Academic Journal
Primary biliary cholangitis: pathogenic mechanisms
| العنوان: | Primary biliary cholangitis: pathogenic mechanisms |
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| المؤلفون: | Prieto, Jesús, Bañales Asurmendi, Jesús María, Medina, Juan F. |
| سنة النشر: | 2021 |
| المجموعة: | ADDI: Repositorio Institucional de la Universidad del País Vasco / Euskal Herriko Unibertsitatea (UPV/EHU - Basque Country University) |
| مصطلحات موضوعية: | Ae2 KO mice, antimitochondrial antibodies, biliary bicarbonate umbrella, epigenetic mechanisms, female predominance, miR-506, mitophagy, Na+-independent Cl-/HCO3- anion exchanger 2, pHi disturbance, promoter hypermethylation, soluble adenylyl cyclase |
| الوصف: | Purpose of review Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease. Recent findings PBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses. Summary PBC can be considered as a disorder of Cl-/HCO3- ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0267-1379 1531-7056 |
| Relation: | https://journals.lww.com/co-gastroenterology/Fulltext/2021/03000/Primary_biliary_cholangitis__pathogenic_mechanisms.5.aspx; Current Opinion in Gastroenterology 37(2) : 91-98 (2021); http://hdl.handle.net/10810/50539 |
| DOI: | 10.1097/MOG.0000000000000703 |
| الاتاحة: | http://hdl.handle.net/10810/50539 https://doi.org/10.1097/MOG.0000000000000703 |
| Rights: | info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by-nc-nd/3.0/es/ ; This is an open access article distributed under the terms of the CreativeCommons Attribution-Non Commercial-No Derivatives License 4.0(CCBY-NC-ND), where it is permissible to download and share the workprovided it is properly cited. The work cannot be changed in any way orused commercially without permission from the journal. ; Atribución-NoComercial-SinDerivadas 3.0 España |
| رقم الانضمام: | edsbas.AC9040BA |
| قاعدة البيانات: | BASE |
| تدمد: | 02671379 15317056 |
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| DOI: | 10.1097/MOG.0000000000000703 |