Elucidation of a pathogenesis of IgG4-related disease and establishment of a novel treatment

• Project/Area Number: 26461487
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kanazawa University
• Principal Investigator: Kawano Mitsuhiro 金沢大学, 附属病院, 講師 (20361983)
• Co-Investigator(Kenkyū-buntansha): 山田 和徳 金沢大学, 医薬保健学総合研究科, 特任准教授 (90397224)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: IgG4関連疾患 / APRIL / BAFF / マウスモデル / モデルマウス

Outline of Final Research Achievements

The purpose of this study was to analyze the role of a proliferation-inducing ligand (APRIL) in patients with IgG4-related disease (IgG4-RD). APRIL was expressed in kidney inflammation, and corticosteroid treatment decreased the expression of APRIL in the renal tissue of patients with IgG4-related kidney disease. We found that the main APRIL-producing cells were M2 macrophages. We also confirmed the expression of APRIL in the inflammatory lesion of Lat Y136F knock-in mice. Treatment with APRIL-blocking antibody suppressed the development of the kidney lesions in these mice. Furthermore, we confirmed the high expression level of BAFF in the lesions of patients with IgG4-RD and Lat Y136F knock-in mice. These data indicate that APRIL and BAFF are related to the pathogenesis of IgG4-RD.

Research Products

• [Journal Article] Factors related to renal cortical atrophy development after glucocorticoid therapy in IgG4-related kidney disease: a retrospective multicenter study (2016)
  • Author(s): Mizushima I, Yamamoto M, Inoue D, Nishi S, Taniguchi Y, Ubara Y, Matsui S, Yasuno T, Nakashima H, Takahashi H, Yamada K, Nomura H, Yamagishi M, Saito T, Kawano M.
  • Journal Title: Arthritis Res Ther. 18(1):273,2016 Volume: 18(1) Pages: 273-273
  • NAID: 120006325353
  • Peer Reviewed / Open Access
• [Journal Article] Distribution and components of interstitial inflammation and fibrosis in IgG4-related kidney disease: Analysis of autopsy specimens (2016)
  • Author(s): Hara S, Kawano M, Mizushima I, Harada K, Takata T, Saeki T, Ubara Y, Sato Y, Nagata M.
  • Journal Title: Hum Pathol. Volume: 55 Pages: 164-173
  • DOI: 10.1016/j.humpath.2016.05.010
  • NAID: 120007129427
  • Peer Reviewed / Open Access
• [Journal Article] IgG4-Related Kidney Disease and IgG4-Related Retroperitoneal Fibrosis. (2016)
  • Author(s): Kawano M, Yamada K.
  • Journal Title: Semin Liver Dis Volume: 36(3) Issue: 03 Pages: 283-290
  • DOI: 10.1055/s-0036-1584316
  • Peer Reviewed
• [Journal Article] Recovery of renal function after glucocorticoid therapy for IgG4-related kidney disease with renal dysfunction. (2016)
  • Author(s): Saeki T, Kawano M, Mizushima I, Yamamoto M, Wada Y, Ubara Y, Nakashima H, Ito T, Yamazaki H, Narita I, Saito T.
  • Journal Title: Clin Exp Nephrol. Volume: 20(1) Issue: 1 Pages: 87-93
  • DOI: 10.1007/s10157-015-1140-0
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of IgG4-positive clones in affected organs of IgG4-related disease. (2016)
  • Author(s): Kakuchi Y, Yamada K, Ito K, Hara S, Fujii H, Yamagishi M, Kawano M.
  • Journal Title: Mod Rheumatol. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Pericardial Involvement in IgG4-related Disease (2015)
  • Author(s): Mori K, Yamada K, Konno T, Inoue D, Uno Y, Watanabe M, Okuda M, Oe K, Kawano M, Yamagishi M
  • Journal Title: Internal Medicine Volume: 54 Issue: 10 Pages: 1231-1235
  • DOI: 10.2169/internalmedicine.54.3856
  • NAID: 130005069788
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] A case developing minimal change disease during the course of IgG4-related disease. (2015)
  • Author(s): Yamada K, Zoshima T, Ito K, Mizushima I, Hara S, Horita S, Nuka H, Hamano R, Fujii H, Yamagishi M, Kawano M.
  • Journal Title: Mod Rheumatol. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] A condition closely mimicking IgG4-related disease despite the absence of serum IgG4 elevation and IgG4-positive plasma cell infiltration. (2015)
  • Author(s): Hara S, Kawano M, Mizushima I, Yamada K, Fujita K, Harada K, Matsumura M, Yamagishi M, Sato Y, Yamaguchi Y, Nakanuma Y, Nagata M.
  • Journal Title: Mod Rheumatol. Volume: 印刷中
  • NAID: 120007135033
  • Peer Reviewed
• [Journal Article] A condition closely mimicking IgG4-related disease despite the absence of serum IgG4 elevation and IgG4-positive plasma cell infiltration. (2014)
  • Author(s): Hara S, Kawano M, Mizushima I, Yamada K, Fujita K, Harada K, Matsumura M, Yamagishi M, Sato Y, Yamaguchi Y, Nakanuma Y, Nagata M.
  • Journal Title: Mod Rheumatol Volume: 0 Issue: 5 Pages: 0-0
  • DOI: 10.3109/14397595.2014.916836
  • NAID: 120007135033
  • Peer Reviewed / Open Access
• [Journal Article] Clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis: a retrospective multicenter study. (2014)
  • Author(s): Mizushima I, Inoue D, Yamamoto M, Yamada K, Saeki T, Ubara Y, Matsui S, Masaki Y, Wada T, Kasashima S, Harada K, Takahashi H, Notohara K, Nakanuma Y, Umehara H, Yamagishi M, Kawano M.
  • Journal Title: Arthritis Res Ther. Volume: 16 Issue: 4
  • DOI: 10.1186/ar4671
  • NAID: 120006460360
  • Peer Reviewed / Open Access
• [Journal Article] IgG4-related disease and its pathogenesis-cross-talk between innate and acquired immunity. (2014)
  • Author(s): Umehara H, Nakajima A, Nakamura T, Kawanami T, Tanaka M, Dong L, Kawano M.
  • Journal Title: Int Immunol. Volume: 26 Issue: 11 Pages: 585-95
  • DOI: 10.1093/intimm/dxu074
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of pancreatic endocrine function in patients with IgG4-related diseases, in whom autoimmune pancreatitis was ruled out by diagnostic imaging. (2014)
  • Author(s): Ito N, Yagi K, Kawano M, Mori Y, Okazaki S, Chujo D, Takeda Y, Kobayashi J, Yamagishi M.
  • Journal Title: Endocr J. Volume: 61 Pages: 765-72
  • NAID: 130004684904
  • Peer Reviewed / Open Access
• [Journal Article] IgG4-related kidney disease (2014)
  • Author(s): Saeki T, Kawano M
  • Journal Title: Kidney Int Volume: 85(2) Issue: 2 Pages: 251-257
  • DOI: 10.1038/ki.2013.393
  • NAID: 40017420481
  • Peer Reviewed
• [Journal Article] Primary Sjögren's syndrome with chronic tubulointerstitial nephritis and lymphadenopathy mimicking IgG4-related disease (2013)
  • Author(s): Kawano M, Suzuki Y, Yamada K, Mizushima I, Matsumura M, Nakajima K, Yamagishi M, Yamaguchi Y
  • Journal Title: Mod Rheumatol Volume: (Epub ahead of print) Issue: 4 Pages: 637-641
  • DOI: 10.3109/14397595.2013.844303
  • Peer Reviewed
• [Presentation] Analysis of 84 patients with IgG4-related disease and malignancy (2016)
  • Author(s): Yamada K, Mizushima I, Nomura H, Kawano M
  • Organizer: American College of Rheumatology 2016 Annual Meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Clinical and Laboratory Features of IgG4-Related Retroperitoneal Fibrosis/Periarteritis in Japan: Retrospective Multicenter Study of 99 Cases (2016)
  • Author(s): Mizushima I, Kasashima S, Yamamoto M, Saeki T, Yamada K, Inoue D, Kasashima F, Matsumoto Y, Amiya E, Notohara K, Sato Y, Zen Y, Kawa S, Kawano M, Ishizaka N
  • Organizer: American College of Rheumatology 2016 Annual Meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] An International, Multi-Specialty Validation Study of the IgG4-Related Disease Responder Index (2016)
  • Author(s): Wallace Z, Khosroshahi A, Carruthers M, Corrado C, Choi HK, Culver E, Cortazar F, Ebbo M, Fernandes A, Frulloni L, Karadag O, Kawa S, Kawano M, Kim MH, Lanzillotta M, Matsui S, Perugino C, Okazaki K, Hart P, Ryu JH, Saeki T, Schleinitz N, Tanasa P, Umehara H, Webster G, Zhang W, Stone JH
  • Organizer: American College of Rheumatology 2016 Annual Meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] The Relationship Between Serum Cholinesterase, Number of Organ Involvement and Fibrotic Markers in Japanese Patients with IgG4-Related Disease (2016)
  • Author(s): Inotani S, Taniguchi Y, Kawano M, Maeda N, Nishikawa H, Matsuura M, Inoue K, Horino T, Fujimoto S, Terada Y
  • Organizer: American College of Rheumatology 2016 Annual Meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] IgG4関連腎臓病においてステロイド治療前の腎機能障害が治療後腎萎縮出現に与える影響 (2016)
  • Author(s): 水島伊知郎，山本元久，山田和徳，谷口義典，乳原善文，中島衡，西慎一，川野充弘
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-06-17
• [Presentation] IgG4関連疾患85例における悪性腫瘍合併例の臨床的解析 (2016)
  • Author(s): 山田和徳，水島伊知郎，川野充弘
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-04-21
• [Presentation] IgG4関連腎臓病におけるステロイド治療後の腎萎縮出現に関与する因子の検討 (2016)
  • Author(s): 水島伊知郎，山本元久，山田和徳，谷口義典，乳原善文，松井祥子，中島衡，西慎一，川野充弘
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-04-21
• [Presentation] IgG4関連疾患333例の臨床像の検討 (2016)
  • Author(s): 山田和徳，山本元久，佐伯敬子，水島伊知郎，松井祥子，高橋裕樹，山岸正和，川野充弘，川茂幸
  • Organizer: 第113回日本内科学会総会・講演会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-15
• [Presentation] Baseline clinical and laboratory features of IgG4-related disease: retrospective Japanese multicenter study of 333 cases (2015)
  • Author(s): Kazunori Yamada, Motohisa Yamamoto, Takako Saeki, Ichiro Mizushima, Shoko Matsui, Hiroki Takahashi, Mitsuhiro Kawano, and Shigeyuki Kawa
  • Organizer: 2015 ACR/ARHP Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] Clinical and laboratory features of IgG4-related disease: retrospective Japanese multicenter study of 328 cases (2015)
  • Author(s): Kazunori Yamada, Motohisa Yamamoto, Takako Saeki, Ichiro Mizushima, Hiroki Takahashi, Mitsuhiro Kawano, and Shigeyuki Kawa
  • Organizer: EULAR 2015
  • Place of Presentation: Roma, Italy
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] IgG4関連疾患における抗核抗体の意義 (2015)
  • Author(s): 原怜史，堀田成人，額裕海，蔵島乾，伊藤清亮，會津元彦，藤井博，山田和徳，川野充弘
  • Organizer: 第59回日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-04-23
• [Presentation] IgG4陽性形質細胞浸潤を伴う尿細管間質性腎炎を認めた多中心性キャッスルマン病の3例 (2015)
  • Author(s): 蔵島乾，原怜史，堀田成人，額裕海，伊藤清亮，會津元彦，藤井博，山田和徳，川野充弘
  • Organizer: 第59回日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-04-23
• [Presentation] IgG4関連疾患モデルマウスの確立とその応用 ～IgG4関連疾患におけるAPRILの関与～ (2015)
  • Author(s): 山田和徳、塚正彦、伊藤清亮、早稲田優子、鈴木康倫、覚知泰志、小野江為人、松井祥子、川野充弘
  • Organizer: 第8回 IgG4研究会
  • Place of Presentation: 福岡
  • Year and Date: 2015-03-21
  • Invited
• [Presentation] A Case of Multicentric Castleman's Disease with IgG4 Related Disease Like Multiorgan Lesions Including Tubulointerstitial Nephritis (2014)
  • Author(s): Takeshi Zoshima, Kazunori Yamada, Mitsuhiro Kawano
  • Organizer: Kidney Week 2014
  • Place of Presentation: Philadelphia
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] IgG4関連肺疾患モデルマウスの確立～Lat Y136F knock-inマウスの肺病変の解析～ (2014)
  • Author(s): 山田和徳、早稲田優子 、塚正彦 、渡辺知志 、 伊藤清亮、林龍二、川野充弘、松井祥子
  • Organizer: 第23回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2014-09-13
• [Presentation] IgG4関連腎臓病の診断と治療 (2014)
  • Author(s): 川野充弘
  • Organizer: 第23回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2014-09-13
  • Invited
• [Presentation] Evaluation of Lung Lesions in LATY136F Mutant Mice ~Are They recognized as the models of IgG4 related lung disease?~ (2014)
  • Author(s): Yuko Waseda, Shoko Matsui, Kazunori Yamada, Satoshi Watanabe, Kiyoaki Ito, Ryo Matsunuma, Hazuki Takato, Yukari Ichikawa, Masahide Yasui, Mitsuhiro Kawano, Masahiko Zuka, Helmut Prosch , Christian Herold and Kazuo Kasahara
  • Organizer: European Respiratory Society International Congress 2014
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] IgG4関連疾患の経過中に 微小変化型ネフローゼ症候群 を発症した1例 (2014)
  • Author(s): 山田和徳、蔵島乾、伊藤清亮、堀田成人、額裕海、濱野良子、藤井博、川野充弘
  • Organizer: 第26回中部リウマチ学会
  • Place of Presentation: 新潟
  • Year and Date: 2014-08-29 – 2014-08-30
• [Presentation] 剖検腎におけるIgG4関連腎臓病の病理組織学的解析 (2014)
  • Author(s): 水島伊知郎，川野充弘，佐伯敬子，乳原善文，大原信哉，佐藤康晴，山田和徳，中島 衡，西 慎一，山口 裕，久野 敏，山中宣昭，長田道夫，斉藤喬雄
  • Organizer: 第57回日本腎臓学会・学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] Involvement of macrophages and a proliferation-inducing ligand (APRIL) in IgG4-related inflammatory abdominal aortic aneurysm (2014)
  • Author(s): I. Mizushima, S. Kasashima, K. Yamada, K. Harada, Y. Nakanuma, M. Yamagishi and M. Kawano
  • Organizer: Annual European Congress of Rheumatology
  • Place of Presentation: Paris
  • Year and Date: 2014-06-11 – 2014-06-14
• [Presentation] IgG4関連腎臓病におけるステロイド初期投与量の検討 (2014)
  • Author(s): 佐伯敬子、川野充弘、水島伊知郎、山本元久、乳原善文、中島衛、伊藤朋之、山崎肇、成田一衛、斉藤喬雄
  • Organizer: 第58回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] IgG4関連動脈周囲炎の臨床経過に関する多施設共同後方視的研究 (2014)
  • Author(s): 水島伊知郎、山田和徳、山本元久、佐伯敬子、乳原善文、松井祥子、正木康史、和田隆志、梅原久範、川野充弘
  • Organizer: 第58回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 頭蓋内血管病変を合併したIgG4関連疾患の1例 (2014)
  • Author(s): 山田和徳、藤澤雄平、水島伊知郎、北田欽也、鈴木康倫、伊藤清亮、濱野良子、藤井博、川野充弘
  • Organizer: 第58回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-24 – 2014-04-26
• [Book] IgG4関連疾患 実践的臨床から病因へ (2015)
  • Author(s): 中村誠司、住田孝之、川茂幸、川野充弘
  • Total Pages: 208
  • Publisher: 前田書店/金沢