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.