WEKO3
アイテム
Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis
http://hdl.handle.net/10271/0002000516
http://hdl.handle.net/10271/0002000516c90bac27-0b2c-4691-8105-7ecaff6d921a
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
論文本文 (10.9 MB)
|
|
| Item type | 共通アイテムタイプ / Common item types(1) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 公開日 | 2025-09-09 | |||||||||||
| タイトル | ||||||||||||
| タイトル | Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis | |||||||||||
| 言語 | ||||||||||||
| 言語 | eng | |||||||||||
| キーワード | ||||||||||||
| 主題 | Primary biliary cholangitis | |||||||||||
| キーワード | ||||||||||||
| 主題 | Mouse model | |||||||||||
| キーワード | ||||||||||||
| 主題 | Bile acids | |||||||||||
| キーワード | ||||||||||||
| 主題 | Fibrosis | |||||||||||
| キーワード | ||||||||||||
| 主題 | Chenodeoxycholic acid | |||||||||||
| その他のタイトル | ||||||||||||
| その他のタイトル | 免疫寛容破綻と胆汁酸負荷：原発性胆汁性胆管炎の免疫病態と自然経過における難問を解決する | |||||||||||
| 資源タイプ | ||||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||||||
| 資源タイプ | doctoral thesis | |||||||||||
| アクセス権 | ||||||||||||
| アクセス権 | open access | |||||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||||||
| 著者 |
山下, 真帆
× 山下, 真帆
|
|||||||||||
| 書誌情報 |
en : Journal of Autoimmunity 巻 136, p. 103027, 発行日 2023-03-28 |
|||||||||||
| 出版者 | ||||||||||||
| 出版者 | Elsevier | |||||||||||
| 権利 | ||||||||||||
| 権利情報 | Copyright 2023 Elsevier Ltd. | |||||||||||
| 抄録 | ||||||||||||
| 内容記述タイプ | Abstract | |||||||||||
| 内容記述 | Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC. | |||||||||||
| 学位名 | ||||||||||||
| 学位名 | 博士（医学） | |||||||||||
| 学位の区分 | ||||||||||||
| 内容記述 | doctoral | |||||||||||
| 学位の分野 | ||||||||||||
| 内容記述 | 医学系研究科 | |||||||||||
| 学位授与機関 | ||||||||||||
| 学位授与機関名 | 浜松医科大学 | |||||||||||
| 学位授与機関名 | Hamamatsu University School of Medicine | |||||||||||
| 学位授与年月日 | ||||||||||||
| 学位授与年月日 | 2024-09-20 | |||||||||||
| 学位授与番号 | ||||||||||||
| 学位授与番号 | 甲第995号 | |||||||||||
| PISSN | ||||||||||||
| 収録物識別子 | 0896-8411 | |||||||||||
| EISSN | ||||||||||||
| 収録物識別子 | 1095-9157 | |||||||||||
| NII書誌ID (NCID) | ||||||||||||
| 収録物識別子 | AA10717368 | |||||||||||
| PubMed番号 (PMID) | ||||||||||||
| 関連識別子 | 36996700 | |||||||||||
| 出版社DOI | ||||||||||||
| 関連識別子 | https://doi.org/10.1016/j.jaut.2023.103027 | |||||||||||
| 要旨⇔論文へのリンク | ||||||||||||
| 関連識別子 | http://hdl.handle.net/10271/0002000248 | |||||||||||
| 関連名称 | 学位論文要旨 | |||||||||||
| 出版タイプ | ||||||||||||
| 出版タイプ | VoR | |||||||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||||
