Positive selection of B cells expressing low densities of self-reactive BCRs

J Exp Med. 2004 Mar 15;199(6):843-53. doi: 10.1084/jem.20030955.

Abstract

B cell tolerance or autoimmunity is determined by selective events. Negative selection of self-reactive B cells is well documented and proven. In contrast, positive selection of conventional B cells is yet to be firmly established. Here, we demonstrate that developing self-reactive B cells are not always highly sensitive to the deletion mechanisms imposed by membrane-bound self-antigens. At low amounts, membrane-bound antigens allow survival of B cells bearing a single high affinity self-reactive B cell receptor (BCR). More importantly, we show that forced allelic inclusion modifies B cell fate; low quantities of self-antigen induce the selection and accumulation of increased numbers of self-reactive B cells with decreased expression of antigen-specific BCRs. By directly measuring antigen binding by intact B cells, we show that the low amounts of self-antigen select self-reactive B cells with a lower association constant. A fraction of these B cells is activated and secretes autoantibodies that form circulating immune complexes with self-antigen. These findings demonstrate that conventional B cells can undergo positive selection and that the fate of a self-reactive B cell depends on the quantity of self-antigen, the number of BCRs engaged, and on its overall antigen-binding avidity, rather than on the affinity of individual BCRs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • Autoimmunity*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / physiology*
  • Bromodeoxyuridine
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Immune Tolerance
  • Iodine Radioisotopes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muramidase / immunology
  • Muramidase / metabolism
  • Receptors, Antigen, B-Cell / immunology*
  • Receptors, Antigen, B-Cell / metabolism

Substances

  • Autoantigens
  • Iodine Radioisotopes
  • Receptors, Antigen, B-Cell
  • hen egg lysozyme
  • Muramidase
  • Bromodeoxyuridine