2022 Fiscal Year Final Research Report
Direct Autoantibody-mediated BBB rupture in SLE
| Project/Area Number |
19K08918
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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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| Review Section |
Basic Section 54020:Connective tissue disease and allergy-related
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| Research Institution | Kitasato University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | 全身性エリテマトーデス / 血液脳関門 / 自己抗体 / NPSLE / タイトジャンクション |
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| Outline of Final Research Achievements |
We revealed that stimulation of vascular endothelial cell lines in vitro with anti-Sm antibodies, which are autoantibodies specific to systemic lupus erythematosus (SLE), leads to a decrease in claudin-5, a tight junction-consisting protein. Measurement of active MMP-2 in the culture supernatant of stimulated vascular endothelial cell lines with anti-Sm antibodies using zymography showed that the conversion to the active form of MMP-2 was promoted. Under the presence of a specific MMP-2 inhibitor, the decrease in claudin-5 was restored. Additionally, captopril, which has a pleiotropic effect inhibiting microglia and MMP-2, also restored the degradation of claudin-5. These findings suggest potential effects of autoantibodies on central nervous system disorders.
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| Free Research Field |
膠原病学
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| Academic Significance and Societal Importance of the Research Achievements |
SLE特異的自己抗体が直接的に血管内皮細胞に作用し、血液脳関門を破綻させる可能性を明らかとしたことは、SLE患者において中枢神経病変でも自己抗体を中心とした特異的免疫異常を是正することが治療の1つとなり得ることを明示している。さらにカプトプリルのようなマイクログリア抑制や血液脳関門の破綻の阻止に関わる複数の役割を持つ薬剤がSLEにおける中枢神経病変の免疫抑制療法に加え重要なメカニズムに基づく治療薬の1つになり得る可能性を示唆している。メカニズムに基づく分子としての治療ターゲットの1つが明らかとなったことは今後の病態解明、治療法の確立において非常に意義深いと考える。
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