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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.

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


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.


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

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