Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China.
PLoS One. 2012;7(8):e41644. doi: 10.1371/journal.pone.0041644. Epub 2012 Aug 27.
Auto-reactive B lymphocytes and its abnormal CD40 signaling play important roles in the pathogenesis of systemic lupus erythematosus (SLE). In this study, we analyzed CD40 expression and CD40/CD154 induced activation of NF-κB signaling pathway in B cells from SLE patients. B cells from healthy volunteers and tonsilar B cells from chronic tonsillitis were used as negative and positive controls. Results showed CD40-induced NF-κB signaling was constitutively activated in B cells from active lupus patients, including decreased CD40 in raft portion, increased phosphorylation and degradation of IκBα, phosphorylation of P65, as well as increased nuclear translocation of P65, P50, c-Rel, which could be blocked by anti-CD154. CD154 stimulation could induce further phosphorylation and degradation of IκBα, as well as phosphorylation of P65 and nuclear translocation of P65. In addition, CD40-induced kinase activities in B cells from lupus patients mimicked that of tonsil B cells, in that IKKα/β were more activated compared to normal B cells. CD40-induced NF-κB activity was blocked by both IκB phosphorylation and proteosome degradation inhibitors in both lupus and normal B cells. All together, our findings revealed that canonical NF-κB signaling is constitutively activated in active lupus and is mediated by CD154/CD40. CD40 induced NF-κB activation is different in human lupus B lymphocytes compared with normal B cells.
自身反应性 B 淋巴细胞及其异常的 CD40 信号转导在系统性红斑狼疮（SLE）的发病机制中起重要作用。在这项研究中，我们分析了来自 SLE 患者的 B 细胞中 CD40 的表达及其与 CD154 诱导的 NF-κB 信号通路的激活。健康志愿者的 B 细胞和慢性扁桃体炎的扁桃体 B 细胞分别作为阴性和阳性对照。结果表明，来自活动期狼疮患者的 B 细胞中 CD40 诱导的 NF-κB 信号通路持续激活，包括筏状部分 CD40 减少，IκBα 的磷酸化和降解增加，P65 的磷酸化，以及 P65、P50、c-Rel 的核易位增加，这些均可被抗 CD154 阻断。CD154 刺激可进一步诱导 IκBα 的磷酸化和降解，以及 P65 的磷酸化和 P65 的核易位。此外，狼疮患者的 B 细胞中 CD40 诱导的激酶活性与扁桃体 B 细胞相似，即与正常 B 细胞相比，IKKα/β 更为活跃。在狼疮和正常 B 细胞中，NF-κB 活性均被 IκB 磷酸化和蛋白酶体降解抑制剂阻断。总之，我们的研究结果表明，在活动期狼疮中，经典 NF-κB 信号通路持续激活，并由 CD154/CD40 介导。与正常 B 细胞相比，CD40 诱导的 NF-κB 激活在人类狼疮 B 淋巴细胞中存在差异。
