Do anti-DNA antibodies play a role in the pathogenesis of systemic lupus erythematosus by binding/entering live cells?
| Project/Area Number |
16K08929
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Kubota Tetsuo 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (90205138)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 抗DNA抗体 / 全身性エリテマトーデス / エンドサイトーシス / 抗リン脂質抗体症候群 / 抗リン脂質抗体 / Toll-like receptors / 自己抗体 / 膠原病 / 抗エノラーゼ1抗体 / 肺高血圧症 |
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| Outline of Final Research Achievements |
This study aimed to clarify the pathogenic role of anti-DNA antibodies which are produced specifically in systemic lupus erythematosus (SLE). A monoclonal antibody WB-6 was demonstrated to cross-react with beta-2-glycoprotein I and DNA. We found it binds to cell surface DNA, and enters live monocytes accompanying DNA, which results in activation of intracellular DNA sensors to induce expression of tissue factor. These results suggest a novel mechanism in pathogenesis of antiphospholipid syndrome accompanied by SLE. On the other hand, another monoclonal anti-DNA antibody 2C10, which is specific to double-stranded DNA and does not cross-react with beta-2-glycoprotein I, also entered live monocytes by endocytosis. As a result, it induced secretion of several proinflammatory cytokines which is known to be elevated in SLE via activation of the TLR9 and AIM2 signaling pathways. These results established a simple and useful assay system to reproduce a pathological state resembling SLE.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は，抗DNA抗体の病態形成上の役割を明らかにすることを目的として実施された。リン脂質と交差反応するモノクローナル抗体WB-6は，細胞表面のDNAに結合して単球の細胞内に取り込まれ，細胞内のDNAセンサーを刺激して組織因子の発現を誘導した。一方，リン脂質と交差反応しない抗体2C10は，やはり単球などの細胞内に取り込まれたが，その結果，全身性エリテマトーデスにおける産生亢進が知られている炎症性サイトカインの産生が誘導された。抗DNA抗体と言っても，その詳細な特異性の違いによって，誘導される病態も大きく異なることが観察され，今後の病態形成機構の研究に有用な知見を提供することができた。
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Report
(5 results)
Research Products
(21 results)
