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

Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease (IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-alpha and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 mu g of polyinosinic-polycytidylic acid [poly (I:C)]. Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-alpha and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 mu g of poly (I:C) developed severe AIP equivalent to that induced by 100 mu g of poly (I:C) upon co-housing with mice treated with 100 mu g of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 mu g of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 mu g of poly (I:C). Induction of severe AIP in mice with 10 mu g of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-alpha and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs.