Autoimmune pancreatitis results from loss of TGFbeta signalling in S100A4-positive dendritic cells.
OBJECTIVE
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.


CONCLUSIONS
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.
Boomershine
C S
CS
Department of Medicine, Vanderbilt-Ingram Cancer, Vanderbilt University, Nashville 37232, Tennessee, USA.
Chamberlain
A
A
Kendall
P
P
Afshar-Sharif
A-R
AR
Huang
H
H
Washington
M K
MK
Lawson
W E
WE
Thomas
J W
JW
Blackwell
T S
TS
Bhowmick
N A
NA
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000032:analysis; D001327:Autoimmune Diseases / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis; D049109:Cell Proliferation; D002678:Chimera; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010195:Pancreatitis / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D001616:beta-Galactosidase / Q000032:analysis
D001323:Autoantibodies; D015415:Biomarkers; D018125:Receptors, Transforming Growth Factor beta; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D001616:beta-Galactosidase