ＩｇＧ４関連疾患の病態解明に向けて－Ｔ細胞機能異常に基づいたモデルマウスの確立

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23591460
• Research Institution: Kanazawa University
• Principal Investigator: 川野 充弘 金沢大学, 大学病院, 講師 (20361983)
• Co-Investigator(Kenkyū-buntansha): 山田 和徳 金沢大学, 大学病院, 助教 (90397224)
• Keywords: IgG4関連疾患 / モデルマウス / Th2 / APRIL

Research Abstract

IgG4関連疾患の病態ついては未だに不明な点が多く、本疾患の病態の解明のために、適切な疾患モデル動物が必要と考えられる。我々は、Th2優位の免疫反応を有するLat Y136F変異マウスが新規IgG4関連疾患モデルマウスとなり得るか検討した。
Lat Y136F変異マウスは腎臓、膵臓、唾液腺において、導管および血管周囲に形質細胞浸潤および線維化を認めた。浸潤している主な細胞はIgG1（ヒトのIgG4に対応）であった。これらの所見より、Lat Y136F変異マウスはヒトのIgG4関連疾患と類似した病変を形成することが明らかになった。またLat Y136F変異マウスに4週齢または7週齢よりステロイドを腹腔内投与するとステロイド投与群はコントロール群と比較して病変は軽度となった。以上よりLat Y136F変異マウスは新規IgG4関連疾患モデル動物と考えられた。
申請者らは、ヒトのIgG4関連腎臓病において、形質細胞生存シグナルのひとつである、a proliferation inducing ligand (APRIL)の発現を確認した。さらにステロイド投与によりAPRILの発現低下を認めることも明らかにした。そこで、前年度よりLat Y136F変異マウスに4週齢よりAPRIL阻止抗体またはコントロールIgGを投与し、7週齢で組織を検討した。本年度は、前年度から引き続き、APRIL投与群およびコントロール群の組織学的検討を行った。その結果、Lat Y136F変異マウスの腎臓において、APRIL阻止抗体投与群では、有意に浸潤細胞数の低下が認められた。これらの結果よりAPRILがIgG4関連疾患の病態形成に深く関与していると考えられた。

Research Products

• [Journal Article] IgG4-related kidney disease (2014)
  • Author(s): Saeki T, Kawano M
  • Journal Title: Kidney Int Volume: 85(2) Pages: 251-257
  • DOI: 10.1038/ki.2013.393
  • Peer Reviewed
• [Journal Article] Immunoglobulin class switching to IgG4 in Warthin tumor and analysis of serum IgG4 levels and IgG4-positive plasma cells in the tumor. (2014)
  • Author(s): Aga M, Kondo S, Yamada K, Wakisaka N, Yagi-Nakanishi S, Tsuji A, Endo K, Murono S, Ito M, Muramatsu M, Kawano M, Yoshizaki T
  • Journal Title: Hum Pathol Volume: 45(4) Pages: 793-801
  • DOI: 10.1016/j.humpath.2013.11.012
  • 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, Yamagish M, Umehara H, Yamaguchi Y, Nagata M, Kawano M
  • Journal Title: Clin Nephrol Volume: 79(3) Pages: 246-252
  • DOI: 10.5414/CN107114
  • Peer Reviewed
• [Journal Article] Prurigo nodularis-like skin eruptions in a patient with IgG4-related disease (2013)
  • Author(s): Hamaguchi Y, Yamada K, Kawano M, Fujimoto M, Takehara K
  • Journal Title: Eur J Dermatol Volume: 23(4) Pages: 541-542
  • DOI: 10.1684/ejd.2013.2077
  • Peer Reviewed
• [Journal Article] Warthin's tumor associated with IgG4-related disease. (2013)
  • Author(s): Aga M, Kondo S, Yamada K, Sawada-Kitamura S, Yagi-Nakanishi S, Endo K, Wakisaka N, Murono S, Kawano M, Yoshizaki T.
  • Journal Title: Auris Nasus Larynx Volume: 40(5) Pages: 514-517
  • DOI: 10.1016/j.humpath.2013.11.012
  • Peer Reviewed
• [Presentation] Clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis: a retrospective multicenter study (2014)
  • Author(s): Ichiro Mizushima, Dai Inoue, Motohisa Yamamoto, Kazunori Yamada, Takako Saeki, Yoshifumi Ubara, Shoko Matsui, Yasufumi Masaki, Takashi Wada, Satomi Kasashima, Kenichi Harada, Hiroki Takahashi, Kenji Notohara, Yasuni Nakanuma, Hisanori Umehara, Masakazu Yamagishi, and Mitsuhiro Kawano
  • Organizer: Second International Symposium on IgG4 & Related Disease, Feb 17, 2014
  • Place of Presentation: Honolulu, USA
  • Year and Date: 20140219-20140219
• [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: Second International Symposium on IgG4 & Related Disease
  • Place of Presentation: Honolulu, USA
  • Year and Date: 20140216-20140219
• [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: Second International Symposium on IgG4 & Related Disease
  • Place of Presentation: Honolulu, USA
  • Year and Date: 20140216-20140219
• [Presentation] Overview of New Entities within the IgG4-RD spectrum (2014)
  • Author(s): Mitsuhiro Kawano
  • Organizer: Second International Symposium on IgG4 & Related Disease, Feb 17, 2014
  • Place of Presentation: Honolulu, USA
  • Year and Date: 20140216-20140219
  • Invited
• [Presentation] Histopathological analysis of IgG4-related kidney disease: hints from an autopsy series of 5 cases (2013)
  • Author(s): Ichiro Mizushima, Mitsuhiro Kawano, Takako Saeki, Yoshifumi Ubara, Nobuya Ohara, Yasuharu Sato, Kazunori Yamada, Hitoshi Nakashima, Shinichi Nishi, Yutaka Yamaguchi, Satoshi Hisano, Nobuaki Yamanaka, Michio Nagata, and Takao Saito.
  • Organizer: ASN Kidney Week 2013
  • Place of Presentation: Atlanta, USA
  • Year and Date: 20131105-20131110
• [Presentation] Inhibition of APRIL suppresses disease progression in an IgG4-related disease mice model (2013)
  • Author(s): Yamada K, Zuka M, Ito K, Suzuki Y, Kakuchi Y, Onoe T, Matsumura M, Yamagishi M, Izui S, Huard B, Malissen M, Malissen B, Kawano M.
  • Organizer: 12th International Symposium on Sjögren's Syndrome
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20131009-20131012
• [Presentation] Prurigo nodularis-like skin eruptions in a patient with IgG4-related disease (2013)
  • Author(s): Fujimoto M, Hamaguchi Y, Yamada K, Kawano M, Takehara K.
  • Organizer: 12th International Symposium on Sjögren's Syndrome
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20131009-20131012
• [Presentation] Clinical characteristics and the course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis (2013)
  • Author(s): Ichiro Mizushima, Dai Inoue, Kazunori Yamada, Takako Saeki, Yoshifumi Ubara, Yasunori Suzuki, Hiroshi Fujii, Masami Matsumura, Masakazu Yamagishi, Kenji Notohara, Mitsuhiro Kawano.
  • Organizer: Annual European Congress of Rheumatology 2013
  • Place of Presentation: Madrid, Spain
  • Year and Date: 20130612-20130615
• [Book] IgG4-Related Disease (2013)
  • Author(s): Hisanori Umehara, Kazuichi Okazaki, John H. Stone, Shigeyuki Kawa, Mitsuhiro Kawano
  • Total Pages: 237
  • Publisher: Springer