Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

被引：73

作者：

Arai, Yasuyuki ^{[1
]}

Yamashita, Kouhei ^{[1
]}

Kuriyama, Katsutoshi ^{[2
]}

Shiokawa, Masahiro ^{[2
]}

Kodama, Yuzo ^{[2
]}

Sakurai, Toshiharu ^{[3
]}

Mizugishi, Kiyomi ^{[1
]}

Uchida, Kazushige ^{[4
]}

Kadowaki, Norimitsu ^{[1
]}

Takaori-Kondo, Akifumi ^{[1
]}

Kudo, Masatoshi ^{[3
]}

Okazaki, Kazuichi ^{[4
]}

Strober, Warren ^{[5
]}

Chiba, Tsutomu ^{[2
]}

Watanabe, Tomohiro ^{[2
,5
,6
]}

机构：

[1] Kyoto Univ, Dept Hematol & Oncol, Grad Sch Med, Kyoto 6068507, Japan

[2] Kyoto Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Kyoto 6068507, Japan

[3] Kinki Univ, Dept Gastroenterol & Hepatol, Sch Med, Osaka 5898511, Japan

[4] Kansai Med Univ, Dept Gastroenterol & Hepatol, Osaka 5731191, Japan

[5] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA

[6] Kyoto Univ, Ctr Innovat Immunoregulat Technol & Therapeut, Grad Sch Med, Kyoto 6068507, Japan

来源：

JOURNAL OF IMMUNOLOGY | 2015年 / 195卷 / 07期

基金：

日本学术振兴会;

关键词：

NEUTROPHIL EXTRACELLULAR TRAPS; REGULATORY T-CELLS; IGG4; INVOLVEMENT; RESPONSES; DISEASE; BAFF; AUTOANTIBODIES; PATHOGENESIS; MECHANISMS;

D O I：

10.4049/jimmunol.1500971

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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-alpha 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-alpha, and with pDC depletion and IFN-alpha-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-alpha. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-alpha-expressing pDCs and had significantly higher serum IFN-alpha 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-alpha 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-alpha is a major cause of murine AIP; in addition, the increased pDC production of IFN-alpha and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease.

引用

页码：3033 / 3044

页数：12

共 57 条

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