Rodriguez Oscar L, Qiu Xiang, Shields Kaitlyn, Dunn Christoper, Singh Amit, Kaileh Mary, Watson Corey T, Sen Ranjan
Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
bioRxiv. 2025 May 24:2025.05.19.654982. doi: 10.1101/2025.05.19.654982.
The peripheral antibody repertoire is shaped by inherited genetic variation and selection during B cell development. However, how the repertoire changes across developmental stages-and the relative impact of genetics and selection in establishing the antibody repertoire-remain largely unknown. To dissect the individual and combined effects of these factors, we integrated antibody repertoire transcriptomics across pro-B, pre-B, immature, and naive B cells with single-molecule real-time long-read DNA sequencing of the immunoglobulin heavy (IGH), kappa (IGK), and lambda (IGL) chain loci. We find that IGH genetic variants establish gene usage biases at the pro-B stage that persist throughout development. In contrast, IGK and IGL repertoires are extensively remodeled during maturation, consistent with receptor editing. Surprisingly, IGH variants also exert trans effects on light chain gene usage, suggesting coordinated constraints on heavy-light chain pairing. Principal component and allele-specific analyses reveal that genetics primarily shapes the heavy chain repertoire, while selection more strongly influences light chain diversity. These findings define distinct dynamics of antibody repertoire development and underscore the importance of personal immunogenomics in understanding individual immune responses.
外周抗体库由B细胞发育过程中的遗传变异和选择所塑造。然而，抗体库在不同发育阶段如何变化，以及遗传和选择在建立抗体库中的相对影响，在很大程度上仍然未知。为了剖析这些因素的个体和综合影响，我们将前B细胞、前B细胞、未成熟B细胞和幼稚B细胞的抗体库转录组学与免疫球蛋白重链（IGH）、κ链（IGK）和λ链（IGL）基因座的单分子实时长读长DNA测序相结合。我们发现IGH基因变异在前B细胞阶段建立了基因使用偏好，这种偏好贯穿整个发育过程。相比之下，IGK和IGL库在成熟过程中会广泛重塑，这与受体编辑一致。令人惊讶的是，IGH变异也会对轻链基因使用产生反式作用，这表明对重链-轻链配对存在协同限制。主成分分析和等位基因特异性分析表明，遗传因素主要塑造重链库，而选择对轻链多样性的影响更强。这些发现定义了抗体库发育的不同动态，并强调了个人免疫基因组学在理解个体免疫反应中的重要性。
