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Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires.

Authors :
DeKosky, Brandon J.
Lungu, Oana I.
Daechan Park
Johnson, Erik L.
Charab, Wissam
Chrysostomou, Constantine
Kuroda, Daisuke
Ellington, Andrew D.
Ippolito, Gregory C.
Gray, Jeffrey J.
Georgiou, George
Source :
Proceedings of the National Academy of Sciences of the United States of America; 5/10/2016, Vol. 113 Issue 19, pE2636-E2645, 10p
Publication Year :
2016

Abstract

Elucidating how antigen exposure and selection shape the human antibody repertoire is fundamental to our understanding of B-cell immunity. We sequenced the paired heavy- and light-chain variable regions (VH and VL, respectively) from large populations of single B cells combined with computational modeling of antibody structures to evaluate sequence and structural features of human antibody repertoires at unprecedented depth. Analysis of a dataset comprising 55,000 antibody clusters from CD19<superscript>+</superscript>CD20<superscript>+</superscript>CD27<superscript>-</superscript> IgM-naive B cells, >120,000 antibody clusters from CD19<superscript>+</superscript>CD20<superscript>+</superscript>CD27<superscript>+</superscript> antigen- experienced B cells, and >2,000 RosettaAntibody-predicted structural models across three healthy donors led to a number of key findings: (i) VH and VL gene sequences pair in a combinatorial fashion without detectable pairing restrictions at the population level; (ii) certain VH:VL gene pairs were significantly enriched or depleted in the antigen-experienced repertoire relative to the naive repertoire; (iii) antigen selection increased antibody paratope net charge and solvent-accessible surface area; and (iv) public heavy-chain third complementarity-determining region (CDR-H3) antibodies in the antigen-experienced repertoire showed signs of convergent paired light-chain genetic signatures, including shared light-chain third complementarity-determining region (CDR-L3) amino acid sequences and/or Vκ,λ-Jκ,λ genes. The data reported here address several longstanding questions regarding antibody repertoire selection and development and provide a benchmark for future repertoire-scale analyses of antibody responses to vaccination and disease. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
113
Issue :
19
Database :
Complementary Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
115316921
Full Text :
https://doi.org/10.1073/pnas.1525510113