Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis.
Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis.
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DOI：
10.1002/hep.24194
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发表时间：
2011-04
期刊：
影响因子：
13.5
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
--
作者：
Shimoda, Shinji;Harada, Kenichi;Niiro, Hiroaki;Shirabe, Ken;Taketomi, Akinobu;Maehara, Yoshihiko;Tsuneyama, Koichi;Nakanuma, Yasuni;Leung, Patrick;Ansari, Aftab A.;Gershwin, M. Eric;Akashi, Koichi
原发性胆汁性肝硬化（PBC）的特征是与小胆管破坏相关的慢性非化脓性破坏性胆管炎（CNSDC）。虽然在针对线粒体自身抗原的适应性免疫应答的解剖方面取得了显著进展，但越来越多的数据表明先天免疫机制在诱导慢性胆道病变中的作用。我们已经利用我们的能力，分离肝单核细胞（LMC）的亚群，并在此检查的作用，Toll样受体（TLR），其配体和自然杀伤（NK）细胞在调节细胞毒活性对胆管上皮细胞（BEC）。特别地，我们证明了在由TLR 3配体（TLR 3-L）刺激的单核细胞（Mo）合成的干扰素（IFN）-α存在下，Toll样受体4配体（TLR 4-L）刺激的NK细胞破坏自体BEC。事实上，与疾病对照组相比，PBC患者肝脏Mo产生的IFN-α显著增加。PBC患者的肝NK细胞的细胞毒活性与对照组的NK细胞相比也有显著增加，但仅当NK细胞在TLR 3-L和TLR 4-L刺激的LMC连接后制备时。这些功能数据得到了免疫组化观察的支持，即PBC患者肝组织中分散在破坏的小胆管周围的CD 56阳性NK细胞的存在增加，比对照组更频繁。总之，这些数据突出了TLR 3-L和TLR 4-L刺激后Mo和NK细胞的不同作用的关键差异。
Primary biliary cirrhosis (PBC) is characterized by chronic non-suppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. Although there have been significant advancements in the dissection of the adaptive immune response against the mitochondrial autoantigens, there is increasing data that suggests a contribution of innate immune mechanisms in inducing chronic biliary pathology. We have taken advantage of our ability to isolate subpopulations of liver mononuclear cells (LMC) and examined herein the role of toll-like receptors (TLR), their ligands and natural killer (NK) cells in modulating cytotoxic activity against biliary epithelial cells (BECs). In particular, we demonstrate that toll-like receptor 4 ligand (TLR4-L) stimulated NK cells destroy autologous BECs in the presence of interferon (IFN)-α synthesized by TLR 3 ligand (TLR3-L) stimulated monocytes (Mo). Indeed, IFN-α production by hepatic Mo is significantly increased in patients with PBC compared to disease controls. There were also marked increases in the cytotoxic activity of hepatic NK cells from PBC patients compared to NK cells from controls but only when the NK cells were prepared following ligation of both TLR3-L and TLR4-L stimulated LMC. These functional data are supported by the immunohistochemical observation of an increased presence of CD56 positive NK cells scattered around destroyed small bile ducts more frequently in liver tissues from PBC patients than controls. In conclusion, these data highlight critical differences in the varied roles of Mo and NK cells following TLR3-L and TLR4-L stimulation.
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影响因子：
20.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Gershwin, M. Eric
影响因子：
13.5
作者：
Shimoda, Shinji;Harada, Kenichi;Akashi, Koichi
通讯作者：
Akashi, Koichi