title: Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis.
abstract: The abnormal immune response accompanying IgG4-related autoimmune pancreatitis (AIP) is presently unclear. In this study, we examined the role of plasmacytoid dendritic cell (pDC) activation and IFN-α production in this disease as well as in a murine model of AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid). We found that the development of AIP in treated MRL/Mp mice occurred in parallel with pancreatic accumulation of pDCs producing IFN-α, and with pDC depletion and IFN-α-blocking studies, we showed that such accumulation was necessary for AIP induction. In addition, we found that the pancreas of treated MRL/Mp mice contained neutrophil extracellular traps (NETs) shown previously to stimulate pDCs to produce IFN-α. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-α-expressing pDCs and had significantly higher serum IFN-α levels than healthy controls. In addition, the inflamed pancreas of these patients but not controls also contained NETs that were shown to be capable of pDC activation. More importantly, patient pDCs cultured in the presence of NETs produced greatly increased levels of IFN-α and induced control B cells to produce IgG4 (but not IgG1) as compared with control pDCs. These data suggest that pDC activation and production of IFN-α is a major cause of murine AIP; in addition, the increased pDC production of IFN-α and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease.
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Yasuyuki
authors: Y
authors: Arai
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; tmhrwtnb@kuhp.kyoto-u.ac.jp kouhei@kuhp.kyoto-u.ac.jp.
authors: Kouhei
authors: K
authors: Yamashita
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Katsutoshi
authors: K
authors: Kuriyama
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Masahiro
authors: M
authors: Shiokawa
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Yuzo
authors: Y
authors: Kodama
authors: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka 589-8511, Japan;
authors: Toshiharu
authors: T
authors: Sakurai
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Kiyomi
authors: K
authors: Mizugishi
authors: Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 573-1191, Japan;
authors: Kazushige
authors: K
authors: Uchida
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Norimitsu
authors: N
authors: Kadowaki
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Akifumi
authors: A
authors: Takaori-Kondo
authors: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka 589-8511, Japan;
authors: Masatoshi
authors: M
authors: Kudo
authors: Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 573-1191, Japan;
authors: Kazuichi
authors: K
authors: Okazaki
authors: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors: Warren
authors: W
authors: Strober
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Tsutomu
authors: T
authors: Chiba
authors: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan tmhrwtnb@kuhp.kyoto-u.ac.jp kouhei@kuhp.kyoto-u.ac.jp.
authors: Tomohiro
authors: T
authors: Watanabe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D065206:Extracellular Traps / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000097:blood; D008297:Male; D051379:Mice; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D010179:Pancreas / Q000276:immunology* / Q000473:pathology; D010195:Pancreatitis / Q000276:immunology* / Q000473:pathology; D011070:Poly I-C
chemical_list: D053264:B-Cell Activating Factor; D007074:Immunoglobulin G; D016898:Interferon-alpha; C505719:TNFSF13B protein, human; D011070:Poly I-C