Regulated somatic hypermutation enhances antibody affinity maturation Journal Article
| Authors: | Merkenschlager, J.; Pyo, A. G. T.; Silva Santos, G. S.; Schaefer-Babajew, D.; Cipolla, M.; Hartweger, H.; Gitlin, A. D.; Wingreen, N. S.; Nussenzweig, M. C. |
| Article Title: | Regulated somatic hypermutation enhances antibody affinity maturation |
| Abstract: | Germinal centres are specialized microenvironments where B cells undergo affinity maturation. B cells expressing antibodies whose affinity is improved by somatic hypermutation are selected for expansion by limiting numbers of T follicular helper cells. Cell division is accompanied by mutation of the immunoglobulin genes, at what is believed to be a fixed rate of around 1 × 10−3 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 B cells 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 B cell lineages and enhance the outcomes of antibody affinity maturation. © The Author(s) 2025. |
| Keywords: | controlled study; sequence analysis; genetics; mutation; nonhuman; flow cytometry; mouse; animal; cytology; metabolism; animals; mice; cell division; biological model; cell maturation; dendritic cell; genotype; immunoglobulin; enzyme activation; b lymphocyte; b-lymphocytes; germinal center; antigen presentation; immunology; somatic hypermutation; activation induced cytidine deaminase; immunoglobulin heavy chain; immune response; antigen; messenger rna; microenvironment; mutation rate; doxycycline; major histocompatibility complex; immunoglobulin light chain; antibody; mutagenesis; cell cycle g1 phase; g1 phase; theoretical model; antibody affinity; immunization; maturation; somatic hypermutation, immunoglobulin; models, immunological; phylogenetic tree; b lymphocyte receptor; clonal expansion; hapten antibody; cell component; female; article; biological processes; interferometry; tfh cell; single cell rna seq; severe acute respiratory syndrome coronavirus 2; sars-cov-2; lethal mutation |
| Journal Title: | Nature |
| Volume: | 641 |
| Issue: | 8062 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-05-08 |
| Start Page: | 495 |
| End Page: | 502 |
| Language: | English |
| DOI: | 10.1038/s41586-025-08728-2 |
| PUBMED: | 40108475 |
| PROVIDER: | scopus |
| PMCID: | PMC12058521 |
| DOI/URL: | |
| Notes: | Source: Scopus |
