Elucidation of pathophysiology and development of treatment for IgG4-related disease (RD)

• Project/Area Number: 15K15290
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: CHIBA Tsutomu 京都大学, 医学研究科, 名誉教授 (30188487)
• Co-Investigator(Kenkyū-buntansha): 児玉 裕三 京都大学, 医学研究科, 助教 (80378687)
• Research Collaborator: SEKIGUCHI Kiyotoshi ; SHIOKAWA Masahiro ; KURIYAMA Katsutoshi
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IgG4関連疾患 / 自己免疫性膵炎 / 自己抗体 / IgG / IgG4 / Extracellular matrix / 抗原

Outline of Final Research Achievements

According to the hypothesis that IgG4-related disease (RD) is an autoimmune disease, we tried to clarify the existence of and roles for autoantibodies in patients with IgG4-RD. We first confirmed that injection of IgG in the sera of patients with IgG4-RD induced autoimmune pancreatitis (AIP)-like lesions in mouse pancreas. We also observed that the injected IgG was localized in extracellular matrix (ECM) including basement membrane of pancreatic acini together with C1q, suggesting that the autoantibody in patients’ serum recognizes some ECM protein in the pancreas. Thus, we established ELISA for various laminins, and found that about 50% of the patients with IgG4-RD had antibody against laminin α5β1γ1 -E8 in their sera, but none of normal subjects, patients with pancreatic cancer or those with chronic pancreatitis had this antibody. We concluded this antibody has pathogenic role by dissociating acinar cells from ECM.

Research Products

• [Journal Article] Clinical features, treatment response, and outcome of IgG4-related sclerosing cholangitis (2017)
  • Author(s): Tanaka A, Tazuma S, Okazaki K, Nakazawa T, Inui K, Chiba T, Takikawa H
  • Journal Title: Clin Gastroenterol Hepatol Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] How to diagnose IgG4-related disaease (2017)
  • Author(s): Umehara H, Okazaki K, Kawano M, Mimori T, Chiba T
  • Journal Title: Ann Rheum Dis Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Current approach to the diagnosis of IgG4-related disease-Combination of comprehensive diagnostic and organ-specific criteria. (2017)
  • Author(s): Umehara H, Okazaki K, Nakamura T, Nakamura-Satoh T, Nakajima A, Kawano M, Mimori T, Chiba T
  • Journal Title: Mod Rheum Volume: 印刷中 Issue: 3 Pages: 381-391
  • DOI: 10.1080/14397595.2017.1290911
  • Peer Reviewed
• [Journal Article] Diagnosis of autoimmune pancreatitis by endoscopic ultrasonography -guided fine-needle aspiration using a 22-gauge needle: a prospective multicenter study. (2016)
  • Author(s): Kanno A, Masamune A, Fujishima F, Iwashita T, Kodama Y, Katanuma A, Ohara H, Kitano M, Inoue H, Itoi T, Mizuno N, Miyakawa H, Mikata R, Irisawa A, Sato S, Notohara K, Shimosegawa T.
  • Journal Title: Gastrointest Endosc. Volume: 84 Issue: 5 Pages: 797-797
  • DOI: 10.1016/j.gie.2016.03.1511
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pathogenicity of Immunoglobulin G in Patients with IgG4-related Disease. (2016)
  • Author(s): Shiokawa M, Kodama Y, Kuriyama K, Yoshimura K, Tomono T, Morita T, Kakiuchi N, Matsumori T, Mima A, Nishikawa Y, Ueda T, Tsuda M, Yamauchi Y, Minami R, Sakuma Y, Ota Y, Maruno T, Kurita A, Sawai Y, Tsuji Y, Uza N, Matsumura K, Watanabe T, Notohara K, Tsuruyama T, Seno H, Chiba T.
  • Journal Title: Gut Volume: 未定 Issue: 8 Pages: 3292-3301
  • DOI: 10.1136/gutjnl-2015-310336
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatiti (2016)
  • Author(s): Watanabe T, Sadakane Y, Yagama N, Sakurai T, Ezoe H, Kudo M, Chiba T, Strober W
  • Journal Title: Mucosal Immunol. Volume: in press Issue: 5 Pages: 1234-49
  • DOI: 10.1038/mi.2015.144
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Is Serum IgG in Patients with AIP Pathogenic? (2017)
  • Author(s): Shiokawa Masahiro, Kodama Yuzo, Seno, Hiroshi, Chiba Tsutomu,
  • Organizer: International Symposium on IgG4-RD & Fibrosis
  • Place of Presentation: ハワイ
  • Year and Date: 2017-02-15
  • Int'l Joint Research
• [Presentation] IgG4関連疾患におけるIgGの病原性と標的抗原の解明 (2016)
  • Author(s): 塩川雅広、児玉裕三、千葉勉
  • Organizer: ＪＤＤＷ2016 第24回日本消化器関連学会週間
  • Place of Presentation: 神戸
  • Year and Date: 2016-11-03
• [Presentation] Chemokine CXCL16 Plays a Critical Role in the Development of Severe Acute Pancreatitis (2016)
  • Author(s): Sakuma Y, Kodama Y, Matsumori T, Tomono T, Kakiuchi N, Mima A, Yamauchi Y, Nishikawa Y, Tsuda M, Ueda T, Kuriyama K, Maruno T, Ota Y, Shiokawa M, Tsuji Y, Uza N, Watanabe T, Nakase H, Seno H, Chiba T
  • Organizer: Digestive Disease Week 2016
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] Pathogenic Role of IgG in Patients With IgG4-Related Disease on Neonatal Mice. (2016)
  • Author(s): Shiokawa M, Kodama Y, Kuriyama K, Tomono T, Morita T, Kakiuchi N, Matsumori T, Mima A, Nishikawa Y, Ueda T, Tsuda M, Yamauchi Y, Sakuma Y, Ota Y, Maruno T, Uza N, Seno H, Chiba T
  • Organizer: Digestive Disease Week 2016
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] Pathogenic Role of IgG in Patients with IgG4-related Disease on Neonatal Mice (2016)
  • Author(s): Shiokawa M, Kodama Y, Kuriyama K, Yoshimura K, Tomono T, Morita T, Kakiuchi N, Matsumori T, Mima A, Nishikawa Y, Ueda T, Tsuda M, Yamauchi Y, Minami R, Sakuma Y, Ota Y, Maruno T, Kurita A, Sawai Y, Tsuji Y, Uza N, Matsumura K, Watanabe T, Notohara K, Tsuruyama T, Seno H, Chiba T
  • Organizer: DDW
  • Place of Presentation: San Diego
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] IgG4 関連疾患におけるIgG の病原性と標的抗原の解明 (2016)
  • Author(s): 塩川雅広、児玉裕三、千葉勉
  • Organizer: 第１０２回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-21
• [Presentation] IgG4関連疾患におけるIgGの病原性と標的抗原の解明 (2016)
  • Author(s): 塩川 雅広、児玉 裕三、妹尾 浩、千葉 勉
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 新宿 京王プラザホテル
  • Year and Date: 2016-04-21
• [Presentation] 自己免疫性膵炎におけるIgGの病原性と抗原同定 (2016)
  • Author(s): 塩川雅広、児玉裕三、垣内伸之、友野輝子、松森友昭、上田樹、津田喬之、西川義浩、山内雄揮、佐久間洋二朗、栗山勝利、宇座徳光、妹尾浩、千葉勉
  • Organizer: 第33回日本胆膵病態・生理研究会
  • Place of Presentation: 大阪