Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis.
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| Abstract |
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.
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| Authors | Maho Yamashita, Akira Honda, Shin Shimoyama, Masahiro Umemura, Kazuyoshi Ohta, Takeshi Chida, Hidenao Noritake, Nobuhito Kurono, Mayuko Ichimura-Shimizu, Koichi Tsuneyama, Teruo Miyazaki, Atsushi Tanaka, Patrick S C Leung, M Eric Gershwin, Takafumi Suda, Kazuhito Kawata |
| Journal | Journal of autoimmunity (J Autoimmun) Vol. 136 Pg. 103027 (04 2023) ISSN: 1095-9157 [Electronic] England |
| PMID | 36996700 (Publication Type: Journal Article) |
| Copyright | Copyright © 2023 Elsevier Ltd. All rights reserved. |
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