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

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 heatkilled 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.

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

“…by immunization with self-antigens, injection of pathogens [35] or via adoptive transfer of autoreactive cells or T regs [36][37][38]. However, such models can be highly variable.…”

Commensal Flora, is it an Unwelcomed Companion as a Triggering Factor of Autoimmune Pancreatitis?

“…These slowly progressive steps eventually lead to the development of autoimmune diseases. Modified from previous reports (Haruta et al, 2010a; Yanagisawa et al, 2011). …”

“…The pancreas in the recipient RAG2 −/− mice showed cellular infiltration in the exocrine pancreas, especially around the pancreatic ducts, indicating that the E. coli -inoculated mouse spleen cells possess the ability to reproduce pathological alterations in the pancreas of naïve mice. Similarly, when the spleen cells of donor S. intermedius -inoculated mice were transferred to RAG2 −/− mice, primary biliary cirrhosis (PBC)-like cholangitis in the liver was induced, similar to that seen in the donor (Haruta et al, 2010b). The AIP-like inflammatory region in the pancreases of recipient mice with spleen cells transferred from E. coli -inoculated mice (Haruta et al, 2010a), showed that most of the cellular infiltrates in the target organs were CD3-positive, indicating that these cells in both models originated from the donor mice.…”

“…with heat-killed E. coli weekly for 8 weeks, marked cellular infiltration with fibrosis was observed in the exocrine pancreas accompanied by a high serum gamma globulin level and the production of autoantibodies against CA-II and LF. Bacterial infection apparently triggered AIP-like pathological alterations in mice that strikingly resembled AIP in humans (Haruta et al, 2010a). …”

Are Dysregulated Inflammatory Responses to Commensal Bacteria Involved in the Pathogenesis of Hepatobiliary-Pancreatic Autoimmune Disease? An Analysis Using Mice Models of Primary Biliary Cirrhosis and Autoimmune Pancreatitis

“…with heat-killed E. coli weekly for 8 weeks, marked cellular infiltration with fibrosis was observed in the exocrine pancreas accompanied by a high serum gamma-globulin level and the production of autoantibodies against CA-II and LF. Bacterial infection apparently triggered autoimmune pancreatitis-like pathological alterations in mice that strikingly resembled AIP in humans [61]. …”