W. M. Keck Laboratory for Structural Biology, Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Rockville, MD, United States.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, MD, United States.
Front Immunol. 2018 Feb 1;9:117. doi: 10.3389/fimmu.2018.00117. eCollection 2018.
Affinity maturation is the process whereby the immune system generates antibodies of higher affinities during a response to antigen. It is unique in being the only evolutionary mechanism known to operate on a molecule in an organism's own body. Deciphering the structural mechanisms through which somatic mutations in antibody genes increase affinity is critical to understanding the evolution of immune repertoires. Next-generation sequencing (NGS) has allowed the reconstruction of antibody clonal lineages in response to viral pathogens, such as HIV-1, which was not possible in earlier studies of affinity maturation. Crystal structures of antibodies from these lineages bound to their target antigens have revealed, at the atomic level, how antibodies evolve to penetrate the glycan shield of envelope glycoproteins, and how viruses in turn evolve to escape neutralization. Collectively, structural studies of affinity maturation have shown that increased antibody affinity can arise from any one or any combination of multiple diverse mechanisms, including improved shape complementarity at the interface with antigen, increased buried surface area upon complex formation, additional interfacial polar or hydrophobic interactions, and preorganization or rigidification of the antigen-binding site.
亲和力成熟是指免疫系统在对抗原的反应过程中产生更高亲和力抗体的过程。它是唯一已知在生物体自身分子上起作用的进化机制。解析体细胞突变如何增加抗体基因亲和力的结构机制对于理解免疫库的进化至关重要。下一代测序（NGS）使得对病毒病原体（如 HIV-1）的抗体克隆谱系进行重建成为可能，而这在以前的亲和力成熟研究中是不可能的。来自这些谱系与靶抗原结合的抗体的晶体结构在原子水平上揭示了抗体如何进化以穿透包膜糖蛋白的聚糖屏蔽，以及病毒如何进化以逃避中和。总之，亲和力成熟的结构研究表明，抗体亲和力的增加可以来自任何一种或多种不同机制的组合，包括与抗原结合界面的形状互补性提高、复合物形成时埋藏表面积增加、额外的界面极性或疏水性相互作用以及抗原结合位点的预组织或刚性化。
