美国布莱根妇女医院Duane R. Wesemann团队的研究揭示体细胞超突变解锁抗体特异性超出了主要曲目。相关论文于2025年5月7日发表在《免疫学》杂志上。

课题组研究人员研究了基于SHM的抗体进化是否仅限于通过初级库中的V(D)J重组建立的特异性。通过多种免疫模型跟踪预定义的非特异性B细胞，发现GCs内的非同源B细胞经历了SHM。在有限的B细胞竞争条件下，这些B细胞对不同模型抗原的多个表位产生了新的抗原识别。系统发育分析发现了导致新抗原亲和力的多种突变途径，增强的T细胞共刺激进一步促进了新抗原的识别。他们的数据支持一个模型，在这个模型中，B细胞的竞争——而不是对特异性亲和力的内在要求——限制了通过SHM产生新的亲和力，突出了哺乳动物适应性免疫系统探索V(D)J依赖性初级库编码的抗体-抗原相互作用的能力，证明了SHM不仅在成熟方面而且在重塑特异性方面的灵活性。

据介绍，B细胞体细胞超突变（SHM）和生发中心（GCs）的选择增强了抗体对抗原的亲和力。

附：英文原文

Title: Somatic hypermutation unlocks antibody specificities beyond the primary repertoire

Author: Teng Zuo, Avneesh Gautam, Shahab Saghaei, Sweta N. Khobragade, Rahaman Ahmed, Azadeh Mahdavinia, Mehrdad Zarghami, Gaspar A. Pacheco, Kenneth Green, Meghan Travers, Nicholas Garcia, Zahra Allahyari, Vishal Rao, Sachin Kumar, Robert Novak, Joyce K. Hwang, Duane R. Wesemann

Issue&Volume: 2025-05-07

Abstract: B cell somatic hypermutation (SHM) and selection in germinal centers (GCs) enhance antibody affinity for antigen. Here, we investigated whether SHM-based antibody evolution is restricted to specificities established through V(D)J recombination in the primary repertoire. Tracking pre-defined non-specific B cells across multiple immunization models revealed that non-cognate B cells within GCs undergo SHM. Under conditions of limited B cell competition, these B cells generated de novo antigen recognition to multiple epitopes across diverse model antigens. Phylogenetic analyses identified diverse mutational pathways leading to new antigen affinities, and enhanced T cell co-stimulation further promoted new antigen recognition. Our data support a model in which B cell competition—rather than an intrinsic requirement for specific affinity—limits the emergence of new affinities through SHM, highlighting the mammalian adaptive immune system’s ability to explore antibody-antigen interactions beyond those encoded by the V(D)J-dependent primary repertoire, demonstrating the flexibility of SHM in not only ripening but also reshaping specificity.

DOI: 10.1016/j.immuni.2025.04.014

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00177-3