Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells

Abstract

Dysbiosis contributes to the development of autoimmune pancreatitis

Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease

“…Thus, these serum cytokine assays revealed that patients with type 1 AIP and IgG4-RD were characterized by elevated serum IFN-α and IL-33 concentrations. These serum cytokine data were fully consistent with our recent studies in which pDC-mediated production of IFN-α and IL-33 was shown to play a pathogenic role in the development of experimental AIP and human type 1 AIP 1,[15][16][17][18][19] .…”

“…In addition, the induction of remission by PSL markedly lowered the serum concentrations of IgG4, IFN-α, and IL-33. As has been shown in previous reports, including our own, the activation of IFN-α and IL-33 is involved in the immunopathogenesis of experimental AIP and human type 1 AIP/IgG4-RD 1,[15][16][17][18][19]30,31 . However, the utility of serum IFN-α and IL-33 levels as biomarkers of type 1 AIP/IgG4-RD has never been evaluated.…”

“…Therefore, to find additional markers for the differential diagnosis between type 1 AIP and pancreatic cancer (perhaps IFN-α and IL-33 serum levels) is essential, and will be the focus of our next study. We have previously demonstrated that murine experimental AIP and human type 1 AIP/IgG4-RD are characterized by pancreatic accumulation of pDCs, which produce large amounts of IFN-α and IL-33 1,[15][16][17][18][19] . Importantly, the development of experimental AIP depends on the activation of signaling pathways triggered by pDC-derived IFN-α and IL-33, since the depletion of pDCs or inhibition of IFN-α or IL-33-mediated signaling pathways effectively prevented the development of experimental AIP 15,16 .…”

“…Indeed, peripheral blood pDCs from type 1 AIP/IgG4-RD patients enhanced IgG4 production by healthy B cells in a T cell-independent and IFN-α-dependent manner 15 . More importantly, increased production of IFN-α and IL-33 by pDCs mediated chronic fibroinflammatory responses in both experimental AIP and human type 1 AIP 1, [15][16][17][18][19] . Thus, T cell-independent cytokines produced by antigen-presenting cells, including pDCs, may be involved in the elevation of serum IgG1 and IgG4 concentrations in patients with type 1 AIP/IgG4-RD.…”

“…Recently, we reported that the production of interferon (IFN)-α and interleukin (IL)-33 by plasmacytoid dendritic cells (pDCs) mediates chronic fibroinflammatory responses in experimental AIP and human type 1 AIP 1,[15][16][17][18][19] . Our previous studies provided evidence that pancreatic accumulation of pDCs, which may produce large amounts of IFN-α and IL-33, underlies the immunopathogenesis of type 1 AIP and IgG4-RD 1,[15][16][17][18][19] . Furthermore, we had a case of type 1 AIP and IgG4-RD in which the serum concentrations of IFN-α and IL-33, rather than the serum concentration of IgG4, were highly associated with disease activity 20 .…”