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Public Baseline and shared response structures support the theory of antibody repertoire functional commonality

The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for th...

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Autores principales: Raybould, Matthew I. J., Marks, Claire, Kovaltsuk, Aleksandr, Lewis, Alan P., Shi, Jiye, Deane, Charlotte M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951972/
https://www.ncbi.nlm.nih.gov/pubmed/33647011
http://dx.doi.org/10.1371/journal.pcbi.1008781
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author Raybould, Matthew I. J.
Marks, Claire
Kovaltsuk, Aleksandr
Lewis, Alan P.
Shi, Jiye
Deane, Charlotte M.
author_facet Raybould, Matthew I. J.
Marks, Claire
Kovaltsuk, Aleksandr
Lewis, Alan P.
Shi, Jiye
Deane, Charlotte M.
author_sort Raybould, Matthew I. J.
collection PubMed
description The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared (‘public’) antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve (‘baseline’) antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples (‘Public Baseline’ structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes (‘Public Response’ structures). We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening.
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spelling pubmed-79519722021-03-22 Public Baseline and shared response structures support the theory of antibody repertoire functional commonality Raybould, Matthew I. J. Marks, Claire Kovaltsuk, Aleksandr Lewis, Alan P. Shi, Jiye Deane, Charlotte M. PLoS Comput Biol Research Article The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared (‘public’) antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve (‘baseline’) antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples (‘Public Baseline’ structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes (‘Public Response’ structures). We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening. Public Library of Science 2021-03-01 /pmc/articles/PMC7951972/ /pubmed/33647011 http://dx.doi.org/10.1371/journal.pcbi.1008781 Text en © 2021 Raybould et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Raybould, Matthew I. J.
Marks, Claire
Kovaltsuk, Aleksandr
Lewis, Alan P.
Shi, Jiye
Deane, Charlotte M.
Public Baseline and shared response structures support the theory of antibody repertoire functional commonality
title Public Baseline and shared response structures support the theory of antibody repertoire functional commonality
title_full Public Baseline and shared response structures support the theory of antibody repertoire functional commonality
title_fullStr Public Baseline and shared response structures support the theory of antibody repertoire functional commonality
title_full_unstemmed Public Baseline and shared response structures support the theory of antibody repertoire functional commonality
title_short Public Baseline and shared response structures support the theory of antibody repertoire functional commonality
title_sort public baseline and shared response structures support the theory of antibody repertoire functional commonality
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951972/
https://www.ncbi.nlm.nih.gov/pubmed/33647011
http://dx.doi.org/10.1371/journal.pcbi.1008781
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