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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / pathology
  • Gene Rearrangement, B-Lymphocyte*
  • Humans
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin Isotypes / genetics
  • Immunoglobulin Joining Region / genetics
  • Immunoglobulin Variable Region / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Multigene Family
  • Receptors, Antigen, B-Cell / genetics*
  • Somatic Hypermutation, Immunoglobulin*


  • Immunoglobulin Isotypes
  • Immunoglobulin Joining Region
  • Immunoglobulin Variable Region
  • Receptors, Antigen, B-Cell