IBM Research Zürich, Rüschlikon, Switzerland.
ETH Zürich, Automatic Control Laboratory, Zurich, Switzerland.
Front Immunol. 2019 Apr 3;10:689. doi: 10.3389/fimmu.2019.00689. eCollection 2019.
Germinal centers (GCs) are specialized compartments within the secondary lymphoid organs, where B cells proliferate, differentiate, and mutate their antibody genes. Upon exit from the GC, B cells terminally differentiate into plasma cells or memory B cells. While we have a good comprehension of plasma cell differentiation, memory B cell differentiation is still incompletely understood. In this paper, we extend previous models of the molecular events underlying B cell differentiation with new findings regarding memory B cell formation, and present a quantitative stochastic model of the intracellular and extracellular dynamics governing B cell maturation and exit from the GC. To simulate this model, we develop a novel extension to the Gillespie algorithm that enables the efficient stochastic simulation of the system, while keeping track of individual cell properties. Our model is able to explain the dynamical shift from memory B cell to plasma cell production over the lifetime of a GC. Moreover, our results suggest that B cell fate selection can be explained as a process that depends fundamentally on antigen affinity.
生发中心（GCs）是次级淋巴器官中的特化隔室，其中 B 细胞增殖、分化并突变其抗体基因。在离开 GC 后，B 细胞终末分化为浆细胞或记忆 B 细胞。虽然我们对浆细胞分化有很好的理解，但记忆 B 细胞分化仍不完全清楚。在本文中，我们扩展了之前关于 B 细胞分化的分子事件的模型，增加了关于记忆 B 细胞形成的新发现，并提出了一个定量的随机模型，用于控制 B 细胞成熟和离开 GC 的细胞内和细胞外动力学。为了模拟这个模型，我们开发了一种新的 Gillespie 算法扩展，能够有效地模拟系统的随机过程，同时跟踪单个细胞的特性。我们的模型能够解释 GC 寿命内从记忆 B 细胞到浆细胞产生的动态转变。此外，我们的结果表明，B 细胞命运选择可以解释为一个基本依赖于抗原亲和力的过程。
