The ubiquitylation system as a potential therapeutic target for rheumatic diseases

• Project/Area Number: 26461468
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Yokohama City University
• Principal Investigator: YOSHIMI Ryusuke 横浜市立大学, 附属病院, 助教 (70585265)
• Co-Investigator(Kenkyū-buntansha): 岳野 光洋 日本医科大学, 医学部, 准教授 (50236494) ; 上田 敦久 横浜市立大学, 医学研究科, 客員研究員 (60295483)
• 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膠原病学

Outline of Final Research Achievements

The up-regulation of type I interferon (IFN)-inducible genes, which is called “IFN signature”, is observed in several rheumatic diseases, such as systemic lupus erythematosus (SLE). In this study, we investigated the role of TRIM family proteins in the “IFN signature” using peripheral blood mononuclear cells (PBMC) from patients with the rheumatic diseases. Although the mRNA level of TRIM21 was significantly higher in PBMC from patients with SLE as compared to healthy controls (HC), proteasome-dependent degradation of IRF proteins, which are substrates of TRIM21, was impaired in SLE. The expression level of TRIM27 mRNA was significantly lower in PBMC from patients with SLE as compared to HC. The expression level of TBK1 protein, which is the substrate of TRIM27 and promotes type IFN production, was upregulated in SLE. These results suggest that dysregulation or dysfunction of TRIM family proteins leads to the overproduction of type I IFNs in SLE.

Research Products

• [Journal Article] Musculoskeletal ultrasonography delineates ankle symptoms in rheumatoid arthritis. (2017)
  • Author(s): Toyota Y, Tamura M, Kirino Y, Sugiyama Y, Tsuchida N, Kunishita Y, Kishimoto D, Kamiyama R, Miura Y, Minegishi K, Yoshimi R, Ueda A, Nakajima H.
  • Journal Title: Mod Rheumatol. Volume: 27 Issue: 3 Pages: 425-429
  • DOI: 10.1080/14397595.2016.1222650
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diagnostic test accuracy of ultrasound for synovitis in rheumatoid arthritis: systematic review and meta-analysis. (2017)
  • Author(s): Takase-Minegishi K, Horita N, Kobayashi K, Yoshimi R, Kirino Y, Ohno S, Kaneko T, Nakajima H, Wakefield RJ, Emery P.
  • Journal Title: Rheumatology (Oxford). Volume: 印刷中 Issue: 1 Pages: 49-58
  • DOI: 10.1093/rheumatology/kex036
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 関節エコー入門（前篇）関節超音波検査の基礎知識. (2017)
  • Author(s): 吉見竜介
  • Journal Title: Medicina. Volume: 54 Pages: 583-589
  • Acknowledgement Compliant
• [Journal Article] Continuous evolution of clinical phenotype in 578 Japanese patients with Behcet's disease: a retrospective observational study. (2016)
  • Author(s): Kirino Y, Ideguchi H, Takeno M, Suda A, Higashitani K, Kunishita Y, Takase-Minegishi K, Tamura M, Watanabe T, Asami Y, Uehara T, Yoshimi R, Yamazaki T, Sekiguchi A, Ihata A, Ohno S, Ueda A, Igarashi T, Nagaoka S, Ishigatsubo Y, Nakajima H.
  • Journal Title: Arthritis Res Ther Volume: 2016 Issue: 1 Pages: 217-217
  • DOI: 10.1186/s13075-016-1115-x
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 全身性自己免疫疾患におけるユビキチンリガーゼの役割. (2016)
  • Author(s): 吉見竜介
  • Journal Title: 別冊 BIO Clinica 慢性炎症と疾患. Volume: 5 Pages: 157-163
  • Acknowledgement Compliant
• [Presentation] Functional analysis of macrophages in Behcet’s disease: C-C chemokine receptor type 1 (CCR1) and IL-10 are implicated in pathogenesis of the disease. (2016)
  • Author(s): Hiroto Nakano, Yohei Kirino, Momoko Ohno, Kana Higashitani, Mitsuhiro Takeno, Ryusuke Yoshimi, Hideaki Nakajima
  • Organizer: American College of Rheumatology 80th Annual Meeting
  • Place of Presentation: ワシントンD.C.（アメリカ合衆国）
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] The role of tripartite motif-containing 21 in interferon signature of systemic lupus erythematosus. (2016)
  • Author(s): Reikou Kamiyama, Ryusuke Yoshimi, Yumiko Sugiyama, Yosuke Kunishita, Daiga Kishimoto, Toshinori Tsukahara,Yukiko Asami, Yohei Kirino, Mitsuhiro Takeno, Atsuhisa Ueda, Keiko Ozato, Hideaki Nakajima
  • Organizer: American College of Rheumatology 80th Annual Meeting
  • Place of Presentation: ワシントンD.C.（アメリカ合衆国）
  • Year and Date: 2016-11-14
• [Presentation] The 8-Joint ultrasound score is a useful marker for monitoring therapeutic response in rheumatoid arthritis. (2016)
  • Author(s): Ryusuke Yoshimi, Yukihiro Toyota, Naomi Tsuchida, Yumiko Sugiyama, Yosuke Kunishita, Daiga Kishimoto, Reikou Kamiyama, Kaoru Minegishi, Maasa Tamura, Yukiko Asami, Yohei Kirino, Shigeru Ohno, Hideaki Nakajima
  • Organizer: American College of Rheumatology 80th Annual Meeting
  • Place of Presentation: ワシントンD.C.（アメリカ合衆国）
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] 関節リウマチにおける最重症関節部位に関する患者評価と関節超音波検査の乖離． (2016)
  • Author(s): 吉見竜介, 豊田行健, 土田奈緒美, 杉山裕美子, 國下洋輔, 岸本大河, 神山玲光, 峯岸薫, 浜真麻, 桐野洋平, 岳野光洋, 大野滋, 石ヶ坪良明, 上田敦久
  • Organizer: 第65回日本アレルギー学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-06-18
• [Presentation] 強皮症における抗SS-A抗体やリウマチ因子の臨床的意義． (2016)
  • Author(s): 神山玲光, 吉見竜介, 土田奈緒美, 杉山裕美子, 峯岸薫, 田村真麻, 桐野洋平, 上原武晃, 浅見由希子, 関口章子, 出口治子, 井畑淳, 大野滋, 川井孝子, 五十嵐俊久, 長岡章平, 石ヶ坪良明, 上田敦久
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-22
• [Presentation] The discrepancy between patient’s evaluation and ultrasonography assessment on the most affected joint in rheumatoid arthritis. (2016)
  • Author(s): Ryusuke Yoshimi, Yukihiro Toyota, Naomi Tsuchida, Yumiko Sugiyama, Yosuke Kunishita, Daiga Kishimoto, Reikou Kamiyama, Kaoru Minegishi, Maasa Hama, Yohei Kirino, Mitsuhiro Takeno, Yoshiaki Ishigatsubo, Shigeru Ohno, Atsuhisa Ueda
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-21
• [Presentation] Association between macrophages and proteinuria in lupus nephritis. (2016)
  • Author(s): Daiga Kishimoto, Yohei Kirino, Maasa Tamura, Yukihiro Toyota, Ryusuke Yoshimi, Atsuhisa Ueda
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-21
• [Presentation] Functional analysis of macrophages in Behcet’s disease. (2016)
  • Author(s): Hiroto Nakano, Yohei Kirino, Kana Higashitani, Mitsuhiro Takeno, Ryusuke Yoshimi, Yoshiaki Ishigatsubo, Atsuhisa Ueda
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-04-21
• [Presentation] 免疫抑制療法中に汎発性帯状疱疹および侵襲性肺アスペルギルス症を発症して死亡した関節リウマチの一例． (2016)
  • Author(s): 吉見竜介, 杉山裕美子, 國下洋輔, 仲野寛人, 比嘉令子, 寒川整, 石ヶ坪良明, 上田敦久
  • Organizer: 第90回日本感染症学会総会・学術講演会
  • Place of Presentation: 仙台国際センター・新展示施設（宮城県仙台市）
  • Year and Date: 2016-04-15
• [Presentation] SLE病態ではIRFファミリーのユビキチン化が減少している． (2015)
  • Author(s): 神山玲光, 吉見竜介, 岸本大河, 岳野光洋, 上田敦久, 尾里啓子, 石ヶ坪良明.
  • 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 – 2015-04-25
• [Presentation] SLE病態ではIRFファミリーのユビキチン化が減少している． (2015)
  • Author(s): 神山玲光, 吉見竜介, 岸本大河, 岳野光洋, 上田敦久, 尾里啓子, 石ヶ坪良明
  • 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（愛知県名古屋市）
  • Year and Date: 2015-04-23
• [Presentation] The dysfunction of the E3 ubiquitin ligase TRIM21 in systemic lupus erythematosus. (2014)
  • Author(s): Reikou Kamiyama, Ryusuke Yoshimi, Toshinori Tsukahara, Atsuhisa Ueda, Mitsuhiro Takeno, Keiko Ozato, Yoshiaki Ishigatsubo.
  • Organizer: The American Association of Immunologists 101st Annual Meeting
  • Place of Presentation: Lawrence Convention Center（Pittsburgh, Pennsylvania, USA）
  • Year and Date: 2014-05-02 – 2014-05-06
• [Presentation] 全身性エリテマトーデスにおけるTRIM21の役割． (2014)
  • Author(s): 神山玲光, 吉見竜介, 國下洋輔, 岸本大河, 峯岸薫, 浜真麻, 桐野洋平, 浅見由希子, 上田敦久, 上田敦久, 岳野光洋, 石ヶ坪良明.
  • Organizer: 第58回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 強皮症において抗SS-A抗体は指尖潰瘍の発現と関連する． (2014)
  • Author(s): 吉見竜介, 渡邉俊幸, 小林幸司, 神山玲光, 峯岸薫, 浜真麻, 桐野洋平, 浅見由希子, 山崎哲, 関口章子, 須田昭子, 出口治子, 井畑淳, 上田敦久, 大野滋, 岳野光洋, 川井孝子, 五十嵐俊久, 長岡章平, 石ヶ坪良明.
  • Organizer: 第58回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
  • Year and Date: 2014-04-24 – 2014-04-26