Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands.
Front Immunol. 2021 Sep 20;12:734282. doi: 10.3389/fimmu.2021.734282. eCollection 2021.
Germinal center (GC) reactions are vital to the correct functioning of the adaptive immune system, through formation of high affinity, class switched antibodies. GCs are transient anatomical structures in secondary lymphoid organs where specific B cells, after recognition of antigen and with T cell help, undergo class switching. Subsequently, B cells cycle between zones of proliferation and somatic hypermutation and zones where renewed antigen acquisition and T cell help allows for selection of high affinity B cells (affinity maturation). Eventually GC B cells first differentiate into long-lived memory B cells (MBC) and finally into plasma cells (PC) that partially migrate to the bone marrow to encapsulate into long-lived survival niches. The regulation of GC reactions is a highly dynamically coordinated process that occurs between various cells and molecules that change in their signals. Here, we present a system-level perspective of T cell-mediated GC B cell differentiation, presenting and discussing the experimental and computational efforts on the regulation of the GCs. We aim to integrate Systems Biology with B cell biology, to advance elucidation of the regulation of high-affinity, class switched antibody formation, thus to shed light on the delicate functioning of the adaptive immune system. Specifically, we: i) review experimental findings of internal and external factors driving various GC dynamics, such as GC initiation, maturation and GCBC fate determination; ii) draw comparisons between experimental observations and mathematical modeling investigations; and iii) discuss and reflect on current strategies of modeling efforts, to elucidate B cell behavior during the GC tract. Finally, perspectives are specifically given on to the areas where a Systems Biology approach may be useful to predict novel GCBC-T cell interaction dynamics.
生发中心（GC）反应对于适应性免疫系统的正常功能至关重要，它通过形成高亲和力、类别转换的抗体来实现。GC 是次级淋巴器官中的短暂解剖结构，在那里，特异性 B 细胞在识别抗原后，在 T 细胞的帮助下，经历类别转换。随后，B 细胞在增殖和体细胞超突变区和重新获得抗原和 T 细胞帮助的选择高亲和力 B 细胞（亲和力成熟）区之间循环。最终，GC B 细胞首先分化为长寿命记忆 B 细胞（MBC），最终分化为浆细胞（PC），部分迁移到骨髓中，封装到长寿命的生存龛中。GC 反应的调节是一个高度动态协调的过程，涉及到各种细胞和分子之间的信号变化。在这里，我们提出了一种 T 细胞介导的 GC B 细胞分化的系统水平视角，介绍和讨论了 GC 调节的实验和计算研究。我们旨在将系统生物学与 B 细胞生物学相结合，推进对高亲和力、类别转换抗体形成的调控机制的阐明，从而揭示适应性免疫系统的微妙功能。具体来说，我们：i）回顾了驱动各种 GC 动力学的内部和外部因素的实验发现，如 GC 的启动、成熟和 GCBC 命运决定；ii）比较了实验观察和数学建模研究之间的差异；iii）讨论和反思了当前建模研究的策略，以阐明 GC 过程中 B 细胞的行为。最后，特别关注系统生物学方法在预测新的 GCBC-T 细胞相互作用动力学方面可能有用的领域。
