis. We will also positionally clone the genes critical for causing liver disease using currently available congenic strains as well as novel congenic strains that will be generated. Based upon these data, adoptive transfer strategies using NOD.c3c4- and 2445-scid recipients will define the pathogenic effector cells required for the development of liver disease. We submit that this model offers significant potential for not only enhancing our understanding of PBC, but also autoimmunity in general. PBC is the prototypic autoimmune disease with a tissue specific impact, but a constant non-tissue specific autoreactivity, features closely reproduced in this model. Finally, because this murine model of PBC is pathologically and immunologieally similar to human PBC, it opens the possibility of discriminative analysis of initiating events and eventually study of therapeutic interventions.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Dissecting genetic control of autoimmunity in NOD congenic mice
    William M Ridgway
    University of Pittsburgh, Pittsburgh, PA, USA
    Immunol Res 36:189-95. 2006
  2. ncbi Animal models of primary biliary cirrhosis: materials and methods
    Patrick S C Leung
    Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
    Methods Mol Biol 900:291-316. 2012
  3. ncbi CD4+ CD25+ Foxp3+ regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice
    Hua Xing Wei
    Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
    J Immunol 181:7221-9. 2008
  4. pmc The unfinished business of primary biliary cirrhosis
    Carlo Selmi
    Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Italy
    J Hepatol 49:451-60. 2008
  5. pmc Animal models of primary biliary cirrhosis
    Ya Hui Chuang
    Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Chang Te Street, Taipei, Taiwan
    Clin Liver Dis 12:333-47; ix. 2008
  6. pmc Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice
    Guo Xiang Yang
    Division of Rheumatology, University of California at Davis, Davis, CA 95616, USA
    Hepatology 47:1974-82. 2008
  7. ncbi The causes of primary biliary cirrhosis: Convenient and inconvenient truths
    M Eric Gershwin
    Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA
    Hepatology 47:737-45. 2008
  8. ncbi Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency
    Yu Nakagome
    Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980 8574, Japan
    J Autoimmun 29:20-9. 2007
  9. pmc Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity
    Javid P Mohammed
    Division of Immunobiology, Cincinnati Children s Hospital, Cincinnati, OH 45229, USA
    J Immunol 187:337-49. 2011
  10. pmc B cells promote hepatic inflammation, biliary cyst formation, and salivary gland inflammation in the NOD.c3c4 model of autoimmune cholangitis
    Yuki Moritoki
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA
    Cell Immunol 268:16-23. 2011

Scientific Experts

  • Yoshiyuki Ueno
  • M Eric Gershwin
  • William M Ridgway
  • Yuki Moritoki
  • Zhe Xiong Lian
  • Guo Xiang Yang
  • Koichi Tsuneyama
  • Weici Zhang
  • Aftab A Ansari
  • Ross L Coppel
  • Ian R Mackay
  • Ya Hui Chuang
  • Linda S Wicker
  • Patrick S C Leung
  • Javid P Mohammed
  • Daniel B Rainbow
  • Laurence B Peterson
  • Katsunori Yoshida
  • Y Moritoki
  • Z X Lian
  • K Wakabayashi
  • Willy Hsu
  • W Zhang
  • K Tsuneyama
  • Osamu Kido
  • G X Yang
  • M E Gershwin
  • Kanji Wakabayashi
  • Zhigang Tian
  • Richard A Flavell
  • Hua Xing Wei
  • Koji Fukushima
  • Tooru Shimosegawa
  • Carlo Selmi
  • Yu Nakagome
  • Amy Dhirapong
  • Paul A Lyons
  • Michael E Fusakio
  • Yuehong Wu
  • Heather I Fraser
  • Carolyn Moule
  • John A Todd
  • Paul B Savage
  • Patrick S Leung
  • Jochen Mattner
  • Jan Clark
  • Hiroki Tsukamoto
  • Kara M Hunter
  • Marsha Wills-Karp
  • Gerard A Morris
  • Masanobu Tsuda
  • R L Coppel
  • I R Mackay
  • Shyr Te Ju
  • Christopher Bowlus
  • Jun Inoue
  • Robert Dunn
  • W M Ridgway
  • Keith Lindor
  • K Yoshida
  • Xiao Song He
  • P S C Leung
  • Shu Man Fu
  • Ian MacKay
  • Rahul Sharma
  • Yanyan Tao
  • Joseph Tuscano
  • A A Ansari
  • Douglas M Jefferson
  • L S Wicker
  • Y Ilan
  • T Hibi
  • Marilyn Kehry
  • Haiming Wei
  • Massimo Zuin
  • Bofeng Li
  • Ruth Y Lan
  • Rui Sun
  • Takayuki Kogure

Detail Information

Publications19

  1. pmc Dissecting genetic control of autoimmunity in NOD congenic mice
    William M Ridgway
    University of Pittsburgh, Pittsburgh, PA, USA
    Immunol Res 36:189-95. 2006
    ..This review will illustrate some of the genetically controlled phenotypes we have investigated, which shed light upon autoimmune features relevant to human type 1 diabetes, systemic lupus erythematosus, and primary biliary cirrhosis...
  2. ncbi Animal models of primary biliary cirrhosis: materials and methods
    Patrick S C Leung
    Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
    Methods Mol Biol 900:291-316. 2012
    ..Finally, we stress the importance of realizing the strengths and limitations of the animal models are essential in data analysis and their application in therapeutic studies...
  3. ncbi CD4+ CD25+ Foxp3+ regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice
    Hua Xing Wei
    Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
    J Immunol 181:7221-9. 2008
    ..These results indicate that CD4(+)CD25(+) Tregs play an important role in limiting the liver injury in Con A-induced hepatitis via a TGF-beta-dependent mechanism...
  4. pmc The unfinished business of primary biliary cirrhosis
    Carlo Selmi
    Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Italy
    J Hepatol 49:451-60. 2008
    ..However, this research has still not led to successful translation for specific therapy...
  5. pmc Animal models of primary biliary cirrhosis
    Ya Hui Chuang
    Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Chang Te Street, Taipei, Taiwan
    Clin Liver Dis 12:333-47; ix. 2008
    ..However, in the past 2 years, several spontaneous and two induced models of PBC were described. This article reviews the data on these animal models and places it in the perspective of human PBC and generic autoimmunity...
  6. pmc Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice
    Guo Xiang Yang
    Division of Rheumatology, University of California at Davis, Davis, CA 95616, USA
    Hepatology 47:1974-82. 2008
    ..In contrast, B6/Rag(-/-) recipients of CD4(+) T cells from dnTGFbetaRII mice predominantly developed inflammatory bowel disease associated with higher levels of serum interferon gamma and tumor necrosis factor alpha...
  7. ncbi The causes of primary biliary cirrhosis: Convenient and inconvenient truths
    M Eric Gershwin
    Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA
    Hepatology 47:737-45. 2008
    ..We present these data under the umbrella of convenient truths that support this thesis as well as some inconvenient truths that are not readily accommodated by current theory...
  8. ncbi Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency
    Yu Nakagome
    Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980 8574, Japan
    J Autoimmun 29:20-9. 2007
    ..c3c4 mice secondary to impaired biliary cell apoptosis with exposure of mitochondrial antigens, loss of tolerance and subsequent development of multi-lineage anti-mitochondrial responses...
  9. pmc Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity
    Javid P Mohammed
    Division of Immunobiology, Cincinnati Children s Hospital, Cincinnati, OH 45229, USA
    J Immunol 187:337-49. 2011
    ..These data strongly support the hypothesis that allelic variation of the Cd101 gene, located in the Idd10 region, alters the severity of liver autoimmunity induced by N. aromaticivorans...
  10. pmc B cells promote hepatic inflammation, biliary cyst formation, and salivary gland inflammation in the NOD.c3c4 model of autoimmune cholangitis
    Yuki Moritoki
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA
    Cell Immunol 268:16-23. 2011
    ..c3c4 mice, illustrating a critical role of B cells in modulating specific organ pathology and, in particular, in exacerbating both the biliary disease and the sialadenitis...
  11. ncbi CD8 T cells mediate direct biliary ductule damage in nonobese diabetic autoimmune biliary disease
    Guo Xiang Yang
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616, USA
    J Immunol 186:1259-67. 2011
    ..ABD mice do develop the antipyruvate dehydrogenase Abs typical of human PBC. The NOD.ABD strain is a model of immune dysregulation affecting two organ systems, most likely by mechanisms that do not completely coincide...
  12. ncbi Murine models of autoimmune cholangitis
    Yoshiyuki Ueno
    Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
    Curr Opin Gastroenterol 26:274-9. 2010
    ..These models have great potential for illustrating the cause and the cellular events that lead to biliary-specific damage. The purpose of this review is to summarize recent progress in these models...
  13. pmc B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice
    Yuki Moritoki
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA
    Hepatology 50:1893-903. 2009
    ....
  14. ncbi Compensatory role of inducible annexin A2 for impaired biliary epithelial anion-exchange activity of inflammatory cholangiopathy
    Osamu Kido
    Tohoku University Graduate School of Medicine, Sendai, Japan
    Lab Invest 89:1374-86. 2009
    ....
  15. pmc Beta-glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis
    W Zhang
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA
    Clin Exp Immunol 157:359-64. 2009
    ..These data suggest that further work on GC in models of CD8(+) T-mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease...
  16. ncbi B cells suppress the inflammatory response in a mouse model of primary biliary cirrhosis
    Yuki Moritoki
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California, USA
    Gastroenterology 136:1037-47. 2009
    ..Mice that express a dominant-negative form of transforming growth factor-beta receptor restricted to T cells (dnTGF-betaRII) develop antimitochondrial antibodies and liver inflammation similar to human primary biliary cirrhosis...
  17. pmc Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis
    Weici Zhang
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA
    Hepatology 49:545-52. 2009
    ....
  18. pmc Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(-/-) mice
    Willy Hsu
    Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA
    Hepatology 49:133-40. 2009
    ..In conclusion, on loss of Treg function in mice, CD8 T cells mediate biliary ductular damage whereas CD4 T cells mediate induction of colon-specific autoimmunity...
  19. pmc Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization
    K Wakabayashi
    Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA
    Clin Exp Immunol 155:577-86. 2009
    ..We believe this model will allow the rigorous dissection of early immunogenetic cause of biliary damage...