Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Liver Int. 2013 Feb;33(2):312-20. doi: 10.1111/liv.12049. Epub 2012 Dec 11.
BACKGROUND/AIMS: We have reported the involvement of deregulated autophagy and subsequent cellular senescence in biliary epithelial lesions in primary biliary cirrhosis (PBC). Given that mitochondria are a major target of autophagy, we hypothesized that deregulated autophagy of mitochondria may be involved in autoimmune pathogenesis in PBC.
We examined immunohistochemically the expression of pyruvate dehydrogenase complex-E2 component (PDC-E2) and cytochrome c oxidase, subunit I (CCO), in livers taken from patients with PBC (n = 42) and control livers (n = 76). The colocalization of mitochondrial antigens with an autophagy marker microtubule-associated protein-light chain 3β (LC3), a deregulated autophagy marker p62/sequestosome-1 (p62) and a lysosomal marker LAMP-1 was examined by double immunofluorescence. We examined the colocalization of mitochondrial antigens with LC3, p62 and LAMP-1 and the cell-surface expression of PDC-E2 in cultured biliary epithelial cells (BECs) treated with various stresses.
Intense granular expression of PDC-E2 and CCO was seen in the damaged small bile ducts (SBDs) in PBC and the expression was significantly more frequent in PBC than in control livers (P < 0.01). The granular expression of mitochondrial antigens was colocalized with LC3 in damaged SBDs in PBC. The accumulation of LC3-expressing punctae colocalized with PDC-E2 and CCO was significantly more increased in cultured BECs treated with various stresses. The cell-surface expression of PDC-E2 was induced by various stresses in BECs.
Deregulated autophagy may contribute to the abnormal expression of mitochondrial antigens and may be involved in the autoimmune pathogenesis of bile duct lesions in PBC.
背景/目的：我们已经报道了原发性胆汁性肝硬化（PBC）中的胆管上皮病变中存在失调的自噬和随后的细胞衰老。鉴于线粒体是自噬的主要靶点，我们假设线粒体的失调自噬可能参与 PBC 的自身免疫发病机制。
我们通过免疫组织化学方法检测了来自 PBC 患者（n=42）和对照肝脏（n=76）的肝脏中丙酮酸脱氢酶复合物-E2 成分（PDC-E2）和细胞色素 c 氧化酶，亚基 I（CCO）的表达。通过双免疫荧光检查线粒体抗原与自噬标记物微管相关蛋白轻链 3β（LC3）、失调自噬标记物 p62/自噬体-1（p62）和溶酶体标记物 LAMP-1 的共定位。我们检测了在各种应激下培养的胆管上皮细胞（BEC）中，线粒体抗原与 LC3、p62 和 LAMP-1 的共定位以及 PDC-E2 的细胞表面表达。
在 PBC 中受损的小胆管（SBD）中观察到 PDC-E2 和 CCO 的强烈颗粒表达，其表达在 PBC 中明显比在对照肝脏中更频繁（P<0.01）。在 PBC 中受损的 SBD 中，线粒体抗原的颗粒表达与 LC3 共定位。在各种应激下处理的培养 BEC 中，LC3 表达的点状积累与 PDC-E2 和 CCO 的共定位明显增加。PDC-E2 的细胞表面表达在 BEC 中被各种应激诱导。
失调的自噬可能有助于线粒体抗原的异常表达，并可能参与 PBC 胆管病变的自身免疫发病机制。
