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Front Immunol. 2018 Aug 10;9:1784. doi: 10.3389/fimmu.2018.01784. eCollection 2018.

Combined Influence of B-Cell Receptor Rearrangement and Somatic Hypermutation on B-Cell Class-Switch Fate in Health and in Chronic Lymphocytic Leukemia.

Author information

1
The Wellcome Sanger Institute, Hinxton, United Kingdom.
2
Department of Medicine, Division of Infectious Diseases, Imperial College London, London, United Kingdom.
3
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
4
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

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 isotype-resolved 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.

KEYWORDS:

B cells; B-cell receptor seq; chronic lymphocytic leukemia; isotype switching; repertoire analysis

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