Bioinformatics Laboratory, Epidemiology and Data Science, Amsterdam Public Health research institute, Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands.
Department for Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
PLoS Comput Biol. 2022 Jun 3;18(6):e1010168. doi: 10.1371/journal.pcbi.1010168. eCollection 2022 Jun.
Affinity maturation is an evolutionary process by which the affinity of antibodies (Abs) against specific antigens (Ags) increases through rounds of B-cell proliferation, somatic hypermutation, and positive selection in germinal centres (GC). The positive selection of B cells depends on affinity, but the underlying mechanisms of affinity discrimination and affinity-based selection are not well understood. It has been suggested that selection in GC depends on both rapid binding of B-cell receptors (BcRs) to Ags which is kinetically favourable and tight binding of BcRs to Ags, which is thermodynamically favourable; however, it has not been shown whether a selection bias for kinetic properties is present in the GC. To investigate the GC selection bias towards rapid and tight binding, we developed an agent-based model of GC and compared the evolution of founder B cells with initially identical low affinities but with different association/dissociation rates for Ag presented by follicular dendritic cells in three Ag collection mechanisms. We compared an Ag collection mechanism based on association/dissociation rates of B-cell interaction with presented Ag, which includes a probabilistic rupture of bonds between the B-cell and Ag (Scenario-1) with a reference scenario based on an affinity-based Ag collection mechanism (Scenario-0). Simulations showed that the mechanism of Ag collection affects the GC dynamics and the GC outputs concerning fast/slow (un)binding of B cells to FDC-presented Ags. In particular, clones with lower dissociation rates outcompete clones with higher association rates in Scenario-1, while remaining B cells from clones with higher association rates reach higher affinities. Accordingly, plasma cell and memory B cell populations were biased towards B-cell clones with lower dissociation rates. Without such probabilistic ruptures during the Ag extraction process (Scenario-2), the selective advantage for clones with very low dissociation rates diminished, and the affinity maturation level of all clones decreased to the reference level.
亲和力成熟是一种进化过程，通过该过程，针对特定抗原（Ag）的抗体（Ab）的亲和力通过 B 细胞增殖、体细胞超突变和生发中心（GC）中的阳性选择而增加。B 细胞的阳性选择取决于亲和力，但亲和力鉴别和基于亲和力的选择的潜在机制尚不清楚。有人提出，GC 中的选择取决于 B 细胞受体（BcR）与 Ag 的快速结合，这在动力学上是有利的，以及 BcR 与 Ag 的紧密结合，这在热力学上是有利的；然而，尚未表明 GC 中是否存在对动力学特性的选择偏向。为了研究 GC 对快速和紧密结合的选择偏向，我们开发了一个基于代理的 GC 模型，并比较了具有最初相同低亲和力但滤泡树突状细胞（FDC）呈现的 Ag 的结合/解离率不同的创始 B 细胞在三种 Ag 收集机制中的进化。我们比较了一种基于 B 细胞与呈现的 Ag 之间相互作用的结合/解离率的 Ag 收集机制（方案 1）与基于亲和力的 Ag 收集机制的参考方案（方案 0）。模拟表明，Ag 收集机制会影响 GC 动力学和 GC 输出，涉及 B 细胞与 FDC 呈现的 Ag 的快速/缓慢（不）结合。特别是，在方案 1 中，解离率较低的克隆比结合率较高的克隆具有竞争优势，而结合率较高的克隆中的剩余 B 细胞则达到更高的亲和力。因此，浆细胞和记忆 B 细胞群体偏向于解离率较低的 B 细胞克隆。如果在 Ag 提取过程中没有这种概率性的破裂（方案 2），则解离率非常低的克隆的选择优势减弱，所有克隆的亲和力成熟水平降低到参考水平。
