Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis
Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis
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DOI：
10.1053/j.gastro.2007.01.039
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发表时间：
2007-04-01
期刊：
影响因子：
29.4
通讯作者：
Sumitran-Holgersson, Suchitra
中科院分区：
文献类型：
--
作者：
Karrar, Azza;Broome, Ulrika;Sumitran-Holgersson, Suchitra
背景与目的：原发性硬化性胆管炎(PSC)是一种以肝胆管破坏为主要表现的自身免疫性肝病。胆管上皮细胞抗体(BEC-Ab)在PSC中出现频率较高。在这里，我们研究了这些抗体在导致BEC功能障碍中使用的机制和信号通路。方法：对33例抗-BEC抗体阳性的PSC患者的免疫球蛋白(Ig)G和免疫球蛋白F(Ab)‘(2)组分进行免疫分析。结果：PSC-Ig G刺激BECs可诱导BECs表达Toll样受体(TLR)4和TLR9，细胞外信号调节激酶(ERK)1/2及转录因子ELK-1和核因子kappaB特异性磷酸化，ERK1/2特异性抑制剂可抑制BECs上ELK-1的磷酸化和TLR4的蛋白表达，但不抑制TLR9的蛋白表达。在脂多糖和CpG DNA的进一步刺激下，表达TLR的BECs产生高水平的IL-1β、IL-8、干扰素-γ、肿瘤坏死因子a、粒细胞-巨噬细胞集落刺激因子和转化生长因子β。胆管TLR4和TLR9在伴有BEC-Ab的PSC患者中的阳性率为58%，而在无BEC-Ab的PSC患者中为14%，在疾病对照肝脏中的阳性率也较低。结论：PSC与BEC-Ab结合可启动ERK1/2信号转导和TLR上调，从而诱导BEC产生细胞因子/趋化因子，从而可能导致炎性细胞的募集。因此，在PSC中，BEC不仅是免疫攻击的目标，也可能是自身破坏的积极参与者和调解人。BEC-Ab可能是PSC胆管炎的重要调节因子。
Background & Aims: Primary sclerosing cholangitis (PSC) is an autoimmune liver disease with destruction of hepatic bile ducts. A high frequency of biliary epithelial cell antibodies (BEC-Ab) is present in PSC. Here, we studied the mechanisms and signaling pathways used by these Ab in causing BEC dysfunction. Methods: Immunoassays were performed using freshly isolated BECs to study the signaling capacity of purified immunoglobulin (Ig) G and F(ab)'(2) fractions from 33 patients with PSC with anti-BEC-Ab. Results: We provide evidence that stimulation of BECs with PSC IgG, but not control IgG, induced expression of Toll-like receptor (TLR) 4 and TLR9 and specific phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 as well as the transcription factors ELK-1 and nuclear factor kappa B. A specific inhibitor of ERK1/2 abrogated phosphorylation of ELK-1 and protein expression of TLR4 but not TLR9 on BECs. TLR-expressing BECs, when further stimulated with lipopolysaccharide and CpG DNA, produced high levels of interleukin-1 beta, interleukin-8, interferon gamma, tumor necrosis factor a, granulocyte-macrophage colony-stimulating factor, and transforming growth factor beta. Bile ducts stained positively for TLR4 and TLR9 in 58% of liver specimens taken from patients with PSC with BEC-Ab, as compared with 14% in those without BEC-Ab and also less frequently in diseased control livers. Conclusions: Our data show that binding of PSC BEC-Ab initiates ERK1/2 signaling and up-regulation of TLR, which upon ligation induces BECs to produce cytokines/chemokines, leading to the possible recruitment of inflammatory cells. Thus, in PSC, BECs are not only targets of the immune attack but may also be active participants and mediators of their own destruction. BEC-Ab may be critical regulators of cholangitis in PSC.