2020 Fiscal Year Final Research Report
Discovery of new drug target modifiying the function of blood-brain barrier and blood-nerve barrier
| Project/Area Number |
18K07526
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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) |
2018-04-01 – 2021-03-31
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| Keywords | 自己免疫性神経疾患 / 血液脳関門 / GRP78抗体 / 視神経脊髄炎 / 傍腫瘍性小脳変性症 |
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| Outline of Final Research Achievements |
Objective: The purpose of this project is to develop the assay for identifying the antigen against IgG from the patients with neuro-inflammatory disorders, which cause the BBB disruption using our human in vitro BBB model. Methods: We identified IgG from patients with the neuro-inflammatory disease, which induced NF-κB p65 nuclear translocation in human brain microendothelial cell lines (TY10). We developed the novel assay to detect cell-surface antigen against IgG from the neuro-inflammatory disease. Results: IgGs from paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS) [LEMS-PCD] shows the most ability to give rise to nuclear translocation of NF-κB p65. We detected glucose-regulated protein (GRP)78 autoantibodies in the IgG of LEMS-PCD. Conclusions: We identified GRP78 autoantibodies from LEMS-PCD patients having biological effects on BBB-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 |
傍腫瘍性小脳変性症を合併したランバート・イートン筋無力症の発症機序が明らかとなった．GRP78は癌細胞とBBB構成内皮細胞の細胞表面に多く発現しており，細胞表面に発現するGRP78はNF-κBシグナル活性に関与する．さらに，担癌患者では血中にGRP78抗体が検出されることが報告されている．傍腫瘍性小脳変性症を合併したランバート・イートン筋無力症発症の病態機序として，GRP78とP/Q型VGCCは癌細胞表面に発現しており，腫瘍との交差免疫により産生されたGRP78抗体によるBBB破綻が，同じ機序より産生されたP/Q型VGCC抗体の脳内流入を促進し小脳機能障害を惹起する可能性が考えられた．
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