Widespread impact of immunoglobulin V-gene allelic polymorphisms on antibody reactivity
Meng Yuan,
Ziqi Feng,
Huibin Lv,
Natalie So,
Ivana R. Shen,
Timothy J.C. Tan,
Qi Wen Teo,
Wenhao O. Ouyang,
Logan Talmage,
Ian A. Wilson,
Nicholas C. Wu
Affiliations
Meng Yuan
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Ziqi Feng
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Huibin Lv
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
Natalie So
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Ivana R. Shen
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Timothy J.C. Tan
Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Qi Wen Teo
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
Wenhao O. Ouyang
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Logan Talmage
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Ian A. Wilson
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Nicholas C. Wu
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; Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Corresponding author
Summary: 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.
