Autoimmune pancreatitis results from loss of TGFβ signalling in S100A4-positive dendritic cells. Issue 9 (21st July 2009)

• Record Type: Journal Article
• 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
• Is Part Of: Gut. Volume 58:Issue 9(2009)
• Page Start: 1267
• Page End: 1274
• Publication Date: 2009-07-21
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2008.170779
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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 Tgfbr2 fspKO, was used to determine the direct role of TGFβ in S100A4 + cells. Immunohistochemical studies suggested that Tgfbr2 fspKO 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 Tgfbr2 fspKO 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 Tgfbr2 fspKO 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 Tgfbr2 fspKO DCs in adult mice suggested a developmental event in mAIP pathogenesis. Tgfbr2 fspKO DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells. Conclusion: The development of mAIP in the Tgfbr2 fspKO 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.