Nonequilibrium Antigen Recognition during Infections and Vaccinations,Physical Review X

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Nonequilibrium Antigen Recognition during Infections and Vaccinations
Physical Review X ( IF 11.6 ) Pub Date : 2024-08-14 , DOI: 10.1103/physrevx.14.031026
Roberto Morán-Tovar ₁ , Michael Lässig ₁

Affiliation

The initial immune response to an acute primary infection is a coupled process of antigen proliferation, molecular recognition by naive B cells, and their subsequent clonal expansion. This process contains a fundamental problem: the recognition of an exponentially time-dependent antigen signal. Here, we show that an efficient immune response must be stringently constrained to B-cell lineages with high antigen binding affinity. We propose a tuned proofreading mechanism for primary recognition of new antigens, where the molecular recognition machinery is adapted to the complexity of the immune repertoire. We show that this process produces potent, specific, and fast recognition of antigens, maintaining a spectrum of genetically distinct B-cell lineages as input for affinity maturation. Our analysis maps the proliferation-recognition dynamics of a primary infection to a generalized Luria-Delbrück process, akin to the dynamics of the classic fluctuation experiment. This map establishes a link between signal recognition dynamics and evolution. We derive the resulting statistics of the activated immune repertoire: Antigen binding affinity, expected size, and frequency of active B-cell clones are related by power laws, which define the class of generalized Luria-Delbrück processes. Their exponents depend on the antigen and B-cell proliferation rate, the number of proofreading steps, and the lineage density of the naive repertoire. We extend the model to include spatiotemporal processes, including the diffusion-recognition dynamics of a vaccination. Empirical data of activated mouse immune repertoires are found to be consistent with activation involving about three proofreading steps. The model predicts key clinical characteristics of acute infections and vaccinations, including the emergence of elite neutralizers and the effects of immune aging. More broadly, our results establish infections and vaccinations as a new probe into the global architecture and functional principles of immune repertoires.

Published by the American Physical Society

2024

中文翻译：

感染和疫苗接种期间的非平衡抗原识别

对急性原发性感染的初始免疫反应是抗原增殖、初始 B 细胞的分子识别及其随后的克隆扩增的耦合过程。这个过程包含一个基本问题：识别指数时间依赖性抗原信号。在这里，我们表明有效的免疫反应必须严格限制在具有高抗原结合亲和力的 B 细胞谱系中。我们提出了一种用于新抗原初选的调整校对机制，其中分子识别机制适应免疫库的复杂性。我们表明，这个过程产生对抗原的有效、特异性和快速识别，维持一系列遗传上不同的 B 细胞谱系作为亲和力成熟的输入。我们的分析将原发感染的增殖-识别动力学映射到广义的 Luria-Delbrück 过程，类似于经典波动实验的动力学。该图谱在信号识别动力学和进化之间建立了联系。我们得出激活免疫库的结果统计数据：抗原结合亲和力、预期大小和活性 B 细胞克隆的频率由幂律相关，幂律定义了广义 Luria-Delbrück 过程的类别。它们的指数取决于抗原和 B 细胞增殖率、校对步骤的数量以及朴素库的谱系密度。我们将模型扩展到包括时空过程，包括疫苗接种的扩散识别动力学。发现激活的小鼠免疫库的经验数据与涉及大约三个校对步骤的激活一致。该模型预测了急性感染和疫苗接种的关键临床特征，包括精英中和剂的出现和免疫衰老的影响。更广泛地说，我们的结果将感染和疫苗接种确立为对免疫库的全球结构和功能原理的新探索。美国物理学会 2024 年出版

更新日期：2024-08-14

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