Elucidation for the mechanism of kidney injury and the biomarker related with complement activation in infection associated kidney diseases

2021 Fiscal Year Final Research Report

• Project/Area Number: 17K08992
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Tokyo Medical University
• Principal Investigator: Oda Takashi 東京医科大学, 医学部, 教授 (90531187)
• Co-Investigator(Kenkyū-buntansha): 山田 宗治 東京医科大学, 医学部, 准教授 (10625164) ; 小野 聡 東京医科大学, 医学部, 兼任教授 (30531355) ; 熊谷 裕生 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 教授 (50170048) ; 大澤 勲 順天堂大学, 医学部, 非常勤講師 (60407252) ; 村越 貴子 (浅野貴子) 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 病院 小児科, 助教 (70573666)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Keywords: 補体 / 古典経路 / 副経路 / レクチン経路 / 免疫複合体 / ANCA関連腎炎 / 抗体親和性

Outline of Final Research Achievements

Serum and renal biopsy tissues of ANCA associated glomerulonephritis (AAGN) were evaluated. CICs assessed by the monoclonal rheumatoid factor assay were positive in 65% of AAGN patients. Affinities of ANCAs were evaluated by a competitive inhibition method with ELISA, and All CIC-positive patients revealed to belong to the high-affinity group. Serum C5a and C5b-9, assessed by ELISA, were significantly increased in AAGN patients, and these levels significantly correlated with CIC levels. Immunofluorescence staining on renal tissue sections for complement components, such as C3,C5,C4d,C5b-9,factorBb, mannan-binding lectin serine peptidase (MASP)-1,-2, and mannan-binding lectin (MBL), revealed glomerular deposition of C4d,C5, and C5b-9 in similar distributions in AAGN patients, whereas the deposition of MASP-1,-2, MBL, and factor Bb were minimal. These results suggest the involvement of immune-complex induced complement activation through the classical pathway in the pathogenesis of AAGN.

Free Research Field

腎臓内科

Academic Significance and Societal Importance of the Research Achievements

AAGN患者の腎生検組織と血清を用いた検討で、AAGN患者では免疫複合体が形成され、これが古典経路を介した補体の活性化を惹起し腎障害の発症・進展に関与していることを明らかにした。エクリズマブ(C5)以外にもペグセタコパン(C3), アバコパン (C5aR), イプタコパン(factor B), ダニコパン(factor D)など、各種の補体標的制御薬が次々と開発され、実用化されつつある現状を考えると、本研究のような補体と関連した腎障害機序の解明はすなわち新しい治療法の確立に直結する可能性があり、その意義は重大と考える。