Laboratory Investigation - A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

Research Article

Laboratory Investigation (2010) 90, 1757–1769; doi:10.1038/labinvest.2010.153; published online 23 August 2010
Special Issue – Hepatic and Pancreatic Systems
A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria

Ikuko Haruta1,2, Naoko Yanagisawa1, Shunji Kawamura3, Toru Furukawa4, Kyoko Shimizu2, Hidehito Kato1, Makio Kobayashi3, Keiko Shiratori2 and Junji Yagi1

1. 1Department of Microbiology and Immunology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
2. 2Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
3. 3Department of Pathology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
4. 4Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan

Correspondence: Dr I Haruta, MD, Department of Microbiology and Immunology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162–8666, Japan. E-mail: haruta@research.twmu.ac.jp

Received 30 April 2010; Revised 9 July 2010; Accepted 13 July 2010; Published online 23 August 2010.

Abstract

The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. Here, we investigated the possible involvement of chronic, persistent exposure to avirulent bacteria in the pathogenesis of AIP. C57BL/6 mice were inoculated with heat-killed Escherichia coli weekly for 8 weeks. At 1 week and up to 12 months after the final inoculation, the mice were killed to obtain samples. At 1 week after the final E. coli inoculation, marked cellular infiltration with fibrosis was observed in the exocrine pancreas. Cellular infiltration in the exocrine pancreas was still observed up to 12 months after the completion of E. coli inoculation. At 10 months after the final inoculation, duct-centric fibrosis became obvious. Inflammation around the ducts in the salivary glands was also observed. Furthermore, sera from heat-killed E. coli-inoculated mice possessed anti-carbonic anhydrase, anti-lactoferrin, and antinuclear antibodies. Exposure to E. coli-triggered AIP-like pancreatitis in C57BL/6 mice. We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. Our model might be useful for clarifying the pathogenesis of AIP.
Keywords:

autoantibody; autoimmune pancreatitis; bacteria; innate immunity; salivary gland involvement

full-text:
Laboratory Investigation - A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria