Functionally responsive self-reactive B cells of low affinity express reduced levels of surface IgM

Eur J Immunol. 2014 Apr;44(4):970-82. doi: 10.1002/eji.201344276. Epub 2014 Jan 20.


Somatic gene rearrangement generates a diverse repertoire of B cells, many which have receptors possessing a range of affinities for self-Ag. Newly generated B cells express high and relatively uniform amounts of surface IgM (sIgM), while follicular (FO) B cells express sIgM at widely varying levels. It is plausible, therefore, that downmodulation of sIgM serves as a mechanism to maintain weakly self-reactive B cells in a responsive state by decreasing their avidity for self-Ag. We tested this hypothesis by performing comparative functional tests with FO IgM(hi) and IgM(lo) B cells from the unrestricted repertoire of WT C57BL/6 mice. We found that FO IgM(lo) B cells mobilized Ca(2+) equivalently to IgM(hi) B cells when the same number of sIgM molecules was engaged. In agreement, FO IgM(lo) B cells were functionally competent to produce an antibody response following adoptive transfer. The FO IgM(lo) cell population had elevated levels of Nur77 transcript, and was enriched with nuclear-reactive specificities. Hybridoma sampling revealed that these B-cell receptors were of low affinity. Collectively, these results suggest that sIgM downmodulation by low-affinity, self-reactive B cells preserves their immunocompetence and circumvents classical peripheral tolerance mechanisms that would otherwise reduce diversity within the B cell compartment.

Keywords: B-cell development; Immunocompetence; sIgM down-modulation; self-reactivity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology
  • Antibodies, Antinuclear / metabolism
  • Autoantibodies / immunology*
  • Autoantibodies / metabolism
  • Autoantigens / immunology*
  • Autoantigens / metabolism
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Blotting, Western
  • Calcium / immunology
  • Calcium / metabolism
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Endocytosis / immunology
  • Flow Cytometry
  • Gene Expression / immunology
  • Immunoglobulin M / immunology*
  • Immunoglobulin M / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / immunology
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Receptors, Antigen, B-Cell / immunology
  • Receptors, Antigen, B-Cell / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism


  • Antibodies, Antinuclear
  • Autoantibodies
  • Autoantigens
  • Immunoglobulin M
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Antigen, B-Cell
  • Calcium