Autoimmune pancreatitis results from loss of TGF signalling in S100A4-positive dendritic cells
Year: 2009
Type: article
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 beta (TGFbeta) type II receptor, termed Tgfbr2(fspKO), was used to determine the direct role of TGFbeta 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 TGFbeta 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.
Source: Gut
Authors: C S Boomershine, A Chamberlain, P Kendall, A-R Afshar-Sharif, H Huang, M K Washington, W E Lawson, J W Thomas, T S Blackwell, N A Bhowmick
Institutions: Vanderbilt University, Vanderbilt-Ingram Cancer Center
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: Mechanisms of Dendritic Cell Tolerance in Autoimmune Pancreatitis, G1678012665, G257099293, G2778465911, G3872320933, G4421701820, G4462420853, G5127683418, TGF Beta Signals in Prostate Stromal-Epithelial Interactions, G8274684545, G8639585730, G9000039649, G9000049879, G9000078681, Vanderbilt Infection Pathogenesis and Epidemiology Research Training Program
OpenAlex ID: W2108214913