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Autoimmune pancreatitis results from loss of TGF-ß signaling in S100A4-positive dendritic Cells
  1. Chad S Boomershine (chad.boomershine{at}vanderbilt.edu)
  1. Vanderbilt University, United States
    1. Austin Chamberlin
    1. Vanderbilt University, United States
      1. Peggy Kendall
      1. Vanderbilt University, United States
        1. Ali-Reza Afshar-Sharif
        1. Vanderbilt University, United States
          1. Hongxia Huang
          1. Vanderbilt University, United States
            1. Mary Kay Washington
            1. Vanderbilt University, United States
              1. William Lawson
              1. Vanderbilt University, United States
                1. James W Thomas
                1. Vanderbilt University, United States
                  1. Timothy S Blackwell
                  1. Vanderbilt University, United States
                    1. Neil A Bhowmick (neil.bhowmick{at}vanderbilt.edu)
                    1. Vanderbilt University, United States

                      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 AIP in this disease model.

                      Methods: A transgenic mouse with a S100A4/fibroblast specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor (TGF)-β type II receptor termed Tgfbr2fspKO, was used to determine the direct role of TGF-ß in S100A4+ cells. Immunohistochemical studies suggested Tgfbr2fspKO mice develop interlobular ductal inflammatory infiltrates and produce pancreatic auto-antibodies analogous to human AIP. 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 AIP by six-weeks of age. DC’s were confirmed to express S100A4, a previously reported as a protein expressed by fibroblasts. Adoptive-transfer of bone marrow-derived DCs from Tgfbr2fspKO mice into two-week old syngenic wild type C57BL/6 mice resulted in reproduction of pancreatitis with in six 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 AIP pathogenesis. Tgfbr2fspKO DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells.

                      Conclusion: The development of AIP in the Tgfbr2fspKO mouse model illustrates the role of TGF-ß in maintaining myeloid DC immune tolerance. The loss of immune tolerance in myeloid S100A4+ DCs can mediate AIP.

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