Autoimmune pancreatitis results from loss of TGFβ signalling in S100A4-positive dendritic cells
- C S Boomershine1,
- A Chamberlain2,
- P Kendall1,
- A-R Afshar-Sharif2,
- H Huang2,
- M K Washington3,
- W E Lawson1,
- J W Thomas1,
- T S Blackwell1,
- N A Bhowmick2
- 1Department of Medicine, Vanderbilt-Ingram Cancer, Vanderbilt University, Nashville, Tennessee, USA
- 2Department of Urologic Surgery, Vanderbilt-Ingram Cancer, Vanderbilt University, Nashville, Tennessee, USA
- 3Department of Pathology, Vanderbilt-Ingram Cancer, Vanderbilt University, Nashville, Tennessee, USA
- Correspondence to Dr N A Bhowmick, Department of Urologic Surgery, A-1302 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA; neil.bhowmick{at}vanderbilt.edu
- Revised 1 April 2009
- Accepted 6 April 2009
- Published Online First 21 July 2009
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 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.
Footnotes
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Funding This work was supported by the NIH through CA108646 (to NAB), HL85406 (to WEL), HL068121 and HL085317 (to TSB), and T32HL069765, T32AI007474 and K08DK080219 (to CB).
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Competing interests None.
