Elucidation of the activation mechanism of the complement factor MASP-3 of the alternative complement pathway

• Project/Area Number: 19K07610
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Sekine Hideharu 福島県立医科大学, 医学部, 教授 (40363759)
• Co-Investigator(Kenkyū-buntansha): 町田 豪 福島県立医科大学, 医学部, 講師 (80583632) ; 林 学 福島県立医科大学, 医学部, 助教 (80745787)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 補体因子 / MASP-3 / 第二経路 / レクチン経路 / 認識分子 / 補体レクチン経路 / レクチン経路の糖鎖認識分子 / 補体活性化 / セリンプロテアーゼ / 補体

Outline of Research at the Start

近年国内外の研究で、SLEや加齢黄斑変性、C3腎症、典型および非典型溶血性尿毒症症候群(HUS,aHUS)、虚血再灌流障害などの臓器障害において、補体・第二経路の活性化が炎症の増幅に中心的に作用することが明らかにされつつある。本研究では、第二経路のカスケード反応の最上流で作用する補体因子MASP-3の活性化機構をMASP-3の活性化に関与することが予想されるリコンビナント蛋白や、その蛋白のノックアウトマウスを用いて解明する。その成果は、MASP-3の活性化を制御する手段の開発につながり、最終的に多くの炎症性疾患に対する治療法の開発につながることが期待できる。

Outline of Final Research Achievements

MASP-3 circulates in an active form and forms a complex with recognition molecules of the lectin complex pathway (LP PRMs) in vivo, but its immunological significance is unknown. In this study, four types of mutant recombinant mice MASP-3 (rmMASP-3), which lack the ability to form a complex with LP PRMs, and wild-type rmMASP-3 were administered to mice, and their activation kinetics in vivo were investigated.
As a result, it was found that both of them rapidly changed to the activated forms in the circulation. However, the mutant rmMASP-3 was cleared from the circulation earlier than the wild type rmMASP-3. From these results, it was shown that the complex formation of MASP-3 with LP PRMs is required for the maintenance of MASP-3 in vivo.

Academic Significance and Societal Importance of the Research Achievements

本研究は、第二経路の補体因子であるMASP-3が、なぜレクチン経路の認識分子と複合体を形成するのか、その意義を世界で初めて見出したものであり、補体系のメカニズムの全容解明に大きく貢献する成果である。
補体第二経路は、さまざまな炎症性疾患における増悪因子として知られており、今後MASP-3を標的とする治療戦略を開発する上で、重要な知見をもたらした成果と考えられる。

Research Products

• [Int'l Joint Research] Polish Academy of Sciences(ポーランド)
• [Journal Article] Polymorphisms of the FCN2 Gene 3'UTR Region and Their Clinical Associations in Preterm Newborns (2021)
  • Author(s): Anna S Swierzko, Dariusz Jarych, Gabriela Gajek, Karolina Chojnacka, Paulina Kobiela, Maja Kufelnicka-Babout, Mateusz Michalski, Katarzyna Sobczuk, Agnieszka Szala-Pozdziej, Misao Matsushita, Jan Mazela, Iwona Domzalska-Popadiuk, David C Kilpatrick, Jaroslaw Kalinka, Hideharu Sekine, Maciej Cedzynski
  • Journal Title: Front Immunol Volume: 12
  • DOI: 10.3389/fimmu.2021.741140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Changes in complement activation products after anti-VEGF injection for choroidal neovascularization in age-related macular degeneration and pachychoroid disease (2021)
  • Author(s): Tanaka Keiichiro、Oguchi Yasuharu、Omori Tomoko、Ishida Yumi、Shintake Hiroaki、Tomita Ryutaro、Kasai Akihito、Ogasawara Masashi、Sugano Yukinori、Itagaki Kanako、Ojima Akira、Machida Takeshi、Sekine Hideharu、Sekiryu Tetsuju
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 8464-8464
  • DOI: 10.1038/s41598-021-87340-6
  • Peer Reviewed / Open Access
• [Journal Article] A novel complement inhibitor sMAP-FH targeting both the lectin and alternative complement pathways (2020)
  • Author(s): Takasumi M, Omori T, Machida T, Ishida Y, Hayashi M, Suzuki T, Homma Y, Endo Y, Takahashi M, Ohira H, Fujita T, Sekine H
  • Journal Title: FASEB J Volume: 34 Issue: 5 Pages: 6598-6612
  • DOI: 10.1096/fj.201902475r
  • Peer Reviewed
• [Journal Article] Anaphylatoxin Concentration in Aqueous and Vitreous Humor in the Eyes With Vitreoretinal Interface Abnormalities (2020)
  • Author(s): Yasuharu Oguchi , Tetsuju Sekiryu , Tomoko Omori , Yutaka Kato , Masashi Ogasawara , Yukinori Sugano , Kanako Itagaki , Akira Ojima , Takeshi Machida , Hideharu Sekine
  • Journal Title: Exp Eye Res Volume: 195 Pages: 108025-108025
  • DOI: 10.1016/j.exer.2020.108025
  • Peer Reviewed
• [Journal Article] Association between serum ficolin-1 level and disease progression in primary biliary cholangitis (2020)
  • Author(s): Hayashi Manabu、Abe Kazumichi、Fujita Masashi、Takahashi Atsushi、Sekine Hideharu、Ohira Hiromasa
  • Journal Title: PLOS ONE Volume: 15 Issue: 9 Pages: e0238300-e0238300
  • DOI: 10.1371/journal.pone.0238300
  • Peer Reviewed / Open Access
• [Journal Article] Complement Activation Products and Cytokines in Pachychoroid Neovasculopathy and Neovascular Age-Related Macular Degeneration (2020)
  • Author(s): Kato Yutaka、Oguchi Yasuharu、Omori Tomoko、Shintake Hiroaki、Tomita Ryutaro、Kasai Akihito、Ogasawara Masashi、Sugano Yukinori、Itagaki Kanako、Ojima Akira、Machida Takeshi、Sekine Hideharu、Sekiryu Tetsuju
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 61 Issue: 13 Pages: 39-39
  • DOI: 10.1167/iovs.61.13.39
  • Peer Reviewed / Open Access
• [Journal Article] 感染症と補体・凝固線溶系 (2020)
  • Author(s): 関根英治
  • Journal Title: Thrombosis Medicine Volume: 10 Pages: 274-280
• [Journal Article] Cutting Edge: Role of MASP-3 in the physiological activation of factor D of the alternative complement pathway (2019)
  • Author(s): Manabu Hayashi, Takeshi Machida, Yumi Ishida, Yusuke Ogata, Tomoko Omori, Mika Takasumi, Yuichi Endo, Toshiyuki Suzuki, Masayuki Sekimata, Yoshimi Homma, Masahito Ikawa, Hiromasa Ohira, Teizo Fujita, and Hideharu Sekine
  • Journal Title: The Journal of Immunology Volume: 203 Issue: 6 Pages: 1411-1416
  • DOI: 10.4049/jimmunol.1900605
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Response to comment on “Cutting Edge: Role of MASP-3 in the physiological activation of factor D of the alternative complement pathway” (2019)
  • Author(s): Takeshi Machida, Manabu Hayashi, Teizo Fujita, and Hideharu Sekine
  • Journal Title: The Journal of Immunology Volume: 203 Issue: 12 Pages: 3091-3092
  • DOI: 10.4049/jimmunol.1901087
  • Peer Reviewed
• [Journal Article] Complement activation by autoantigen recognition in the growth process of benign prostatic hyperplasia (2019)
  • Author(s): Hata Junya、Machida Takeshi、Matsuoka Kanako、Hoshi Seiji、Akaihata Hidenori、Hiraki Hiroyuki、Suzuki Toshiyuki、Ogawa Soichiro、Kataoka Masao、Haga Nobuhiro、Ishibashi Kei、Homma Yoshimi、Sekine Hideharu、Kojima Yoshiyuki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 00-00
  • DOI: 10.1038/s41598-019-57001-w
  • Peer Reviewed / Open Access
• [Presentation] MASP-3の活性化におけるレクチン経路の認識分子の役割 (2021)
  • Author(s): 草刈 浩平、石田 由美、大森 智子、鈴木 俊幸、関亦 正幸、町田 豪、関根 英治
  • Organizer: 日本補体学会
• [Presentation] The significance of complex formation of MASP-3 with pattern recognition molecules of the lectin complement pathway in the long-term retention of MASP-3 in the circulation (2021)
  • Author(s): Takeshi Machida, Kohei Kusakari, Yumi Ishida, Tomoko Omori, Toshiyuki Suzuki, Masayuki Sekimata, Teizo Fujita, and Hideharu Sekine
  • Organizer: 28th International Complement Virtual Workshop
  • Int'l Joint Research
• [Presentation] A FUSION PROTEIN OF SMAP AND FACTOR H INHIBITS BOTH THE LECTIN AND ALTERNATIVE COMPLEMENT PATHWAYS IN VIVO (2019)
  • Author(s): Hideharu Sekine, Mika Takasumi, Tomoko Omori, Takeshi Machida, Yumi Ishida, and Teizo Fujita
  • Organizer: The 17th European Meeting on Complement in Human Disease (EMCHD 2019)
  • Int'l Joint Research