AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers
AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers
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DOI：
10.1002/hep.21522
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发表时间：
2007-02-01
期刊：
影响因子：
13.5
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
--
作者：
Moritoki, Yuki;Lian, Zhe-Xiong;Gershwin, M. Eric
我们以前报道过，原发性胆汁性肝硬化（PBC）患者的外周血单个核细胞（PBMC）暴露于CpG后产生的多克隆IgM水平显着高于对照组。此外，PBC患者普遍存在和异常高水平的抗线粒体抗体（AMA）表明B细胞耐受性的严重丧失。我们已经解决了CpG是否会促进AMA的产生以及抑制淋巴细胞钾通道Kv 1.3和KCa 3.1的新实验药物是否可以抑制CpG介导的B细胞活化和AMA产生的问题。用和不用CpG刺激PBMC，随后分析表型，包括TLR 9、CD 86和KCa 3.1的表达，同时测量上清液中的AMA和对对照抗原破伤风类毒素的应答。此外，采用全细胞膜片钳技术研究了PBC患者和对照组B细胞上K+通道的表达。在PBC患者中，CpG诱导PBMC中AMA的分泌，并且还上调B细胞TLR 9、CD 86和KCa 3.1的表达。此外，K+通道阻断剂抑制AMA的分泌，而不减少CpG-B增强的IgM产生。此外，TLR 9和CD 86的上调减少，而不影响B细胞的增殖、B细胞凋亡或存活力。结论：PBC患者B细胞的高反应性促进了B细胞介导的自身免疫反应。
We previously reported that peripheral blood mononuclear cells (PBMCs) from patients with primary biliary cirrhosis (PBC) produce significantly higher levels of polyclonal IgM than controls after exposure to CpG. Furthermore, the prevalence and unusually high levels of antimito-chondrial antibodies (AMAs) in patients with PBC suggest a profound loss of B cell tolerance. We have addressed the issue of whether CpG will promote the production of AMAs and whether new experimental agents that inhibit the lymphocyte potassium channels Kv1.3 and KCa3.1 can suppress CpG-mediated B cell activation and AMA production. PBMCs were stimulated with and without CpG and were subsequently analyzed for phenotype, including expression of TLR9, CD86, and KCa3.1 concurrent with measurements of AMA and responses to a control antigen, tetanus toxoid, in supernatants. Additionally, K+ channel expression on B cells from PBC patients and controls was studied using whole-cell patch-damp technology. In patients with PBC, CpG induces secretion of AMAs in PBMCs and also up-regulates B cell expression of TLR9, CD86, and KCa3.1. Additionally, K+ channel blockers suppress secretion of AMA without a reduction of CpG-B-enhanced IgM production. Furthermore, there is diminished upregulation of TLR9 and CD86 without affecting proliferation of B cells, B cell apoptosis, or viability. Conclusion: These data suggest that the hyperresponsiveness of B cells in PBC accelerates B cell-mediated autoimmunity.