Control of the B cell-intrinsic tolerance programs by ubiquitin ligases cbl and Cbl-b
Control of the B cell-intrinsic tolerance programs by ubiquitin ligases cbl and Cbl-b
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DOI：
10.1016/j.immuni.2007.03.015
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发表时间：
2007-05-01
期刊：
影响因子：
32.4
通讯作者：
Gu, Hua
中科院分区：
文献类型：
--
作者：
Kitaura, Yasuyuki;Jang, Ihn Kyung;Gu, Hua
B细胞受体（BCR）信号传导在B细胞耐受和激活中起着至关重要的作用。在这里，我们发现B细胞特异性消融Cbl和Cbl- B (Cbl（-/-)Cblb(-/-)）的小鼠表现为系统性红斑狼疮（SLE）样自身免疫性疾病。Cbl双重缺乏导致边缘区（MZ）和B1 B细胞大量增加。突变的B细胞在BCR刺激下的增殖和抗体产生方面没有过度反应；然而，B细胞对蛋白抗原的能量似乎受损。与此同时，bcr -近端信号传导，包括Syk酪氨酸激酶、磷脂酶c - γ 2 （plc - γ 2）和rho家族GTP-GDP交换因子Vav的酪氨酸磷酸化和Ca2+动员增强，而在突变B细胞中，衔接蛋白BLNK的酪氨酸磷酸化显著减弱。这些结果表明，这些途径之间的协调丧失是导致B细胞耐受诱导受损的原因。因此，在能量诱导过程中，Cbl蛋白可能通过协调多个bcr -近端信号通路来控制B细胞免疫耐受的内在检查点。
B cell receptor (BCR) signaling plays a critical role in B cell tolerance and activation. Here, we show that mice with B cell-specific ablation of both Cbl and Cbl-b (Cbl(-/-)Cblb(-/-)) manifested systemic lupus erythematosus (SLE)-like autoimmune disease. The Cbl double deficiency resulted in a substantial increase in marginal zone (MZ) and B1 B cells. The mutant B cells were not hyperresponsive in terms of proliferation and antibody production upon BCR stimulation; however, B cell anergy to protein antigen appeared to be impaired. Concomitantly, BCR-proximal signaling, including tyrosine phosphorylation of Syk tyrosine kinase, Phospholipase C-gamma 2 (PLC-gamma 2), and Rho-family GTP-GDP exchange factor Vav, and Ca2+ mobilization were enhanced, whereas tyrosine phosphorylation of adaptor protein BLNK was substantially attenuated in the mutant B cells. These results suggested that the loss of coordination between these pathways was responsible for the impaired B cell tolerance induction. Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction.