Combined influence of B-cell receptor rearrangement and somatic hypermutation on B-cell class-switch fate in health and in chronic lymphocytic leukaemia
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
A diverse B-cell receptor (BCR) repertoire is required to bind a wide range of antigens.
BCRs are generated through genetic recombination and can be diversified through
somatic hypermutation (SHM) or class-switch recombination (CSR). Patterns of repertoire
diversity can vary substantially between different health conditions. We use isotyperesolved
BCR sequencing to compare B-cell evolution and class-switch fate in healthy
individuals and in patients with chronic lymphocytic leukemia (CLL). We show that the
patterns of SHM and CSR in B-cells from healthy individuals are distinct from CLL. We
identify distinct properties of clonal expansion that lead to the generation of antibodies
of different classes in healthy, malignant, and non-malignant CLL BCR repertoires. We
further demonstrate that BCR diversity is affected by relationships between antibody
variable and constant regions leading to isotype-specific signatures of variable gene
usage. This study provides powerful insights into the mechanisms underlying the evolution
of the adaptive immune responses in health and their aberration during disease.
BCRs are generated through genetic recombination and can be diversified through
somatic hypermutation (SHM) or class-switch recombination (CSR). Patterns of repertoire
diversity can vary substantially between different health conditions. We use isotyperesolved
BCR sequencing to compare B-cell evolution and class-switch fate in healthy
individuals and in patients with chronic lymphocytic leukemia (CLL). We show that the
patterns of SHM and CSR in B-cells from healthy individuals are distinct from CLL. We
identify distinct properties of clonal expansion that lead to the generation of antibodies
of different classes in healthy, malignant, and non-malignant CLL BCR repertoires. We
further demonstrate that BCR diversity is affected by relationships between antibody
variable and constant regions leading to isotype-specific signatures of variable gene
usage. This study provides powerful insights into the mechanisms underlying the evolution
of the adaptive immune responses in health and their aberration during disease.
Date Issued
2018-08-10
Date Acceptance
2018-07-19
Citation
Frontiers in Immunology, 2018, 9
ISSN
1664-3224
Publisher
Frontiers Media
Journal / Book Title
Frontiers in Immunology
Volume
9
Copyright Statement
© 2018 Petrova, Muir, McKay, Vassiliou, Smith, Lyons, Russell, Anderson, Kellam and Bashford-Rogers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Sponsor
Wellcome Trust
Grant Number
093724/C/10/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
B-cell receptor seq
chronic lymphocytic leukemia
isotype switching
B cells
repertoire analysis
IMMUNOGENETICS INFORMATION SYSTEM(R)
ANTIGEN RECEPTORS
IN-VIVO
REPERTOIRES
EXPRESSION
MUTATIONS
RESPONSES
INDICATE
SUBSETS
IMGT(R)
Publication Status
Published
Article Number
ARTN 1784
Date Publish Online
2018-08-10