Pancreas

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

¹ Department of Medicine, Vanderbilt-Ingram Cancer, Vanderbilt University, Nashville, Tennessee, USA
² Department of Urologic Surgery, Vanderbilt-Ingram Cancer, Vanderbilt University, Nashville, Tennessee, USA
³ Department 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

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?