Complement mediated hepatocytes injury in a model of autoantibody induced hepatitis.
Complement mediated hepatocytes injury in a model of autoantibody induced hepatitis.
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DOI：
10.1016/j.imbio.2010.08.004
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发表时间：
2011-04
期刊：
影响因子：
2.8
通讯作者：
Lin, Feng
中科院分区：
文献类型：
--
作者：
Tu, Zhidan;Li, Qing;Chou, Hong-Shiue;Hsieh, Ching-Chuang;Meyerson, Howard;Peters, Marion G.;Bu, Hong;Fung, John J.;Qian, Shiguang;Lu, Lina;Lin, Feng
尽管有许多关于自身抗体激活补体在自身免疫性肝炎（AIH）中的报道，但体液免疫在AIH发病机制中的作用仍不清楚。在这份报告中，通过过继转移多克隆兔抗OVA抗体到Hep-OVA Tg小鼠，其中OVA是选择性表达的肝细胞表面，我们发现，过度的补体激活启动的自身抗体压倒了内在的细胞表面补体调节剂的保护，并诱导肝细胞损伤在体外和体内。如通过血清ALT水平和肝组织病理学评估的，抗-OVA抗体在Hep-OVA Tg而非WT C57 BL/6小鼠中诱导肝损伤。免疫组织化学分析显示，抗体给药后，在Hep-OVA Tg小鼠中抗-OVA IgG包被的肝细胞上存在大量补体激活，但在WT小鼠中没有。与这些结果一致，在抗体注射之前通过眼镜蛇毒因子（CVF）消耗补体保护Hep-OVA Tg小鼠免受抗-OVA IgG诱导的肝损伤。此外，用重组小鼠衰变加速因子（一种天然补体抑制剂）治疗Hep-OVA Tg小鼠，可保护其免受自身抗体诱导的肝炎。这些结果表明，补体可以发挥关键作用，在肝特异性自身抗体介导的肝细胞损伤AIH，补体抑制剂，原则上，可以开发为新的治疗AIH。
Despite multiple reports on autoantibody-initiated complement activation in autoimmune hepatitis (AIH), how does the humoral immunity contribute to the pathogenesis of AIH remained unclear. In this report, by adoptively transferring a polyclonal rabbit anti-OVA antibody into Hep-OVA Tg mice in which OVA is selectively expressed on the surface of hepatocytes, we found that excessive complement activation initiated by the autoantibody overwhelmed the protection of intrinsic cell surface complement regulators, and induced hepatocytes injury both in vitro and in vivo. The anti-OVA antibody induced hepatic injury in Hep-OVA Tg but not WT C57BL/6 mice as assessed by serum ALT levels and liver histopathology. Immunohistochemical analyses showed that after the antibody administration, there was massive complement activation on anti-OVA IgG coated hepatocytes in Hep-OVA Tg mice, but not in WT mice. Consistent with these results, depleting complement by cobra venom factor (CVF) prior to antibody injections protected Hep-OVA Tg mice from anti-OVA IgG induced hepatic injury. In addition, treating Hep-OVA Tg mice with recombinant mouse decay accelerating factor, a native complement inhibitor, protected them from autoantibody induced hepatitis. These results suggest that complement could play a pivotal role in liver specific autoantibody mediated hepatocyte injury in AIH, and that complement inhibitors could be, in principle, developed as novel therapeutics against AIH.
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DOI：
10.1016/s0162-3109(00)80299-4
发表时间：
2000-08-01
期刊：
IMMUNOPHARMACOLOGY
影响因子：
--
作者：
Sahu, A;Lambris, JD
通讯作者：
Lambris, JD
影响因子：
12.8
作者：
Buxbaum, James;Qian, Peiqing;Peters, Marion G.
通讯作者：
Peters, Marion G.
影响因子：
2.5
作者：
Czaja, Albert J.
通讯作者：
Czaja, Albert J.
影响因子：
2.2
作者：
KOLBER, MA;QUINONES, RR;HENKART, PA
通讯作者：
HENKART, PA
影响因子：
6.4
作者：
Lin, F;Fukuoka, Y;Medof, ME
通讯作者：
Medof, ME