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We focused attention on the P/Q-type VGCC,against which a majority of LEMS patients carry the specific antibody. This type of VGCC expresses in the motor nerve terminal and also in SCLC.In search of antigenic sites in the P/Q-type VGCC molecular structure, we synthesized peptides corresponding to the extracellular region (S5-S6 linker) of each of the four domains that form the alpha1A subunit of VGCC and tested their antigenicity. In LEMS patients\u0027 sera, some were positive for anti-domain II,and the other were positive for anti-domain IV.Lewis rats immunized with domain II and III peptides, each being conjugated with KLH,showed such characteristic LEMS features as presence of antibodies to P/Q-type VGCC and reduced ACh quantal release. In addition, the possible role of synaptotagmin, a Ca^\u003c++\u003e sensor for exocytosis of synaptic vesicles taking place prior to ACh release, in the pathogenesis of LEMS was studied. 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神経筋接合部疾患におけるイオンチャネルとレセプターの分子病態に関する免疫学的研究
https://doi.org/10.24517/00066224
https://doi.org/10.24517/0006622411e69b47-74bf-466d-a6fd-cac298df40ff
名前 / ファイル | ライセンス | アクション |
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ME-PR-TAKAMORI-M-kaken 1999-7p.pdf (311.4 kB)
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Item type | 報告書 / Research Paper(1) | |||||
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公開日 | 2022-06-03 | |||||
タイトル | ||||||
タイトル | 神経筋接合部疾患におけるイオンチャネルとレセプターの分子病態に関する免疫学的研究 | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | Immunological study in molecular pathophysiology of ion channel | |||||
言語 | ||||||
言語 | jpn | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_18ws | |||||
資源タイプ | research report | |||||
ID登録 | ||||||
ID登録 | 10.24517/00066224 | |||||
ID登録タイプ | JaLC | |||||
著者別表示 |
Takamori, Masaharu
× Takamori, Masaharu |
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提供者所属 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 金沢大学医学部 | |||||
書誌情報 |
平成9(1997)年度 科学研究費補助金 基盤研究(B) 研究成果報告書概要 en : 1997 Fiscal Year Final Research Report Summary 巻 1995 – 1997, p. 7p., 発行日 1999-03-15 |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | (1)Lambert-Eaton筋無力症候群 肺癌との合併頻度の高い本病は,骨格筋支配の末梢神経終末局在の電位依存性カルシウムチャネル(VGCC)を標的とする抗体が主役を演じ,チャネル機能障害の結果,神経終末からのアセチルコリン量子性遊離量が低下し発症する。分子免疫学的研究の結果,以下のことを明らかにした。(1)本病抗体の主たる抗原決定基はVGCCのP/Q型である。(2)P/Q型VGCC分子構造の中での抗体反応領域は,α1サブユニットのドメインIIとIVのS5-S6リンカー領域であった。(3)ドメインIIとIIIS5-S6リンカー領域合成ペプチドを抗原として,動物に疾患モデルを誘導することができた。(4)VGCC周辺機構を構成する蛋白質の一つで,カルシウム・センサーとしての役割を担うシナプトタグミンの,シナプス小胞開口中膜外に露呈する領域に照合して合成ペプチドは,これを抗原として動物を免疫すると,疾患モデルを昨出できた。(5)遺伝子操作で大腸菌に発現させたリコンビナント・シナプトタグミンを抗原として患者血清を検定すると,30%の症例で陽性,その50%は抗VGCC抗体陰性であったので,この蛋白質に対する免疫反応だけでも本病の一時的原因となりうる。(6)VGCCもシナプトタグミンも肺癌組織に発現,癌組織と神経系の免疫学的交叉反応が,発病の根底にあると示唆される。 (2)重症筋無力症 神経筋シナプスの後シナプス・アセチルコリン受容体に対する免疫反応が原因である本病で,特に胸腺腫合併例において,筋収縮疲労が本来のシナプス伝達疲労に加重していること,その原因が胸腺上皮細胞に発現するリアノジン受容体を認識し産生される抗体が筋の興奮収縮関連を阻害するにあることを明らかにした。また、自然発症胸腺腫ラット(Baffalo/Mna種)は,この病態の動物モデルであることを,胸腺の免疫組織化学,免疫学および電気生理学的指標で明らかにした。 |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | (1) Lambert-Eaton myasthenic syndrome (LEMS) LEMS,often ssociated with small cell lung carcinoma (SCLC), impairs the quantal release of acetylcholine (ACh) by antibodies against voltage-gated calcium channel (VGCC) in the motor nerve terminal. We focused attention on the P/Q-type VGCC,against which a majority of LEMS patients carry the specific antibody. This type of VGCC expresses in the motor nerve terminal and also in SCLC.In search of antigenic sites in the P/Q-type VGCC molecular structure, we synthesized peptides corresponding to the extracellular region (S5-S6 linker) of each of the four domains that form the alpha1A subunit of VGCC and tested their antigenicity. In LEMS patients' sera, some were positive for anti-domain II,and the other were positive for anti-domain IV.Lewis rats immunized with domain II and III peptides, each being conjugated with KLH,showed such characteristic LEMS features as presence of antibodies to P/Q-type VGCC and reduced ACh quantal release. In addition, the possible role of synaptotagmin, a Ca^<++> sensor for exocytosis of synaptic vesicles taking place prior to ACh release, in the pathogenesis of LEMS was studied. The peptide corresponging to the extracellular region of synaptotagmin was found antigenic for the induction of an animal model of LEMS.A proportion of human LEMS antibodies reacted with the recombinant synaptotagmin in immunoblot. (2) Myasthenia gravis (MG) In MG in which muscle anti-ACh receptor antibodies play a crucial role, we focused attention on an additional impairment of excitation-contraction coupling in muscle, attributable to a defect caused by antibodies against ryanodine receptor (RyR). Many of MG patients with thymomas contained anti-RyR antibodies in serum ; these sera inhibited the calcium-induced release of calcium in response to caffeine in human muscle cell line. The Buffalo/Mna rat with spontaneous benign thymoma was shown as an animal model of impaired subcellular machineries in MG muscle as evidenced by RyR expressed in thymic epithelial cells, anti-RyR antibodies in serum and reduced contractile forces without abnormality in synaptic transmission and muscle membrane properties. |
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内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 研究課題/領域番号:07457154, 研究期間(年度):1995 – 1997 | |||||
内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 出典:研究課題「神経筋接合部疾患におけるイオンチャネルとレセプターの分子病態に関する免疫学的研究」課題番号07457154 (KAKEN:科学研究費助成事業データベース(国立情報学研究所)) (https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-07457154/074571541997kenkyu_seika_hokoku_gaiyo/)を加工して作成 |
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著者版フラグ | ||||||
出版タイプ | AM | |||||
出版タイプResource | http://purl.org/coar/version/c_ab4af688f83e57aa | |||||
関連URI | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://kaken.nii.ac.jp/search/?qm=60039815 | |||||
関連名称 | https://kaken.nii.ac.jp/search/?qm=60039815 | |||||
関連URI | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457154/ | |||||
関連名称 | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457154/ | |||||
関連URI | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-07457154/074571541997kenkyu_seika_hokoku_gaiyo/ | |||||
関連名称 | https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-07457154/074571541997kenkyu_seika_hokoku_gaiyo/ |