Journal of Clinical Immunology

, Volume 32, Issue 5, pp 1026–1037 | Cite as

Involvement of Commensal Bacteria may Lead to Dysregulated Inflammatory and Autoimmune Responses in a Mouse Model for Chronic Nonsuppurative Destructive Cholangitis

  • Ikuko Haruta
  • Ken Kikuchi
  • Minoru Nakamura
  • Katsuhiko Hirota
  • Hidehito Kato
  • Hiroshi Miyakawa
  • Noriyuki Shibata
  • Yoichiro Miyake
  • Etsuko Hashimoto
  • Keiko Shiratori
  • Junji Yagi



We previously reported a mouse model of primary biliary cirrhosis (PBC)-like chronic nonsuppurative destructive cholangitis (CNSDC), in which frequent injections of Streptococcus intermedius induced CNSDC and autoantibody production. The present study was performed to verify the model by examining 1) the reappearance of the PBC-like CNSDC after lymphocyte transfer from model to naïve mice, 2) the involvement of autophagy, and 3) the influence of the strain difference.


Mice were inoculated with S. intermedius weekly for 8 weeks, then sacrificed to obtain samples. Spleen cells obtained from S. intermedius-inoculated mice were transferred to RAG2-/- mice.


CNSDC and elevated serum level of anti-gp210 titers were observed in S. intermedius-inoculated C57BL/6 mice, similar to the results of our previous report using BALB/c mice. Portal inflammation was induced in the livers of RAG2-/- mice by the transfer of spleen cells from S. intermedius-inoculated C57BL/6 mice. Among the inflammatory cells in the RAG2-/- mice, CD3-positive cells were predominant. Autophagosome-like structures were detected histologically, in the cytoplasm of infiltrated cells around the bile ducts in the livers of S. intermedius-inoculated both C57BL/6 and BALB/c mice. In S. intermedius-inoculated C3H/HeJ mice, inflammation in the portal area was less extensive than that in the hepatic parenchyma.


Bacterial component(s) and sequentially upregulated innate and acquired immune responses, accompanied by autophagy, might trigger CNSDC, via autoimmune mechanisms. Throughout the generation of bacteria-triggered PBC-like CNSDC, strain difference may influence the response to S. intermedius-inoculation in the liver.


Chronic nonsuppurative destructive cholangitis (CNSDC) primary biliary cirrhosis (PBC) bacteria innate immunity gp210 autophagy 



Primary biliary cirrhosis


Anti-mitochondrial antibodies


Lipoteichoic acid


Histone-like protein


Pathogen-associated molecular patterns


Autoimmune pancreatitis




Genome-wide association studies


Toll like receptor


Phosphate buffered saline



The authors thank Professor Takehiko Uchiyama (Tokiwa University) for profound discussion, Mr. Hideyuki Takeiri, Mrs. Noriko Sakayori, Mr. Mizuho Karita and Mr. Yasuhide Shigematsu for their skillful technical assistance, Dr. Yutaka Arimura and Mr. Hidehiro Ueshiba for their help with the series of bacterial inoculations in the mice, and Mr. Masamichi Yoshikawa for the intensive animal care. This work was financially supported in part by Grants-in-Aid for Scientific Research (C23590522 to I.H. and C21590496 to J.Y) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.


The authors declare that we have no conflicts of interest.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ikuko Haruta
    • 1
    • 2
  • Ken Kikuchi
    • 3
  • Minoru Nakamura
    • 4
  • Katsuhiko Hirota
    • 5
  • Hidehito Kato
    • 1
  • Hiroshi Miyakawa
    • 6
  • Noriyuki Shibata
    • 7
  • Yoichiro Miyake
    • 5
  • Etsuko Hashimoto
    • 2
  • Keiko Shiratori
    • 2
  • Junji Yagi
    • 1
  1. 1.Department of Microbiology and ImmunologyTokyo Women’s Medical UniversityShinjuku-kuJapan
  2. 2.Department of Medicine and GastroenterologyTokyo Women’s Medical UniversityShinjuku-kuJapan
  3. 3.Department of Infection Control Science and Department of Bacteriology, Faculty of MedicineJuntendo UniversityBunkyo-kuJapan
  4. 4.Department of Hepatology, Clinical Research Center, National Hospital Organization Nagasaki Medical CenterNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  5. 5.Department of Oral Microbiology, Institute of Health BiosciencesThe University of Tokushima Graduate SchoolTokushimaJapan
  6. 6.Fourth Department of Internal MedicineTeikyo UniversityItabashi-kuJapan
  7. 7.Department of PathologyTokyo Women’s Medical UniversityShinjuku-kuJapan

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