A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation.
A Regulatory Circuit Controlling the Dynamics of NFκB cRel Transitions B Cells from Proliferation to Plasma Cell Differentiation.
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控制 NFκB cRel 动力学的调节电路将 B 细胞从增殖转变为浆细胞分化。
DOI：
10.1016/j.immuni.2019.02.004
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发表时间：
2019
期刊：
影响因子：
32.4
通讯作者：
Hoffmann,Alexander
中科院分区：
文献类型：
--
作者：
Roy,Koushik;Mitchell,Simon;Liu,Yi;Ohta,Sho;Lin,Yu-Sheng;Metzig,MarieOliver;Nutt,StephenL;Hoffmann,Alexander
体液免疫依赖于B细胞的有效激活和随后分化为抗体分泌细胞(ASCs)。转录因子NFκB cRel对B细胞增殖至关重要，但将其已知的调控相互作用纳入Asc分化电路的数学模型中，阻止了Asc在模拟中的产生。事实上，实验性的异位cRel表达通过抑制转录因子Blimp1来抑制ASC的分化，而在野生型(WT)细胞中，cRel在ASC分化过程中通过Blimp1结合Rellocus而被动态抑制。将cRel-Blimp1相互拮抗的双稳态电路纳入多尺度模型，揭示了cRel的动态抑制控制了从B细胞增殖到ASC生成阶段的切换，从而控制了相应的细胞种群动态。我们的研究提供了一种机制上的解释，解释了这种双稳定循环的失调如何导致病理性B细胞群体表型，从而为诊断分层和治疗提供了新的途径。
Humoral immunity depends on efficient activation of B cells and their subsequent differentiation into antibody-secreting cells (ASCs). The transcription factor NFκB cRel is critical for B cell proliferation, but incorporating its known regulatory interactions into a mathematical model of the ASC differentiation circuit prevented ASC generation in simulations. Indeed, experimental ectopic cRel expression blocked ASC differentiation by inhibiting the transcription factor Blimp1, and in wild-type (WT) cells cRel was dynamically repressed during ASC differentiation by Blimp1 binding theRellocus. Including this bi-stable circuit of mutual cRel-Blimp1 antagonism into a multi-scale model revealed that dynamic repression of cRel controls the switch from B cell proliferation to ASC generation phases and hence the respective cell population dynamics. Our studies provide a mechanistic explanation of how dysregulation of this bi-stable circuit might result in pathologic B cell population phenotypes and thus offer new avenues for diagnostic stratification and treatment.
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影响因子：
32.4
作者：
Shaffer, AL;Lin, KI;Staudt, LM
通讯作者：
Staudt, LM
影响因子：
7.2
作者：
Staudt, Louis M.
通讯作者：
Staudt, Louis M.
影响因子：
32.4
作者：
Di Niro R;Lee SJ;Vander Heiden JA;Elsner RA;Trivedi N;Bannock JM;Gupta NT;Kleinstein SH;Vigneault F;Gilbert TJ;Meffre E;McSorley SJ;Shlomchik MJ
通讯作者：
Shlomchik MJ
DOI：
10.1073/pnas.87.12.4727
发表时间：
1990-06-01
影响因子：
11.1
作者：
DUYAO, MP;BUCKLER, AJ;SONENSHEIN, GE
通讯作者：
SONENSHEIN, GE
影响因子：
11.4
作者：
Muto, Akihiko;Ochiai, Kyoko;Igarashi, Kazuhiko
通讯作者：
Igarashi, Kazuhiko