B cell activation triggered by the formation of the small receptor cluster: a computational study.
B cell activation triggered by the formation of the small receptor cluster: a computational study.
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由小受体簇的形成触发的 B 细胞激活：一项计算研究。
DOI：
10.1371/journal.pcbi.1002197
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Lipniacki T
中科院分区：
文献类型：
--
作者：
Hat B;Kazmierczak B;Lipniacki T
我们提出了B细胞受体（BCR）激活早期事件的空间扩展模型，该模型基于免疫受体和Src家族激酶的相互激酶-受体相互作用。这些相互作用导致正反馈，加上由受体的双重磷酸化和Michaelis-Menten去磷酸化动力学引起的两种非线性，负责系统的双稳定性。我们证明了B细胞可以被一个微小的受体簇的形成或细胞核的位移激活。受体和Src激酶首先在受体簇的位点或细胞质最薄的区域被局部激活。然后，激活的行波传播，直到活性扩散到整个细胞膜。在我们假设激酶在细胞质中自由扩散的模型中，我们发现能够启动B细胞活化的聚集受体的比例随着细胞质厚度的减少和激酶扩散的减少而减少。当激酶被限制在细胞膜上时——这是大多数Src家族激酶的情况——即使是由总受体的一小部分组成的簇也会被激活。有趣的是，该系统对总受体水平的适度变化仍然不敏感。该模型提供了一种可能的B细胞活化机制，该机制是由于多价抗原结合形成共定位的小受体簇或在免疫突触形成过程中产生的。B细胞在与合适的配体结合后被激活，从而诱导B细胞受体聚集。即使是包含不到1%的受体的小簇的形成也足以激活。这一观察结果使我们得出了一个模型，在这个模型中，受体簇只是一个开关，它开启了涉及其余受体的激活过程。该模型的思想利用了Src激酶- BCR系统是双稳态的这一事实，因此它的局部激活可能会启动行波的传播，从而在整个膜上传播激活。我们发现，激活簇的最小尺寸随着细胞质厚度和激酶扩散系数的增加而减小。当激酶被限制在膜上时，它特别小。这些发现与B细胞的特性一致，B细胞在激活之前具有极薄的细胞质层，其中Src家族激酶（与受体相互作用）系在膜上。
We proposed a spatially extended model of early events of B cell receptors (BCR) activation, which is based on mutual kinase-receptor interactions that are characteristic for the immune receptors and the Src family kinases. These interactions lead to the positive feedback which, together with two nonlinearities resulting from the double phosphorylation of receptors and Michaelis-Menten dephosphorylation kinetics, are responsible for the system bistability. We demonstrated that B cell can be activated by a formation of a tiny cluster of receptors or displacement of the nucleus. The receptors and Src kinases are activated, first locally, in the locus of the receptor cluster or the region where the cytoplasm is the thinnest. Then the traveling wave of activation propagates until activity spreads over the whole cell membrane. In the models in which we assume that the kinases are free to diffuse in the cytoplasm, we found that the fraction of aggregated receptors, capable to initiate B cell activation decreases with the decreasing thickness of cytoplasm and decreasing kinase diffusion. When kinases are restricted to the cell membrane - which is the case for most of the Src family kinases - even a cluster consisting of a tiny fraction of total receptors becomes activatory. Interestingly, the system remains insensitive to the modest changes of total receptor level. The model provides a plausible mechanism of B cells activation due to the formation of small receptors clusters collocalized by binding of polyvalent antigens or arising during the immune synapse formation. B cells are activated in response to binding of appropriate ligands, which induces the aggregation of B cell receptors. The formation of even small clusters containing less than 1% of all the receptors is sufficient for activation. This observation led us to a model in which the receptor cluster serves only as a switch that turns on the activation process involving also the remaining receptors. The idea of the model exploits the fact the Src kinase - BCR system is bistable, and thus its local activation may start the propagation of a traveling wave, which spreads activation over the entire membrane. We found that the minimal size of the activatory cluster decreases with the thickness of the cytoplasm and kinase diffusion coefficient. It is particularly small when kinases are restricted to the membrane. These findings are consistent with the properties of B cells, which prior to activation have extremely thin cytoplasmic layer and in which Src family kinases (interacting with the receptors) are tethered to the membrane.
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DOI：
10.1073/pnas.73.10.3671
发表时间：
1976-01-01
影响因子：
11.1
作者：
DINTZIS, HM;DINTZIS, RZ;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
5.4
作者：
Kaimachnikov, Nikolai P.;Kholodenko, Boris N.
通讯作者：
Kholodenko, Boris N.
DOI：
10.1016/j.pbiomolbio.2004.01.008
发表时间：
2004-06-01
影响因子：
3.8
作者：
Bhanot, G
通讯作者：
Bhanot, G
影响因子：
4.4
作者：
Das, Jayajit;Kardar, Mehran;Chakraborty, Arup K.
通讯作者：
Chakraborty, Arup K.
影响因子：
7.8
作者：
Kasahara, Kousuke;Nakayama, Yuji;Ikeda, Kikuko;Fukushima, Yuka;Matsuda, Daisuke;Horimoto, Shinya;Yamaguchi, Naoto
通讯作者：
Yamaguchi, Naoto