Bcl-2 obstructs negative selection of autoreactive, hypermutated antibody V regions during memory B cell development

Immunity. 1998 Feb;8(2):189-98. doi: 10.1016/s1074-7613(00)80471-9.

Abstract

We analyzed the participation of a predominant B cell clonotype in the anti-arsonate immune response of mice in which Bcl-2 expression was enforced in B cells. Many of the antibodies expressed by the arsonate-induced memory compartment of these mice were "dual-reactive," displaying increased affinity acquired via V region somatic hypermutation for both arsonate and the autoantigen DNA. The hypermutated antibodies expressed by the anti-arsonate memory B cell compartment of normal mice have increased affinity for arsonate but lack measurable affinity for DNA. Thus, interference with apoptotic pathways allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. These data demonstrate that both positive and negative selection, working in concert with V gene somatic hypermutation, result in the "specificity maturation" of the antibody response.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / genetics
  • Apoptosis
  • Autoimmunity / genetics*
  • B-Lymphocytes / immunology*
  • Cell Nucleus / pathology
  • Clonal Deletion*
  • Consensus Sequence
  • DNA / immunology
  • DNA, Single-Stranded / immunology
  • Haptens / immunology
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Variable Region / genetics
  • Immunologic Memory*
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Sequence Homology, Amino Acid
  • Spleen / cytology
  • Spleen / immunology
  • p-Azobenzenearsonate / immunology

Substances

  • Antibodies, Monoclonal
  • DNA, Single-Stranded
  • Haptens
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Proto-Oncogene Proteins c-bcl-2
  • p-Azobenzenearsonate
  • DNA