洛克菲勒大学Michel C. Nussenzweig研究组在研究中取得进展。他们报道了调节体细胞超突变促进抗体亲和成熟。该研究于2025年3月19日发表于国际一流学术期刊《自然》杂志上。

在这里，研究组通过实验检验了一个理论模型，该模型解释了如何通过改变体细胞超突变率来优化亲和成熟，从而使表达高亲和抗体的细胞分裂更多，但每次分裂时突变更少。从接种SARS-CoV-2疫苗或模型抗原的小鼠中获得的数据与理论模型一致，表明产生高亲和力抗体的细胞缩短了细胞周期的G0/G1期并降低了其突变率。该课题组建议这些机制保护高亲和力的B细胞系和增强抗体亲和成熟的结果。

据悉，生发中心是专门的微环境，B细胞经历亲和成熟。B表达抗体的细胞，其亲和力通过体细胞超突变得到改善，通过限制T滤泡辅助细胞。细胞分裂伴随着免疫球蛋白基因的突变，据信突变的固定速率约为1×10^-3每个碱基对每个细胞分裂3个。由于突变是随机的，因此获得亲和增强突变的概率大于获得亲和增强突变的概率。这种影响可能会加剧，甚至适得其反。表达高亲和力抗体并经历最多细胞分裂的细胞。

附：英文原文

Title: Regulated somatic hypermutation enhances antibody affinity maturation

Author: Merkenschlager, Julia, Pyo, Andrew G. T., Silva Santos, Gabriela S., Schaefer-Babajew, Dennis, Cipolla, Melissa, Hartweger, Harald, Gitlin, Alexander D., Wingreen, Ned S., Nussenzweig, Michel C.

Issue&Volume: 2025-03-19

Abstract: Germinal centres are specialized microenvironments where Bcells undergo affinity maturation. Bcells expressing antibodies whose affinity is improved by somatic hypermutation are selected for expansion by limiting numbers of Tfollicular helper cells. Cell division is accompanied by mutation of the immunoglobulin genes, at what is believed to be a fixed rate of around 1×103 per base pair per cell division1. As mutagenesis is random, the probability of acquiring deleterious mutations outweighs the probability of acquiring affinity-enhancing mutations. This effect might be heightened, and even become counterproductive, in Bcells that express high-affinity antibodies and undergo the greatest number of cell divisions2. Here we experimentally examine a theoretical model that explains how affinity maturation could be optimized by varying the rate of somatic hypermutation such that cells that express higher-affinity antibodies divide more but mutate less per division. Data obtained from mice immunized with SARS-CoV-2 vaccines or a model antigen align with the theoretical model and show that cells producing high-affinity antibodies shorten the G0/G1 phases of the cell cycle and reduce their mutation rates. We propose that these mechanisms safeguard high-affinity Bcell lineages and enhance the outcomes of antibody affinity maturation.

DOI: 10.1038/s41586-025-08728-2

Source: https://www.nature.com/articles/s41586-025-08728-2