Pathophysiological analysis of type 1 autoimmune pancreatitis.

• Project/Area Number: 18K07921
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kochi University (2019-2020); Kansai Medical University (2018)
• Principal Investigator: KAZUSHIGE UCHIDA 高知大学, 教育研究部医療学系臨床医学部門, 教授 (40411516)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 自己免疫性膵炎 / IgG4関連疾患 / 自然免疫 / 自然リンパ球 / 1型自己免疫性膵炎 / マウスモデル / IgG4

Outline of Final Research Achievements

Type 1 autoimmune pancreatitis is a chronic fibro-inflammatory disorder. We previously reported the involvement of M2 macrophages and basophils in autoimmune pancreatitis. It is reported that Group 2 innate lymphoid cells (ILC2s) and basophils play an important role in asthma. Thus, this study investigated the roles of innate lymphoid cells in autoimmune pancreatitis and chronic pancreatitis. We analyzed peripheral ILCs using flow cytometry. The proportions of ILC2s and ILC3s were significantly higher in the autoimmune pancreatitis and chronic pancreatitis groups than in the healthy controls group. The proportion of ILC1s did not differ among three groups. We clarified that elevated ILC2 and ILC3 counts may be involved in the development of chronic pancreatic inflammation in this study.

Academic Significance and Societal Importance of the Research Achievements

1型AIPは様々な膵外病変を呈することが知られていたが、現在ではそれらはIgG4関連疾患とされ1型自己免疫性膵炎はIgG4関連疾患の膵病変として捉えられている。1型AIP、IgG4関連疾患のいずれも日本から発信された疾患概念であり、いままでも日本から多くの研究成果が発表されてきた。このような歴史的背景から、引き続き日本からその病態生理を解明する研究成果が発信され続けることは重要であると考えられる。

Research Products

• [Journal Article] Possible Involvement of Innate Lymphoid Cells in the Development of Chronic Inflammatory Pancreatic Diseases. (2021)
  • Author(s): Ikemune M, Uchida K, Yanagawa M, Tsukuda S, Tomiyama T, Tanaka T, Ando Y, Ikeura T, Yamaguchi T, Fukui T, Nishio A, Okazaki K
  • Journal Title: JOP Volume: 22 Pages: 1-10
  • Peer Reviewed / Open Access
• [Journal Article] IgG4-related disease: Changing epidemiology and new thoughts on a multisystem disease. (2020)
  • Author(s): Floreani A, Okazaki K, Uchida K, Gershwin ME.
  • Journal Title: J Transl Autoimmun . Volume: 4 Pages: 100074-100074
  • DOI: 10.1016/j.jtauto.2020.100074
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interleukin-35 promotes the differentiation of regulatory T cells and suppresses Th2 response in IgG4-related type 1 autoimmune pancreatitis (2020)
  • Author(s): Ito T, Tanaka T, Nakamaru K, Tomiyama T, Yamaguchi T, Ando Y, Ikeura T, Fukui T, Uchida K, Nishio A, Okazaki K.
  • Journal Title: J Gastroenterol . Volume: 55 Issue: 8 Pages: 789-799
  • DOI: 10.1007/s00535-020-01689-5
  • Peer Reviewed
• [Journal Article] Clinical implications of elevated serum interleukin-6 in IgG4-related disease. (2020)
  • Author(s): Tsukuda S, Ikeura T, Ito T, Nakamaru K, Masuda M, Hori Y, Ikemune M, Yanagawa M, Tanaka T, Tomiyama T, Yamaguchi T, Ando Y, Uchida K, Fukui T, Nishio A, Terasawa R, Tanigawa N, Okazaki K
  • Journal Title: PLoS One Volume: 15 Issue: 1 Pages: e0227479-e0227479
  • DOI: 10.1371/journal.pone.0227479
  • Peer Reviewed / Open Access
• [Journal Article] Diffuse Pancreatic Cancer Mimicking Autoimmune Pancreatitis (2019)
  • Author(s): Miyoshi Hideaki、Kano Masataka、Kobayashi Sanshiro、Ito Takashi、Masuda Masataka、Mitsuyama Toshiyuki、Nakayama Shinji、Ikeura Tsukasa、Shimatani Masaaki、Uchida Kazushige、Takaoka Makoto、Okazaki Kazuichi
  • Journal Title: Internal Medicine Volume: 58 Issue: 17 Pages: 2523-2527
  • DOI: 10.2169/internalmedicine.2689-19
  • NAID: 130007700206
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-09-01
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular vesicles microRNA analysis in type 1 autoimmune pancreatitis: Increased expression of microRNA-21. (2019)
  • Author(s): Nakamaru K, Tomiyama T, Kobayashi S, Ikemune M, Tsukuda S, Ito T, Tanaka T, Yamaguchi T, Ando Y, Ikeura T, Fukui T, Nishio A, Takaoka M, Uchida K, Leung PSC, Gershwin ME, Okazaki K.
  • Journal Title: Pancreatology. 2020 Feb 21. pii: S1424-3903(20)30048-X. Volume: pii: S1424-3903 Issue: 3 Pages: 318-324
  • DOI: 10.1016/j.pan.2020.02.012
  • Peer Reviewed
• [Journal Article] Inhibition of the dephosphorylation of eukaryotic initiation factor 2α ameliorates murine experimental pancreatitis (2019)
  • Author(s): Aoi Kazunori、Nishio Akiyoshi、Okazaki Takashi、Takeo Masahiro、Masuda Masataka、Fukui Toshiro、Uchida Kazushige、Okazaki Kazuichi
  • Journal Title: Pancreatology Volume: 19 Issue: 4 Pages: 548-556
  • DOI: 10.1016/j.pan.2019.04.005
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological and immunological features of follicular pancreatitis ? a distinct disease entity characterised by Th17 activation (2019)
  • Author(s): Ryota Hironori、Ishida Mitsuaki、Satoi Sohei、Yanagimoto Hiroaki、Yamamoto Tomohisa、Kosaka Hisashi、Hirooka Satoshi、Yamaki So、Kotsuka Masaya、Matsui Yoichi、Ikeura Tsukasa、Uchida Kazushige、Takaoka Makoto、Okazaki Kazuichi、Tsuta Koji
  • Journal Title: Histopathology Volume: 74 Issue: 5 Pages: 709-717
  • DOI: 10.1111/his.13802
  • Peer Reviewed / Open Access
• [Journal Article] Clinical course of type 1 autoimmune pancreatitis patients without steroid treatment: a Japanese multicenter study of 97 patients. (2018)
  • Author(s): Kubota K, Kamisawa T, Hirano K, Hirooka Y, Uchida K, Ikeura T, Shiomi H, Ohara H, Shimizu K, Arakura N, Kanno A, Sakagami J, Itoi T, Ito T, Ueki T, Nishino T, Inui K, Mizuno N, Yoshida H, Sugiyama M, Iwasaki E, Irisawa A, Okazaki K, Kawa S, Shimosegawa T, Takeyama Y, Chiba T.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Issue: 4 Pages: 223-230
  • DOI: 10.1002/jhbp.541
  • Peer Reviewed
• [Journal Article] Clinical and pathophysiological aspects of type 1 autoimmune pancreatitis. (2018)
  • Author(s): Uchida K, Okazaki K.
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 4 Pages: 475-483
  • DOI: 10.1007/s00535-018-1440-8
  • Peer Reviewed / Open Access
• [Journal Article] Response to the Letter by Poddighe et al. regarding our manuscript “Basophils activated via TLR signaling may contribute to pathophysiology of type 1 autoimmune pancreatitis” (2018)
  • Author(s): Uchida Kazushige、Ynagawa Masato、Okazaki Kazuichi
  • Journal Title: Journal of Gastroenterology Volume: 53 Issue: 6 Pages: 793-794
  • DOI: 10.1007/s00535-018-1460-4
• [Journal Article] Factors in glucocorticoid regimens associated with treatment response and relapses of IgG4-related disease: a multicentre study (2018)
  • Author(s): Shirakashi Mirei、Yoshifuji Hajime、Kodama Yuzo、Chiba Tsutomu、Yamamoto Motohisa、Takahashi Hiroki、Uchida Kazushige、Okazaki Kazuichi、Ito Tetsuya、Kawa Shigeyuki、Yamada Kazunori、Kawano Mitsuhiro et al.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 10262-10262
  • DOI: 10.1038/s41598-018-28405-x
  • NAID: 120007134012
  • Peer Reviewed / Open Access
• [Journal Article] Current Concept of Autoimmune Pancreatitis and IgG4-related Disease (2018)
  • Author(s): Okazaki Kazuichi、Uchida Kazushige
  • Journal Title: American Journal of Gastroenterology Volume: 113 Issue: 10 Pages: 1412-1416
  • DOI: 10.1038/s41395-018-0184-7
  • Peer Reviewed
• [Journal Article] Risk Factors for Pancreatic Stone Formation in Type 1 Autoimmune Pancreatitis: A Long-term Japanese Multicenter Analysis of 624 Patients (2018)
  • Author(s): Ito T, Kawa S, Matsumoto A, Kubota K, Kamisawa T, Okazaki K, Hirano K, Hirooka Y, Uchida K, Masuda A, Ohara H, Shimizu K, Arakura N, Masamune A, Kanno A, Sakagami J, Itoi T, Ito T, Ueki T, Nishino T, Inui K, Mizuno N, Yoshida H, Sugiyama M, Iwasaki E, Irisawa A, Shimosegawa T, Chiba T.
  • Journal Title: Pancreas Volume: 48 Issue: 1 Pages: 49-54
  • DOI: 10.1097/mpa.0000000000001210
  • Peer Reviewed
• [Journal Article] Gastrointestinal manifestation of immunoglobulin G4-related disease: clarification through a multicenter survey. (2017)
  • Author(s): Notohara K, Kamisawa T, Uchida K, Zen Y, Kawano M, Kasashima S, Sato Y, Shiokawa M, Uehara T, Yoshifuji H, Hayashi H, Inoue K, Iwasaki K, Kawano H, Matsubayashi H, Moritani Y, Murakawa K, Oka Y, Tateno M, Okazaki K, Chiba T.
  • Journal Title: J Gastroenterol Volume: - Issue: 7 Pages: 845-853
  • DOI: 10.1007/s00535-017-1420-4
  • Peer Reviewed
• [Presentation] IgG4関連消化器疾患の内視鏡診断と治療 (2021)
  • Author(s): 内田一茂
  • Organizer: 第29回日本消化器内視鏡学会四国セミナー
  • Invited
• [Presentation] 自然免疫反応から見た1型自己免疫性膵炎の病態生理 (2020)
  • Author(s): 内田一茂、岡崎和一
  • Organizer: 第62回日本消化器病学会大会
• [Presentation] 当院における 1 型自己免疫膵炎に対する診断・治療・長期予後の検討 (2019)
  • Author(s): 伊藤崇志, 内田 一茂, 岡崎和一
  • Organizer: 第50回日本膵臓学会大会
• [Presentation] IgG4関連肝胆膵疾患の診断と治療 (2019)
  • Author(s): 内田 一茂
  • Organizer: 第60回日本消化器病学会近畿支部教育講演会
  • Invited
• [Presentation] IgG4関連消化器疾患の現状と課題 (2019)
  • Author(s): 内田 一茂
  • Organizer: 第73回東北支部生涯教育講演会
  • Invited
• [Presentation] IgG4関連疾患と悪性疾患に関する全国調査 (2019)
  • Author(s): 住本貴美、内田一茂、岡崎和一
  • Organizer: 第12回IgG4研究会
• [Presentation] The role of basophils in the pathogenesis of type 1 autoimmune pancreatitis (2018)
  • Author(s): Uchida K, Yanagawa M, Ikeura T, Tanaka T, Tomiyama T, Yamaguchi T, Ando Y, Fukui T, Nishio A, Satoi S, Okazaki K
  • Organizer: oint Meeting of the Asian-Oceanic Pancreatic Association, the Korean Pancreatobiliary Association, and Korean Pancreas Surgery Club 2018
  • Int'l Joint Research
• [Presentation] Involvment of Basophils in Patients with Type 1 Autoimmune Pancreatitis (2018)
  • Author(s): Yanagawa M, Uchida K, Okazaki K
  • Organizer: 49th Annual Meeting of American Pancreatic Association
  • Int'l Joint Research
• [Presentation] １型自己免疫性膵炎における自然免疫の関与 (2018)
  • Author(s): 内田一茂，柳川雅人，岡崎和一
  • Organizer: 第104回日本消化器病学会総会シンポジウム
• [Presentation] 1型免疫性膵炎（AIP）の病態生理における自然免疫の反応の役割 (2018)
  • Author(s): 柳川雅人, 内田一茂, 岡崎和一
  • Organizer: 第49回日本膵臓学会大会シンポジウム
• [Presentation] 内田 一茂、津久田 諭、池浦 司、柳川 雅人、堀 雄一、中丸 洸、伊藤 嵩志、田中 敏宏、富山 尚、安藤 祐悟、山口 隆志、福井 寿朗、西尾 彰功、岡崎 和一 (2018)
  • Author(s): １型自己免疫性膵炎を含むIgG4関連疾患における血清Interleukin-６値とその臨床像の検討
  • Organizer: 第55回日本消化器免疫学会
• [Presentation] １型自己免疫性膵炎のおける好塩基球・ M2マクロファージの関与 (2018)
  • Author(s): 内田一茂、柳川雅人、池宗真美、津久田諭、田中敏広、富山 尚 山口隆志、安藤祐吾、池浦 司、福井寿朗、西尾彰功、岡崎和一
  • Organizer: 第46回日本臨床免疫学会
• [Presentation] 1 型自己免疫性膵炎と慢性膵炎の臨床的・組織学的相違点 (2018)
  • Author(s): 池浦 司、高岡 亮、内田 一茂、島谷 昌明、三好 秀明、光山 俊行、加藤 孝太、堀 雄一、岡崎 和一
  • Organizer: 第35回日本胆膵生理機能研究会