Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis. Issue 136 (April 2023)

• Record Type: Journal Article
• Authors: Yamashita, Maho; Honda, Akira; Shimoyama, Shin; Umemura, Masahiro; Ohta, Kazuyoshi; Chida, Takeshi; Noritake, Hidenao; Kurono, Nobuhito; Ichimura-Shimizu, Mayuko; Tsuneyama, Koichi; Miyazaki, Teruo; Tanaka, Atsushi; Leung, Patrick S.C.; Gershwin, M. Eric; Suda, Takafumi; Kawata, Kazuhito
• Is Part Of: Journal of autoimmunity. Issue 136(2023)
• Publication Date: 2023-04
• Subjects: Primary biliary cholangitis -- Mouse model -- Bile acids -- Fibrosis -- Chenodeoxycholic acid; AE anion exchanger -- ALP alkaline phosphatase -- ALT alanine transaminase -- AST aspartate transaminase -- AMA antimitochondrial antibody -- Asbt apical sodium-dependent bile acid transporter -- BA bile acid -- Bsep bile salt export pump -- CA cholic acid -- CCL2 C–C motif ligand 2 -- CDCA chenodeoxycholic acid -- Col1a1 collagen type I α1 Chain -- CX3CL1 C-X3-C motif chemokine ligand 1 -- CX3CR1 C-X3-C motif chemokine receptor 1 -- DCA deoxycholic ccid -- DKO Cyp2a12/Cyp2c70 double knock out -- ELISA enzyme-linked immunosorbent assay -- FGF15 fibroblast growth factor15 -- Fxr farnesoid X receptor -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- HSC hepatic stellate cells -- IFNγ interferon gamma -- LCA lithocholic acid -- Lxra liver X receptor α -- MCA muricholic acid -- Mdr multidrug resistance protein -- Mmp-2 matrix metallopeptidase 2 -- MNC mononuclear cell -- Mrp multidrug resistance-associated protein -- Ntcp sodium-taurocholate cotransporting polypeptide -- PBC primary biliary cholangitis -- Ppara proliferator-activated receptor α -- Pxr pregnane X receptor -- Shp small heterodimer partner -- Sult sulfotransferase family -- TCA taurocholic acid -- TCDCA taurochenodeoxycholic acid -- TDCA taurodeoxycholic acid -- TGFβ1 transforming growth factor β1 -- TLCA taurolithocholic acid -- TLR Toll-like receptor -- TMCA tauromuricholic acid -- TNFα tumor necrosis factor α -- TUDCA tauroursodeoxycholic acid -- UDCA ursodeoxycholic acid -- WT C57BL/6J -- 2OA 2-octynoic acid -- αSMA α-smooth muscle actin; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2023.103027
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: Human-like hydrophobic BA composition exacerbated autoimmune cholangitis and accelerated liver fibrosis in 2OA-treated mice. The long-term action of hydrophobic BA advanced these stages of hepatic inflammation and fibrosis. Both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC. Our novel murine PBC model is valuable for elucidating the pathogenesis of PBC.