Department of Computational Intelligence and Systems Science, Tokyo Institute of Technology, Yokohama 226-8502, Japan.
Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Sci Rep. 2017 Nov 2;7(1):14888. doi: 10.1038/s41598-017-13993-x.
The BCR constitutively transmits a "tonic" survival signal in the absence of exogenous antigen-binding. However, the strength of tonic BCR signal and its relationship with antigen-triggered survival signal are poorly understood. We found that primary B cells expressing high levels of BCR had elevated BCR tonic signal and increased survival compared with those expressing low levels of BCR. In addition, we found that crosslinking BCR with low doses of F(ab') α-IgM antibodies did not enhance, but rather decreased, B cell survival and that only when most of the BCR were occupied by F(ab') α-IgM antibodies was B cell survival enhanced. Based on these experimental results, we present a mathematical model integrating tonic and antigen-triggered BCR signals. Our model indicates that the signal generated from crosslinked BCR is 4.3 times as strong as the tonic signal generated from free BCR and that the threshold of B cell activation corresponds to the signal generated by crosslinking 61% of the surface BCR. This model also allows the prediction of the survival probability of a B cell based on its initial BCR level and the strength and duration of antigen stimulation, and fits with the mechanism of B cell tolerance.
BCR 在没有外源抗原结合的情况下持续传递“基础”存活信号。然而，基础 BCR 信号的强度及其与抗原触发的存活信号的关系还了解甚少。我们发现，表达高水平 BCR 的原代 B 细胞具有更高的 BCR 基础信号，并且与表达低水平 BCR 的细胞相比，其存活能力增加。此外，我们发现用低剂量的 F(ab')α-IgM 抗体交联 BCR 不会增强，而是会降低 B 细胞的存活能力，只有当大多数 BCR 被 F(ab')α-IgM 抗体占据时，B 细胞的存活能力才会增强。基于这些实验结果，我们提出了一个整合基础和抗原触发的 BCR 信号的数学模型。我们的模型表明，交联 BCR 产生的信号比自由 BCR 产生的基础信号强 4.3 倍，B 细胞激活的阈值对应于交联表面 BCR 的 61%产生的信号。该模型还可以根据 B 细胞初始 BCR 水平以及抗原刺激的强度和持续时间来预测 B 细胞的存活概率，并且与 B 细胞耐受的机制相符。
