Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreactive B cells

J Exp Med. 2003 Oct 6;198(7):1119-26. doi: 10.1084/jem.20030411. Epub 2003 Sep 29.

Abstract

During development, the stochastic process assembling the genes encoding antigen receptors invariably generates B and T lymphocytes that can recognize self-antigens. Several mechanisms have evolved to prevent the activation of these cells and the concomitant development of autoimmune disease. One such mechanism is the induction of apoptosis in developing or mature B cells by engagement of the B cell antigen receptor (BCR) in the absence of T cell help. Here we report that B lymphocytes lacking the pro-apoptotic Bcl-2 family member Bim are refractory to apoptosis induced by BCR ligation in vitro. The loss of Bim also inhibited deletion of autoreactive B cells in vivo in two transgenic systems of B cell tolerance. Bim loss prevented deletion of autoreactive B cells induced by soluble self-antigen and promoted accumulation of self-reactive B cells developing in the presence of membrane-bound self-antigen, although their numbers were considerably lower compared with antigen-free mice. Mechanistically, we determined that BCR ligation promoted interaction of Bim with Bcl-2, inhibiting its survival function. These findings demonstrate that Bim is a critical player in BCR-mediated apoptosis and in B lymphocyte deletion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / immunology
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Autoantigens / immunology
  • B-Lymphocytes / immunology*
  • Bcl-2-Like Protein 11
  • Carrier Proteins / physiology*
  • Lymphocyte Depletion
  • Membrane Proteins*
  • Mice
  • Mice, Inbred C57BL
  • Muramidase / immunology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins*
  • Receptors, Antigen, B-Cell / physiology*

Substances

  • Antibodies, Anti-Idiotypic
  • Apoptosis Regulatory Proteins
  • Autoantigens
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Carrier Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, B-Cell
  • anti-IgM
  • hen egg lysozyme
  • Muramidase