Dendritic Cell-Depleted Mice Develop the Autoimmune Biliary Disease That Serologically and Pathogenically Models Human Primary Biliary Cholangitis

Aim: Primary biliary cholangitis (PBC) is an autoimmune liver disease marked by progressive bile duct damage, leading to bile retention. Dendritic cells (DCs), as antigen-presenting cells, are crucial for immune regulation, and their dysfunction is linked to autoimmunity. This study demonstrates that DC-depleted mice manifest an autoimmune biliary disease resembling human PBC and investigates its mechanism.

Methods: DC-depleted mice were generated by crossbreeding CD11c-Cre and Rosa26-DTA (ID) mice. Hepatobiliary changes were assessed using hematoxylin and eosin staining, serum biochemistry, flow cytometry, and immunohistochemistry. Liver gene expression was analyzed using quantitative polymerase chain reaction (qPCR) and RNA Sequencing. Antimitochondrial antibody (AMA) and IFN-γ secretion were measured through enzyme-linked immunosorbent assay. Wild-type mice were intraperitoneally injected with serum from control mice (IP-Ctrl) or ID mice (IP-ID); in some experiments, anti-PDCE-2-depleted ID serum (IP-ΔPDCE2) was used.

Results: ID mice showed significant portal inflammation, with neutrophils and CD4⁺ T/CD8⁺ T lymphocytes around bile ducts. Serum AMA levels in ID mice were 1.8-fold higher than those of control mice. qPCR revealed higher expression of inflammatory molecules and cytokines (TNF-α, IFN-γ, IL-2, IL-12p35, and N-Ras) in the liver of ID mice. IP-ID mice developed cholangitis within 10 days, marked by CD4⁺ T-cell-dominant infiltration, which was attenuated by depleting anti-PDCE-2 antibodies from ID serum.

Conclusions: DC depletion induces PBC-like serological and histological features, implicating DC dysfunction in immune dysregulation through CD4⁺ T-cell activation and anti-PDCE-2 antibody production. Our ID and IP models show that both T-cell responses and autoantibodies are essential contributors to PBC pathogenesis.

T‐helper cell differentiation; animal models; autoantigens; autoimmune diseases; cholangitis; dendritic cells; immune tolerance.