Deng Weiqi, Niu Xuefeng, He Ping, Yan Qihong, Liang Huan, Wang Yongping, Ning Lishan, Lin Zihan, Zhang Yudi, Zhao Xinwei, Feng Liqiang, Qu Linbing, Chen Ling
State Key Laboratory of Respiratory Disease, Guangdong Laboratory of Computational Biomedicine, Center for Cell Lineage Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
University of Chinese Academy of Science, Beijing, China.
Front Immunol. 2025 Jan 7;15:1471396. doi: 10.3389/fimmu.2024.1471396. eCollection 2024.
Although immunoglobulin (Ig) alleles play a pivotal role in the antibody response to pathogens, research to understand their role in the humoral immune response is still limited.
We retrieved the germline sequences for the IGHV from the IMGT database to illustrate the amino acid polymorphism present within germline sequences of IGHV genes. We aassembled the sequences of IgM and IgD repertoire from 130 people to investigate the genetic variations in the population. A dataset comprising 10,643 SARS-CoV-2 spike-specific antibodies, obtained from COV-AbDab, was compiled to assess the impact of SARS-CoV-2 infection on allelic gene utilization. Binding affinity and neutralizing activity were determined using bio-layer interferometry and pseudovirus neutralization assays. Primary docking was performed using ZDOCK (3.0.2) to generate the initial conformation of the antigen-antibody complex, followed by simulations of the complete conformations using Rosetta SnugDock software. The original and simulated structural conformations were visualized and presented using ChimeraX (v1.5).
We present an allelic atlas of immunoglobulin heavy chain (IgH) variable regions, illustrating the diversity of allelic variants across 33 IGHV family germline sequences by sequencing the IgH repertoire of in the population. Our comprehensive analysis of SARS-CoV-2 spike-specific antibodies revealed the preferential use of specific Ig alleles among these antibodies. We observed an association between Ig alleles and antibody binding epitopes. Different allelic genotypes binding to the same RBD epitope on the spike show different neutralizing potency and breadth. We found that antibodies carrying the IGHV1-6902 allele tended to bind to the RBD E2.2 epitope. The antibodies carrying G50 and L55 amino acid residues exhibit potential enhancements in binding affinity and neutralizing potency to SARS-CoV-2 variants containing the L452R mutation on RBD, whereas R50 and F55 amino acid residues tend to have reduced binding affinity and neutralizing potency. IGHV2-502 antibodies using the D56 allele bind to the RBD D2 epitope with greater binding and neutralizing potency due to the interaction between D56 on HCDR2 and K444 on RBD of most Omicron subvariants. In contrast, IGHV2-5*01 antibodies using the N56 allele show increased binding resistance to the K444T mutation on RBD.
This study provides valuable insights into humoral immune responses from the perspective of Ig alleles and population genetics. These findings underscore the importance of Ig alleles in vaccine design and therapeutic antibody development.
尽管免疫球蛋白（Ig）等位基因在针对病原体的抗体反应中起关键作用，但了解其在体液免疫反应中作用的研究仍然有限。
我们从国际免疫基因组数据库（IMGT）中检索了IGHV的胚系序列，以阐明IGHV基因胚系序列中存在的氨基酸多态性。我们组装了130人的IgM和IgD库序列，以研究人群中的基因变异。汇编了一个包含从COV-AbDab获得的10643种严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突特异性抗体的数据集，以评估SARS-CoV-2感染对等位基因利用的影响。使用生物层干涉术和假病毒中和试验测定结合亲和力和中和活性。使用ZDOCK（3.0.2）进行初步对接以生成抗原-抗体复合物的初始构象，随后使用Rosetta SnugDock软件模拟完整构象。使用ChimeraX（v1.5）对原始和模拟的结构构象进行可视化展示。
我们展示了免疫球蛋白重链（IgH）可变区的等位基因图谱，通过对人群中IgH库进行测序，阐明了33个IGHV家族胚系序列中等位基因变体的多样性。我们对SARS-CoV-2刺突特异性抗体的综合分析揭示了这些抗体中特定Ig等位基因的优先使用情况。我们观察到Ig等位基因与抗体结合表位之间存在关联。结合到刺突上相同受体结合域（RBD）表位的不同等位基因基因型表现出不同的中和效力和广度。我们发现携带IGHV1-6902等位基因的抗体倾向于结合RBD E2.2表位。携带G50和L55氨基酸残基的抗体对RBD上含有L452R突变的SARS-CoV-2变体的结合亲和力和中和效力有潜在增强，而R50和F55氨基酸残基的结合亲和力和中和效力往往降低。使用D56等位基因的IGHV2-502抗体由于HCDR2上的D56与大多数奥密克戎亚变体RBD上的K444之间的相互作用，以更高的结合和中和效力结合到RBD D2表位。相比之下，使用N56等位基因的IGHV2-5*01抗体对RBD上的K444T突变表现出增加的结合抗性。
本研究从Ig等位基因和群体遗传学的角度为体液免疫反应提供了有价值的见解。这些发现强调了Ig等位基因在疫苗设计和治疗性抗体开发中的重要性。
