Clarification of the etiopathogenesis of IgG4-related disease: Establishment of a mouse model based on abnormal T cell functional abnormalities

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591460
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kanazawa University
• Principal Investigator: KAWANO Mitsuhiro 金沢大学, 大学病院, 講師 (20361983)
• Co-Investigator(Kenkyū-buntansha): YAMADA Kazunori 金沢大学, 大学病院, 助教 (90397224)
• Project Period (FY): 2011 – 2013
• Keywords: IgG4関連疾患 / モデルマウス / APRIL

Research Abstract

We evaluated whether Lat Y136F knock-in mice, which show Th2 predominant immunoreaction with increased serum IgG1, a counterpart of human IgG4, are a novel mice model for IgG4-related disease (IgG4-RD). Lat Y136F knock-in mice showed a similar pathology to that of human IgG4-RD in kidney, pancreas and salivary glands, and a good response to corticosteroid. These results suggested that Lat Y136F knock-in mice are a novel mice model for IgG4-RD. Next, we analyzed the role of APRIL in IgG4-RD using Lat Y136F knock-in mice. We administered APRIL blocking antibody to Lat Y136F knock-in mice, and found that the inflammation in kidney in an APRIL blocking antibody group was significantly decreased as compared to that in a control group. This result indicated that APRIL plays some role in the promotion of lesions at least in IgG4-related kidney disease.

Research Products

• [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: Endocrine Journal Volume: (in press)
  • 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: (in press)
  • Peer Reviewed
• [Journal Article] Investigations of IgG4-related disease involving the skin (2013)
  • Author(s): Yamada K, Hamaguchi Y, Saeki T, Yagi K, Ito N, Kakuchi Y, Yamagishi M, Takehara K, Nakanuma Y, Kawano M
  • Journal Title: Mod Rheumatol Volume: 23(5) Pages: 986-93
  • DOI: 10.1007/s10165-012-0786-7
  • Peer Reviewed
• [Journal Article] The clinical course of patients with IgG4-related kidney disease (2013)
  • Author(s): Saeki T, Kawano M, Mizushima I, Yamamoto M, Wada Y, Nakashima H, Homma N, Tsubata Y, Takahashi H, Ito T, Yamazaki H, Saito T, Narita I
  • Journal Title: Kidney Int Volume: 84(4) Pages: 826-33
  • DOI: 10.1038/ki.2013.191
  • Peer Reviewed
• [Journal Article] Henoch-Schönlein purpura nephritis in a patient with IgG4-related disease : A possible association (2013)
  • Author(s): Ito K, Yamada K, Mizushima I, Aizu M, Fujii H, Mizutomi K, Matsumura M, Hayashi K, Yamagishi M, Umehara H, Yamaguchi Y, Nagata M, Kawano M
  • Journal Title: Clin Nephrol Volume: 79(3) Pages: 246-52
  • DOI: 10.5414/CN107114
  • 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)
  • DOI: 10.3109/14397595.2013.844303
  • Peer Reviewed
• [Journal Article] Immunohistochemical Characteristics of IgG4-Related Tubulointerstitial Nephritis : Detailed Analysis of 20 Japanese Cases (2012)
  • Author(s): Kawano M, Mizushima I, Yamaguchi Y, Imai N, Nakashima H, Nishi S, Hisano S, Yamanaka N, Yamamoto M, Takahashi H, Umehara H, Saito T, Saeki T
  • Journal Title: Int J Rheumatol Volume: 2012 Pages: 609795
  • DOI: 10.1155/2012/609795
  • Peer Reviewed
• [Journal Article] Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations (2012)
  • Author(s): Stone JH, Khosroshahi A, Deshpande V, Chan JK, Heathcote JG, Aalberse R, Azumi A, Bloch DB, Brugge WR, Carruthers MN, Cheuk W, Cornell L, Castillo CF, Ferry JA, Forcione D, Klöppel G, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Masaki Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani D, Sato Y, Smyrk T, Stone JR, Takahira M, Umehara H, Webster G, Yamamoto M, Yi E, Yoshino T, Zamboni G, Zen Y, Chari S
  • Journal Title: Arthritis Rheum Volume: 64(10) Pages: 3061-7
  • DOI: 10.1002/art.34593
  • Peer Reviewed
• [Journal Article] Consensus statement on the pathology of IgG4-related disease (2012)
  • Author(s): Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Klöppel G, Heathcote JG, Khosroshahi A, Ferry JA, Aalberse RC, Bloch DB, Brugge WR, Bateman AC, Carruthers MN, Chari ST, Cheuk W, Cornell LD, Fernandez-Del Castillo C, Forcione DG, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Lauwers GY, Masaki Y, Nakanuma Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani DV, Smyrk TC, Stone JR, Takahira M, Webster GJ, Yamamoto M, Zamboni G, Umehara H, Stone JH
  • Journal Title: Mod Pathol Volume: 25(9) Pages: 1181-92
  • DOI: 10.1038/modpathol.2012.72
  • Peer Reviewed
• [Journal Article] Clinical and histological changes associated with corticosteroid therapy in IgG4-related tubulointerstitial nephritis (2012)
  • Author(s): Mizushima I, Yamada K, Fujii H, Inoue D, Umehara H, Yamagishi M, Yamaguchi Y, Nagata M, Matsumura M, Kawano M
  • Journal Title: Mod Rheumatol Volume: 22(6) Pages: 859-70
  • Peer Reviewed
• [Journal Article] Light-microscopic characteristics of IgG4-related tubulointerstitial nephritis : distinction from non-IgG4-related tubulointerstitial nephritis (2012)
  • Author(s): Yoshita K, Kawano M, Mizushima I, Hara S, Ito Y, Imai N, Ueno M, Nishi S, Nomura H, Narita I, Saeki T
  • Journal Title: Nephrol Dial Transplant Volume: 27(7) Pages: 2755-61
  • DOI: 10.1007/s10165-011-0589-2
  • Peer Reviewed
• [Journal Article] Characteristic tubulointerstitial nephritis in IgG4-related disease (2012)
  • Author(s): Yamaguchi Y, Kanetsuna Y, Honda K, Yamanaka N, Kawano M, Nagata M; Japanesestudy group on IgG4-related nephropathy
  • Journal Title: Hum Pathol Volume: 43(4) Pages: 536-49
  • DOI: 10.1016/j.humpath.2011.06.002
  • Peer Reviewed
• [Journal Article] Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease (2012)
  • Author(s): Masaki Y, Kurose N, Yamamoto M, Takahashi H, Saeki T, Azumi A, Nakada S, Matsui S, Origuchi T, Nishiyama S, Yamada K, Kawano M, Hirabayashi A, Fujikawa K, Sugiura T, Horikoshi M, Umeda N, Minato H, Nakamura T, Iwao H, Nakajima A, Miki M, Sakai T, Sawaki T, Kawanami T, Fujita Y, Tanaka M, Fukushima T, Eguchi K, Sugai S, Umehara H
  • Journal Title: Int J Rheumatol Volume: 2012 Pages: 580814
  • DOI: 10.1155/2012/580814
  • Peer Reviewed
• [Journal Article] Clinical Aspects of IgG4-Related Orbital Inflammation in a Case Series of Ocular Adnexal Lymphoproliferative Disorders (2012)
  • Author(s): Takahira M, Ozawa Y, Kawano M, Zen Y, Hamaoka S, Yamada K, Sugiyama K
  • Journal Title: Int J Rheumatol Volume: 2012 Pages: 635473
  • DOI: 10.1155/2012/635473
  • Peer Reviewed
• [Journal Article] Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011 (2012)
  • Author(s): Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, Hamano H, Kamisawa T, Shimosegawa T, Shimatsu A, Nakamura S, Ito T, Notohara K, Sumida T, Tanaka Y, Mimori T, Chiba T, Mishima M, Hibi T, Tsubouchi H, Inui K, Ohara H
  • Journal Title: Mod Rheumatol. Volume: 22(1) Pages: 21-30
  • DOI: 10.1007/s10165-011-0571-z
  • Peer Reviewed
• [Journal Article] Proposal for diagnostic criteria for IgG4-related kidney disease (2011)
  • Author(s): Kawano M, Saeki T, Nakashima H, Nishi S, Yamaguchi Y, Hisano S, Yamanaka N, Inoue D, Yamamoto M, Takahashi H, Nomura H, Taguchi T, Umehara H, Makino H, Saito T
  • Journal Title: Clin Exp Nephrol Volume: 15(5) Pages: 615-26
  • DOI: 10.1007/s10157-011-0521-2
  • Peer Reviewed
• [Journal Article] IgG4-related tubulointerstitial nephritis and hepatic inflammatory pseudotumor without hypocomplementemia (2011)
  • Author(s): Kim F, Yamada K, Inoue D, Nakajima K, Mizushima I, Kakuchi Y, Fujii H, Narumi K, Matsumura M, Umehara H, Yamagishi M, Kawano M
  • Journal Title: Intern Med Volume: 50(11) Pages: 1239-44
  • URL: https://www.jstage.jst.go.jp/article/internalmedicine/50/11/50_11_1239/_article
  • Peer Reviewed
• [Presentation] Inhibition of APRIL suppresses disease progression : Analysis from a novel mouse model for IgG4-related disease (2014)
  • Author(s): Kazunori Yamada, Masahiko Zuka, Kiyoaki Ito, Yasunori Suzuki, Yasushi Kakuchi, Tamehito Onoe, Masakazu Yamagishi, and Mitsuhiro Kawano
  • Organizer: The 2nd International Symposium on IgG4-Related Diseases & Associated Conditions
  • Place of Presentation: HONOLULU, U.S.A
  • Year and Date: 20140216-19
• [Presentation] Abundant APRIL-Producing Macrophages in IgG4-related Kidney Disease (2014)
  • Author(s): Kazunori Yamada, Takahiro Kawakami, Ichiro Mizushima, Ryoko Hamano, Hiroshi Fujii, Masakazu Yamagishi, and Mitsuhiro Kawano
  • Organizer: The 2nd International Symposium on IgG4-Related Diseases & Associated Conditions
  • Place of Presentation: HONOLULU, U.S.A
  • Year and Date: 20140216-19
• [Presentation] Overview of New Entities within the IgG4-RD spectrum (2014)
  • Author(s): Mitsuhiro Kawano
  • Organizer: Second International Symposium on IgG4 & Related Disease
  • Place of Presentation: HONOLULU, U.S.A
  • Year and Date: 20140216-19
• [Presentation] Inhibition of APRIL suppresses disease progression in an IgG4-related disease mice model (2013)
  • Author(s): Kazunori Yamada, Masahiko Zuka, Kiyoaki Ito, Yasunori Suzuki, Yasushi Kakuchi, Tamehito Onoe, Masami Matsumura, Masakazu Yamagishi, Shozo Izui, Bertrand Huard, Marie Malissen, Bernard Malissen and Mitsuhiro Kawano
  • Organizer: 12th International Symposium on Sjögren's syndrome
  • Place of Presentation: Kyoto Hotel Okura, Kyoto, Japan
  • Year and Date: 20131009-12
• [Presentation] シェーグレン症候群の腎病変(IgG4関連腎臓病との比較).シンポジウム1シェーグレン症候群の臓器病変と腺病変の最前線 (2013)
  • Author(s): 川野充弘
  • Organizer: 第22回日本シェーグレン症候群学会
  • Place of Presentation: ブリーゼプラザ,大阪
  • Year and Date: 20130913-14
• [Presentation] IgG4関連疾患の病態形成におけるAPRILの関与:モデルマウスを用いた検討 (2013)
  • Author(s): 山田和徳,塚正彦,伊藤清亮,小野江為人,鈴木康倫,水島伊知郎,濱野良子,藤井博,松村正巳,川野充弘
  • Organizer: 第22回日本シェーグレン症候群学会
  • Place of Presentation: ブリーゼプラザ,大阪
  • Year and Date: 20130913-14
• [Presentation] リウマチ・膠原病疾患におけるIgG4関連疾患.ランチョンセミナーII (2013)
  • Author(s): 川野充弘
  • Organizer: 第25回中部リウマチ学会
  • Place of Presentation: 金沢
  • Year and Date: 20130906-07
• [Presentation] IgG4関連腎臓病.シンポジウム17 IgG4関連疾患 (2013)
  • Author(s): 川野充弘
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 20130418-20
• [Presentation] (2012)
  • Author(s): Takahiro Kawakami, Kazunori Yamada, Ichiro Mizushima, Hiroshi Fujii, Kiyoaki Ito, Shozo Izui, Bertrand Huard, and Mitsuhiro Kawano
  • Organizer: Kidney Week 2012
  • Place of Presentation: San Diego Convention Center, San Diego, USA
  • Year and Date: 20121101-04
• [Presentation] IgG4関連腎臓病におけるAPRIL発現の検討 (2012)
  • Author(s): 山田和徳,川上貴裕,水島伊知郎,鈴木康倫,藤井博,松村正巳,能登原憲司,川野充弘
  • Organizer: 第21回日本シェーグレン症候群学会
  • Place of Presentation: ウェスティン都ホテル京都,京都市
  • Year and Date: 20120907-08
• [Presentation] IgG4関連疾患におけるステロイド維持療法期の再発の検討.ワークショップ71 IgG4関連疾患1 (2012)
  • Author(s): 川野充弘,山田和徳,水島伊知郎,鈴木康倫,谷悠紀子,川村里佳,濱野良子,藤井博,松村正
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 20120426-28
• [Presentation] IgG4-related Disease : Initial Discovery, Evolving Concepts, Up-to-date Knowledge, role of a proliferation inducing ligand(APRIL) (2012)
  • Author(s): Mitsuhiro Kawano
  • Organizer: Special Seminar:IgG4-related Disease
  • Place of Presentation: University of Geneva, Geneva, Switzerland
  • Year and Date: 2012-06-05
• [Presentation] Proposal for diagnostic criteria for IgG4-related kidney disease (2011)
  • Author(s): Mitsuhiro Kawano
  • Organizer: International Symposium for IgG4-related disease
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2011-09-10