Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, United States of America ; Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
PLoS One. 2013 Sep 10;8(9):e74225. doi: 10.1371/journal.pone.0074225. eCollection 2013.
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-γ, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-γ prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-γ is significantly decreased in the liver of IL-23p19(-/-), IL-17A(-/-) and IL-22(-/-) mice compared with controls. However, the ability of T cells to produce IFN-γ was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-γ producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-γ has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-γ-mediated immunopathology.
原发性胆汁性肝硬化（PBC）被认为是一种模型自身免疫性疾病，在鼠类和人类自身免疫中具有最具针对性和特异性的自身抗体，即抗线粒体自身抗体（AMA）。然而，该疾病的治疗进展却落后了。在此，我们利用我们独特的鼠类 PBC 模型，该模型中，用定量结构活性关系（QSAR）鉴定的 2-辛炔酸偶联到 BSA（2OA-BSA）免疫的小鼠会发展出强烈的炎症性胆管炎，与 PBC 患者具有惊人的相似之处。特别是，我们构建了几种独特的基因缺失小鼠，包括缺失 IL-12p40、IL-12p35、IFN-γ、IL-23p19、IL-17A、IL-17F 和 IL-22 的小鼠，用 2OA-BSA 免疫这些动物，并观察免疫病理学的自然史，以确定可能为成功治疗提供线索的关键途径。我们的数据表明，IL-12/Th1 和 IL-23/Th17 都参与了胆管炎，但引发病理学的是 IL-12/Th1 信号通路。事实上，IFN-γ 的缺失可预防疾病并抑制自身抗体。重要的是，缺失 Th17 细胞因子 IL-17A 和 IL-22，但不是 IL-17F，可减轻胆管损伤；IL-17A 敲除小鼠的抗线粒体抗体水平降低。我们进一步证明，与对照组相比，IL-23p19(-/-)、IL-17A(-/-)和 IL-22(-/-)小鼠肝脏中 IFN-γ 的产生显著减少。然而，Th17 细胞因子缺陷小鼠的 T 细胞产生 IFN-γ 的能力不受影响。我们的数据表明，在胆管炎的早期阶段，Th17 途径缺陷会抑制 IFN-γ 产生细胞在肝脏中的积累。总之，虽然 IFN-γ 在 2OA-BSA 诱导的自身免疫性胆管炎发病机制的早期事件中具有关键作用，但 IL-23/Th17 途径增强了 IL-12/IFN-γ 介导的免疫病理学作用。
