Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis
Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis
复制标题
趋化因子（C-X-C 基序）配体 13 促进原发性胆汁性肝硬化中的肝内趋化因子（C-X-C 基序）受体 5 淋巴细胞归巢和异常 B 细胞免疫反应
DOI：
10.1002/hep.27725
复制
发表时间：
2015-06-01
期刊：
影响因子：
13.5
通讯作者：
Hou, Jinlin
中科院分区：
文献类型：
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作者：
Li, Yongyin;Wang, Weibin;Hou, Jinlin
原发性胆汁性肝硬化（PBC）的血清学标志是存在高滴度和特异性抗线粒体抗体（AMA）。虽然PBC患者没有整体免疫缺陷，但存在广泛的B细胞功能失调，包括血清免疫球蛋白M水平升高和对胞嘧啶-磷酸-鸟嘌呤刺激的B细胞反应增强。这种B细胞功能障碍的机制仍然未知。为了解决这一问题，我们集中精力确定PBC患者B细胞亚群的频率和导致B细胞失调的机制，包括与趋化因子（C-X-C基序）受体5（CXCR 5）（+）CD 4（+）T细胞的关系。在此，我们报告，血清和肝内白细胞介素-21（IL-21）的升高被发现在PBC患者，特别是，促进B细胞增殖，信号转导和转录激活因子3磷酸化和AMA生产在体外。更重要的是，在用丙酮酸脱氢酶复合物的重组E2亚基刺激后，PBC中的CXCR 5（+）CD 4（+）T细胞比健康对照产生更高水平的IL-21。此外，分选的CXCR 5（+）CD 4（+）T细胞增加了自体CD 19（+）B细胞产生的AMA。事实上，肝内趋化因子（C-X-C基序）配体13（CXCL 13）（CXCR 5（+）细胞的关键趋化因子）的表达升高在PBC的汇管区内被独特地发现，伴随着CD 4（+）、CXCR 5（+）、CD 19（+）和CD 38（+）细胞的浸润。结论：CXCL 13可促进CD 19（+）B细胞和CXCR 5（+）CD 4（+）T细胞聚集，从而介导IL-21介导的异常AMA反应。这些数据对潜在的免疫治疗具有意义，也反映了PBC肝脏中独特的淋巴生物学。（肝病学2015;61：1998-2007）
The serological hallmark of primary biliary cirrhosis (PBC) is the presence of high titer and specific antimitochondrial antibodies (AMAs). Although there is no global immune defect in patients with PBC, there is widespread dysregulated B-cell function, including increased sera levels of immunoglobulin M and enhanced B-cell responses to cytosine-phosphate-guanine stimulation. The mechanisms involved in this B-cell dysfunction have remained unknown. To address this issue, we focused on identifying the frequencies of B-cell subsets in patients with PBC and the mechanisms that lead to B-cell dysregulation, including the relationships with chemokine (C-X-C motif) receptor 5 (CXCR5)(+)CD4(+)T cells. Herein, we report that elevations of both serum and intrahepatic interleukin-21 (IL-21) were found in patients with PBC and, in particular, promoted B-cell proliferation, signal transducer and activator of transcription 3 phosphorylation and AMA production in vitro. More important, upon stimulation with recombinant E2 subunit of pyruvate dehydrogenase complex, CXCR5(+)CD4(+)T cells in PBC produced higher levels of IL-21 than healthy controls. Additionally, sorted CXCR5(+)CD4(+)T cells increased production of AMAs by autologous CD19(+)B cells. Indeed, elevated expression of intrahepatic chemokine (C-X-C motif) ligand 13 (CXCL13), a key chemokine of CXCR5(+) cells, was uniquely found within the portal tracts in PBC, accompanied by infiltrates of CD4(+), CXCR5(+), CD19(+), and CD38(+) cells. Conclusion: CXCL13 promotes aggregation of CD19(+)B cells and CXCR5(+)CD4(+)T cells, which directs the aberrant AMA response by IL-21. These data have implications for potential immunotherapy and also reflect the unique lymphoid biology in liver of PBC. (Hepatology 2015;61:1998-2007)