Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Cell Rep. 2023 Oct 31;42(10):113194. doi: 10.1016/j.celrep.2023.113194. Epub 2023 Sep 30.
The ability of the human immune system to generate antibodies to any given antigen can be strongly influenced by immunoglobulin V-gene allelic polymorphisms. However, previous studies have provided only limited examples. Therefore, the prevalence of this phenomenon has been unclear. By analyzing >1,000 publicly available antibody-antigen structures, we show that many V-gene allelic polymorphisms in antibody paratopes are determinants for antibody binding activity. Biolayer interferometry experiments further demonstrate that paratope allelic polymorphisms on both heavy and light chains often abolish antibody binding. We also illustrate the importance of minor V-gene allelic polymorphisms with low frequency in several broadly neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus. Overall, this study not only highlights the pervasive impact of V-gene allelic polymorphisms on antibody binding but also provides mechanistic insights into the variability of antibody repertoires across individuals, which in turn have important implications for vaccine development and antibody discovery.
人类免疫系统产生针对任何给定抗原的抗体的能力，可受到免疫球蛋白 V 基因等位基因多态性的强烈影响。然而，之前的研究仅提供了有限的例子。因此，这种现象的普遍性尚不清楚。通过分析 >1000 个公开的抗体-抗原结构，我们表明抗体互补决定区中的许多 V 基因等位基因多态性是抗体结合活性的决定因素。生物层干涉实验进一步证明，重链和轻链上的互补决定区等位基因多态性经常会破坏抗体结合。我们还说明了在几种针对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）和流感病毒的广泛中和抗体中，低频的次要 V 基因等位基因多态性的重要性。总的来说，这项研究不仅强调了 V 基因等位基因多态性对抗体结合的普遍影响，还为个体间抗体库的变异性提供了机制见解，这对疫苗开发和抗体发现具有重要意义。
