Autoimmune pancreatitis results from loss of TGFβ signalling in S100A4-positive dendritic cells

• Published in: Gut Vol. 58; no. 9; pp. 1267 - 1274
• Main Authors: Boomershine, C S, Chamberlain, A, Kendall, P, Afshar-Sharif, A-R, Huang, H, Washington, M K, Lawson, W E, Thomas, J W, Blackwell, T S, Bhowmick, N A
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.09.2009; BMJ Publishing Group; BMJ Group
• Subjects: Biological and medical sciences; Gastroenterology. Liver. Pancreas. Abdomen; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Other diseases. Semiology; Pancreas; Autoimmunity; Dendritic cell; Gastroenterology; Pancreatitis; Digestive diseases; Signalling; Pancreatic disease
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2008.170779

Background and aims:Autoimmune pancreatitis (AIP) is a poorly understood human disease affecting the exocrine pancreas. The goal of the present study was to elucidate the pathogenic mechanisms underlying pancreatic autoimmunity in a murine disease model.Methods:A transgenic mouse with an S100A4/fibroblast-specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor β (TGFβ) type II receptor, termed Tgfbr2fspKO, was used to determine the direct role of TGFβ in S100A4+ cells. Immunohistochemical studies suggested that Tgfbr2fspKO mice develop mouse AIP (mAIP) characterised by interlobular ductal inflammatory infiltrates and pancreatic autoantibody production. Fluorescence-activated cell sorting (FACS)-isolated dendritic cells (DCs) from diseased pancreata were verified to have S100A4-Cre-mediated DNA recombination.Results:The Tgfbr2fspKO mice spontaneously developed mAIP by 6 weeks of age. DCs were confirmed to express S100A4, a previously reported protein expressed by fibroblasts. Adoptive transfer of bone marrow-derived DCs from Tgfbr2fspKO mice into 2-week-old syngenic wild-type C57BL/6 mice resulted in reproduction of pancreatitis within 6 weeks. Similar adoptive transfer of wild-type DCs had no effect on pancreas pathology of the host mice. The inability to induce pancreatitis by adoptive transfer of Tgfbr2fspKO DCs in adult mice suggested a developmental event in mAIP pathogenesis. Tgfbr2fspKO DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells.Conclusion:The development of mAIP in the Tgfbr2fspKO mouse model illustrates the role of TGFβ in maintaining myeloid DC immune tolerance. The loss of immune tolerance in myeloid S100A4+ DCs can mediate mAIP and may explain some aspects of AIP disease pathogenesis.