2023 Fiscal Year Final Research Report
Mechanism of breakdown of blood-brain barrier/blood-nerve barrier in neuroimmunological disorder
| Project/Area Number |
21K07416
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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 52020:Neurology-related
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| Research Institution | Yamaguchi University |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | 神経免疫 / 血液脳関門 / 血液神経関門 |
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| Outline of Final Research Achievements |
Our established human derived blood-brain barrier (BBB) and blood-nerve barrier (BNB)- endothelial cells and sera and IgG from patients with autoimmune neurological disease were used for analysis. We identified GRP78 autoantibodies from MOGAD patients, which induce increased permeability, upregulated adhesion molecules and increased oxidative stress. We also demonstrated that sera from individuals with anti-MAG neuropathy increased transcellular IgM/anti-MAG antibody permeability via autocrine TNF-α secretion and NF-κB signaling in the BNB. Sural nerve biopsy specimens from patients with anti-MAG neuropathy showed higher TNF-α expression levels in BNB endothelial cells and preservation of the structural integrity of the tight junctions and the presence of more vesicles in BNB endothelial cells.
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| Free Research Field |
臨床神経学
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| Academic Significance and Societal Importance of the Research Achievements |
我々はこれまでに視神経脊髄炎関連疾患の血液脳関門破綻をきたす自己抗体GRP78抗体を同定し，その臨床的意義を明らかとしたが，本研究ではMOG抗体関連疾患での血液脳関門破綻をきたす新規自己抗体としてGRP78抗体の役割が明確となった．今後，GRP78モノクローナル抗体を作製し，BBBを操作する薬剤候補となりうるかを検討していきたい．MAG抗体はIgM抗体であるが，高分子の抗体がTNF-αにより誘導され小胞を介してBNBを貫通すること明らかとしたことは，高分子を貫通させる新たなドラッグデリバリーという観点から意義が高い．小胞介在性機序を利用した血液神経関門通過の詳細な分子機序を解明していきたい．
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