The Role of Innate Immunity in IgG4-Related Diseases and the Search for Novel Therapeutic Targets

• Project/Area Number: 17K09999
• 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 Medical University (2019-2022); Kanazawa University (2017-2018)
• Principal Investigator: YAMADA Kazunori 金沢医科大学, 医学部, 准教授 (90397224)
• Co-Investigator(Kenkyū-buntansha): 塚 正彦 金沢大学, 医学系, 教授 (00272956) ; 伊藤 清亮 金沢大学, 附属病院, 医員 (10467110) ; 川野 充弘 金沢大学, 附属病院, 講師 (20361983) ; 水島 伊知郎 金沢大学, 附属病院, 助教 (50645124) ; 原 怜史 金沢大学, 医学系, 助教 (80749820)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: IgG4関連疾患 / 自然免疫 / Toll-like receptor-9 / Galectin-3 / ガレクチン３ / Toll-like receptor

Outline of Final Research Achievements

In salivary gland tissues from patients with IgG4-related diseases, galectin-3, produced by M2 macrophages, is expressed at inflammation sites. It was confirmed that TLR-9 expression coincided with sites of inflammation in the kidneys of LAT Y136F knock-in mice. Thereafter, CpG oligodeoxynucleotides (CpG-ODN), a TLR-9 agonist, were administered to the mice to determine if the lesions could be alleviated by shifting the immune response to a Th1 response. The results demonstrated that administration of CpG-ODN from the age of 6 weeks suppressed the progression of lung lesions. However, when CpG-ODN was administered from the age of 9 weeks, the formation of granulomas was observed.

Academic Significance and Societal Importance of the Research Achievements

IgG4関連疾患における自然免疫の関与については、これまでも報告されているが、今回Gal-3やTLR-9もIgG4関連疾患の病態形成に何らの影響を与えている可能性が示唆された。今後、新規薬剤のターゲットの候補分子としての基礎となるデータを得た点が学術的意義があると考える。

Research Products

• [Journal Article] Olfactory dysfunction in LATY136F knock-in mice (2022)
  • Author(s): Kaneda Misako、Yagi-Nakanishi Sayaka、Ozaki Fumi、Kondo Satoru、Mizuguchi Keishi、Kawano Mitsuhiro、Malissen Marie、Malissen Bernard、Yamada Kazunori、Yoshizaki Tomokazu
  • Journal Title: Auris Nasus Larynx Volume: 49 Issue: 2 Pages: 209-214
  • DOI: 10.1016/j.anl.2021.07.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cases with IgG4-related ophthalmic disease with mass lesions surrounding the optic nerve (2022)
  • Author(s): Hamaoka S, Takahira M, Kawano M, Yamada K, Inoue D, Okuda T, Sugiyama K.
  • Journal Title: Am J Ophthalmol Case Rep. Volume: 2022 Jan 25;25:101324. Pages: 101324-101324
  • DOI: 10.1016/j.ajoc.2022.101324
  • Peer Reviewed
• [Journal Article] Lacrimal Gland and Orbital Lesions in Lat^Y136F Knock-in Mice, a Model for Human IgG4-Related Ophthalmic Disease (2022)
  • Author(s): Hamaoka Shoko、Takahira Masayuki、Kawano Mitsuhiro、Yamada Kazunori、Ito Kiyoaki、Okuda Tetsuhiko、Hatake Sachiyo、Malissen Marie、Malissen Bernard、Sugiyama Kazuhisa
  • Journal Title: Current Eye Research Volume: 47 Issue: 10 Pages: 1402-1409
  • DOI: 10.1080/02713683.2022.2103152
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serum IgG4 levels at diagnosis can predict unfavorable outcomes of untreated patients with IgG4-related disease (2021)
  • Author(s): Mizushima Ichiro、Konishi Masahiro、Sanada Hajime、Suzuki Kazuyuki、Takeji Akari、Zoshima Takeshi、Hara Satoshi、Ito Kiyoaki、Fujii Hiroshi、Yamada Kazunori、Kawano Mitsuhiro
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 13341-13341
  • DOI: 10.1038/s41598-021-92814-8
  • Peer Reviewed / Open Access
• [Journal Article] The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease (2021)
  • Author(s): Waseda Y, Yamada K, Mizuguchi K, Ito K, Watanabe S, Zuka M, Ishizuka T, Malissen M, Malissen B, Kawano M, Matsui S.
  • Journal Title: PLoS One Volume: Mar 4; 16 (3) Issue: 3 Pages: 1-12
  • DOI: 10.1371/journal.pone.0247173
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tertiary lymphoid tissue in early‐stage IgG4-related tubulointerstitial nephritis incidentally detected with a tumor lesion of the ureteropelvic junction: a case report (2021)
  • Author(s): Miyanaga Tatsuhito、Mizuguchi Keishi、Hara Satoshi、Zoshima Takeshi、Inoue Dai、Nishioka Ryo、Mizushima Ichiro、Ito Kiyoaki、Fuji Hiroshi、Yamada Kazunori、Sato Yuki、Yanagita Motoko、Kawano Mitsuhiro
  • Journal Title: BMC Nephrology Volume: 22 Issue: 1 Pages: 34-34
  • DOI: 10.1186/s12882-021-02240-1
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analysis of protein-expression changes specific to immunoglobulin G4-related disease (2021)
  • Author(s): Kawanami Takafumi、Kawanami-Iwao Haruka、Takata Takanobu、Ishigaki Yasuhito、Tomosugi Naohisa、Takegami Tsutomu、Yanagisawa Hiroto、Fujimoto Shino、Sakai Tomoyuki、Fujita Yoshimasa、Yamada Kazunori、Mizuta Shuichi、Kawabata Hiroshi、Fukushima Toshihiro、Hirose Yuko、Masaki Yasufumi
  • Journal Title: Clinica Chimica Acta Volume: 523 Pages: 45-57
  • DOI: 10.1016/j.cca.2021.08.025
  • Peer Reviewed / Open Access
• [Journal Article] Different factors underlie recurrent and de novo organ involvement in immunoglobulin G4-related disease. (2020)
  • Author(s): Mizushima I, Tsuge S, Fujisawa Y, Hara S, Suzuki F, Ito K, Fujii H, Yamada K, Kawano M.
  • Journal Title: Rheumatology (Oxford). Volume: 59 Pages: 513-518
  • DOI: 10.1093/rheumatology/kez321
  • Peer Reviewed / Open Access
• [Journal Article] Hypocomplementemia is related to elevated serum levels of IgG subclasses other than IgG4 in IgG4-related kidney disease. (2020)
  • Author(s): Fujisawa Y, Mizushima I, Yamada K, Yamamoto M, Saeki T, Matsui S, Tsuge S, Hara S, Ito K, Fujii H, Takahashi H, Nomura H, Kawa S, Kawano M.
  • Journal Title: Mod Rheumatol. Volume: 13 Issue: 1 Pages: 1-8
  • DOI: 10.1080/14397595.2019.1709942
  • Peer Reviewed / Open Access
• [Journal Article] Impaired expression of innate immunity-related genes in IgG4-related disease: A possible mechanism in the pathogenesis of IgG4-RD (2020)
  • Author(s): Nakamura Takuji, Satoh-Nakamura Tomomi、Nakajima Akio、Kawanami Takafumi、Sakai Tomoyuki、Fujita Yoshimasa et al.
  • Journal Title: Modern Rheumatology Volume: 30 (3) Issue: 3 Pages: 551-557
  • DOI: 10.1080/14397595.2019.1621475
  • Peer Reviewed
• [Journal Article] Clinical and Pathological Characteristics of IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis Diagnosed Based on Experts’ Diagnosis (2019)
  • Author(s): Mizushima Ichiro、Kasashima Satomi、Fujinaga Yasunari、Notohara Kenji、Saeki Takako、Zen Yoh、Inoue Dai、Yamamoto Motohisa、Kasashima Fuminari、Matsumoto Yasushi、Amiya Eisuke、Sato Yasuharu、Yamada Kazunori、Domoto Yukako、Kawa Shigeyuki、Kawano Mitsuhiro、Ishizaka Nobukazu
  • Journal Title: Annals of Vascular Diseases Volume: 12 Issue: 4 Pages: 460-472
  • DOI: 10.3400/avd.oa.19-00085
  • NAID: 130007772896
  • ISSN: 1881-641X, 1881-6428
  • Year and Date: 2019-12-25
  • Peer Reviewed / Open Access
• [Journal Article] LatY136F knock-in mouse model for human IgG4-related disease (2018)
  • Author(s): Yamada Kazunori、Zuka Masahiko、Ito Kiyoaki、Mizuguchi Keishi、Kakuchi Yasushi、Onoe Tamehito、Suzuki Yasunori、Yamagishi Masakazu、Izui Shozo、Malissen Marie、Malissen Bernard、Kawano Mitsuhiro
  • Journal Title: PLOS ONE Volume: 13 Issue: 6 Pages: e0198417-e0198417
  • DOI: 10.1371/journal.pone.0198417
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Abundant a proliferation-inducing ligand (APRIL)-producing macrophages contribute to plasma cell accumulation in immunoglobulin G4-related disease (2018)
  • Author(s): Kawakami Takahiro、Mizushima Ichiro、Yamada Kazunori、Fujii Hiroshi、Ito Kiyoaki、Yasuno Tetsuhiko、Izui Shozo、Yamagishi Masakazu、Huard Bertrand、Kawano Mitsuhiro
  • Journal Title: Nephrology Dialysis Transplantation Volume: 15 Issue: 6 Pages: 960-969
  • DOI: 10.1093/ndt/gfy296
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases. (2017)
  • Author(s): Yamada K, Yamamoto M, Saeki T, Mizushima I, Matsui S, Fujisawa Y, Hara S, Takahashi H, Nomura H, Kawa S, Kawano M.
  • Journal Title: Arthritis Res Ther Volume: 19 Issue: 1 Pages: 262-271
  • DOI: 10.1186/s13075-017-1467-x
  • Peer Reviewed / Open Access
• [Presentation] IgG4関連疾患モデルマウス（LATマウス）におけるCCL8-CCR8経路の病態形成での役割と治療標的の可能性 (2021)
  • Author(s): 本田文香、坪井洋人、安倍沙織、高橋広行、伊藤清亮、山田和徳、川野充弘、近藤裕也、松本功、住田孝之
  • Organizer: 第65回日本リウマチ学会総会・学術集会
• [Presentation] Serum IgG4 levels at diagnosis can predict the outcomes of untreated patients with IgG4-related disease: a Japanese single-center retrospective study. (2018)
  • Author(s): Mizushima I,Suzuki N,Yoshida M,Takeji A,Matsunaga T,Zoshima T,Hara S,Ito K,Fujii H,Yamada K, Kawano M
  • Organizer: Annual European Congress of Rheumatology Jun. 13-16, 2018 (Amsterdam,Netherlands)
  • Int'l Joint Research
• [Presentation] IgG4関連尿細管間質性腎炎におけるステロイド治療開始前の腎機能低下速度の検討 (2018)
  • Author(s): 川野 充弘，水島 伊知郎，谷口 義典，佐伯 敬子，中島 衡，原 怜史，松永 貴弘，藤井 博，山田 和徳
  • Organizer: 第62回日本リウマチ学会総会・学術集会 Apr.26-28,2018（東京）
• [Presentation] Clinical Impact of Peritubular Capillaritis on Renal Prognosis in ANCA-Associated Glomerulonephritis (2017)
  • Author(s): 1.Satoshi Hara, Fae Suzuki, Ichiro Mizushima, Kiyoaki Ito, Hiroshi Fujii, Kazunori Yamada, Mitsuhiro Kawano
  • Organizer: Kidney Week 2017
  • Int'l Joint Research
• [Presentation] IgG4関連疾患の既存病変再燃、新規病変出現に関与する因子の差異 (2017)
  • Author(s): 水島伊知郎、柘植俊介、藤澤雄平、原怜史、鈴木華恵、伊藤清亮、會津元彦、藤井博、山田和徳、川野充弘
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] 低補体血症を合併したIgG4関連腎臓病についての臨床的検討 (2017)
  • Author(s): 藤澤雄平、水島伊知郎、柘植俊介、原怜史、鈴木華恵、伊藤清亮、會津元彦、藤井博、山田和徳、川野充弘
  • Organizer: 第61回日本リウマチ学会総会・学術集会