Departments of Microbiology and Immunology, Tokyo Women's Medical University, 8-1 Kawada-cho, Tokyo, Shinjuku-ku, Japan.
Lab Invest. 2010 Apr;90(4):577-88. doi: 10.1038/labinvest.2010.40. Epub 2010 Feb 8.
Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). We earlier reported that the bacterial lipoteichoic acid was detected at the sites of inflammation around damaged bile ducts in the livers of PBC, and PBC patients' sera showed high titers against streptococcal histone-like protein. Here, we investigated whether chronic bacterial exposure could trigger PBC-like epithelial cell damage in normal mouse. BALB/c mice were repeatedly inoculated with various bacteria for 8 weeks. At 1 week (Group 1) and 3, 4, or 20 months (long term; Group 2) after the final inoculation, mice were killed to obtain samples. In the livers of the Streptococcus intermedius (S.i.)-inoculated mice in Group 1, cellular infiltration was predominantly observed around the bile ducts over the hepatic parenchyma. In the S.i.-inoculated mice in Group 2, portal but not parenchymal inflammation was observed in the livers, and periductal cellular infiltrates were detected in the salivary glands. Both S.i.-inoculated Groups 1 and 2 BALB/c mice sera had antibodies against HuCCT1 biliary epithelial cells, anti-nuclear antibodies, and anti-gp210 antibodies, but not anti-mitochondrial antibodies. Immunoreactivity to histone-like DNA-binding protein of S.i. (S.i.-HLP) was detectable around the sites of chronic nonsuppurative destructive cholangitis in the portal area in the livers of both S.i.-inoculated Groups 1 and 2 BALB/c mice. Furthermore, anti-S.i.-HLP antibody bound to synthetic gp210 peptide, as well. Bacteria triggered PBC-like cholangitis, multifocal epithelial inflammation, and autoantibody production. Bacteria are likely involved in the pathogenesis of PBC and of associated multifocal epithelial inflammation.
细菌感染已成为原发性胆汁性肝硬化（PBC）发病机制的关注焦点。我们之前报道过，在 PBC 患者肝脏中受损胆管周围的炎症部位检测到细菌脂磷壁酸，并且 PBC 患者的血清中针对链球菌组蛋白样蛋白的滴度较高。在这里，我们研究了慢性细菌暴露是否会在正常小鼠中引发 PBC 样上皮细胞损伤。BALB/c 小鼠反复接种各种细菌 8 周。在最后一次接种后 1 周（第 1 组）和 3、4 或 20 个月（长期；第 2 组），处死小鼠以获取样本。在第 1 组的中间链球菌（S.i.）接种小鼠的肝脏中，细胞浸润主要观察到肝实质周围胆管周围。在第 2 组的 S.i.接种小鼠中，肝脏中观察到门脉而不是实质炎症，唾液腺中检测到胆管周围细胞浸润。第 1 组和第 2 组 S.i.接种的 BALB/c 小鼠血清均具有针对 HuCCT1 胆管上皮细胞、抗核抗体和抗 gp210 抗体的抗体，但没有抗线粒体抗体。在第 1 组和第 2 组 S.i.接种的 BALB/c 小鼠的肝脏中，在门脉区慢性非化脓性破坏性胆管炎部位可检测到针对 S.i.的组蛋白样 DNA 结合蛋白（S.i.-HLP）的免疫反应性。此外，抗 S.i.-HLP 抗体也与合成的 gp210 肽结合。细菌引发了 PBC 样胆管炎、多灶性上皮炎症和自身抗体产生。细菌可能参与 PBC 的发病机制以及相关的多灶性上皮炎症。
