Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity

J Exp Med. 2013 Jan 14;210(1):125-42. doi: 10.1084/jem.20120525. Epub 2012 Dec 24.

Abstract

The important subtleties of B cell tolerance are best understood in a diverse immunoglobulin (Ig) repertoire context encoding a full spectrum of autoreactivity. To achieve this, we used mice expressing Igκ transgenes that confer varying degrees of autoreactivity within a diverse heavy chain (HC) repertoire. These transgenes, coupled with a biomarker to identify receptor-edited cells and combined with expression cloning of B cell receptors, allowed us to analyze tolerance throughout B cell development. We found that both the nature of the autoantigen and the Ig HC versus light chain (LC) contribution to autoreactivity dictate the developmental stage and mechanism of tolerance. Furthermore, although selection begins in the bone marrow, over one third of primary tolerance occurs in the periphery at the late transitional developmental stage. Notably, we demonstrate that the LC has profound effects on tolerance and can lead to exacerbated autoantibody production.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • B-Lymphocytes / immunology*
  • Bone Marrow Cells / immunology
  • Immune Tolerance / immunology*
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology
  • Immunoglobulin Light Chains / genetics
  • Immunoglobulin Light Chains / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, B-Cell / immunology

Substances

  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Receptors, Antigen, B-Cell