Enforced expression of Bcl-2 selectively perturbs negative selection of dual reactive antibodies

Dev Immunol. 2001;8(3-4):223-34. doi: 10.1155/2001/83595.

Abstract

We investigated the role of apoptosis in the development of B cell memory by analyzing the (p-azophenylarsonate) Ars response in a line of A strain mice in which expression of human Bcl-2 was enforced in the B cell compartment. Previous studies of the Ars immune response in these A. Bcl-2 mice, demonstrated that a large percentage of the antibodies expressed by the Ars induced memory B cell compartment had accumulated point mutations via somatic hypermutation that increased their affinity for both Ars and the autoantigen DNA ("dual reactive" antibodies). This was in sharp contrast to normal A strain mice which displayed no dual reactive B cells in their Ars induced memory B cell compartment. These data suggested that interference with apoptotic pathways regulated by Bcl-2 allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. Further studies of these mice, reported here, demonstrate that enforced expression of Bcl-2 does not alter serum antibody affinity maturation nor positive selection of B cells expressing somatically mutated antibody with an increased affinity for Ars. Moreover, the somatic hypermutation process was unaffected in A. Bcl-2 mice. Thus, enforced expression of Bcl-2 in A. Bcl-2 mice appears to selectively alter a negative selection process that operates during memory B cell differentiation.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / immunology*
  • Antibodies, Antinuclear / immunology
  • Antibody Affinity
  • Autoimmunity
  • B-Lymphocytes / immunology*
  • Base Sequence
  • Clonal Deletion*
  • DNA / immunology
  • Gene Expression
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Variable Region / genetics
  • Immunologic Memory
  • Mice
  • Mice, Inbred A
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Somatic Hypermutation, Immunoglobulin
  • Spleen / cytology
  • Spleen / immunology
  • p-Azobenzenearsonate / immunology*

Substances

  • Antibodies
  • Antibodies, Antinuclear
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Proto-Oncogene Proteins c-bcl-2
  • p-Azobenzenearsonate
  • DNA