Yuan Meng, Feng Ziqi, Lv Huibin, So Natalie, Shen Ivana R, Tan Timothy J C, WenTeo Qi, Ouyang Wenhao O, Talmage Logan, Wilson Ian A, Wu Nicholas C
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, LaJolla, CA 92037, USA.
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
bioRxiv. 2023 Jun 7:2023.06.06.543969. doi: 10.1101/2023.06.06.543969.
The ability of human immune system to generate antibodies to any given antigen can be strongly influenced by immunoglobulin V gene (IGV) allelic polymorphisms. However, previous studies have provided only a limited number of examples. Therefore, the prevalence of this phenomenon has been unclear. By analyzing >1,000 publicly available antibody-antigen structures, we show that many IGV allelic polymorphisms in antibody paratopes are determinants for antibody binding activity. Biolayer interferometry experiment further demonstrates that paratope allelic mutations on both heavy and light chain often abolish antibody binding. We also illustrate the importance of minor IGV allelic variants with low frequency in several broadly neutralizing antibodies to SARS-CoV-2 and influenza virus. Overall, this study not only highlights the pervasive impact of IGV 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.
人类免疫系统针对任何给定抗原产生抗体的能力会受到免疫球蛋白V基因（IGV）等位基因多态性的强烈影响。然而，以往的研究仅提供了有限的实例。因此，这种现象的普遍性尚不清楚。通过分析1000多个公开可用的抗体-抗原结构，我们发现抗体互补决定区中的许多IGV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突变通常会消除抗体结合。我们还阐述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IGV等位基因变体的重要性。总体而言，本研究不仅突出了IGV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性见解，这反过来对疫苗开发和抗体发现具有重要意义。
