Receptor editing: an approach by autoreactive B cells to escape tolerance.

TLDR

The anti‑double‑stranded DNA antibody studied was isolated from a diseased MRL/lpr mouse and typifies spontaneously arising anti‑DNA antibodies. The authors aimed to determine the fate of anti‑DNA antibody‑bearing B cells in normal mice. They generated transgenic mice carrying the heavy and light chain genes of the antibody to track its expression. In these mice, the transgenic heavy chain is expressed with restricted endogenous light chains that replace the transgenic light chain, allowing B cells to survive deletion and demonstrating that receptor editing enables autoreactive B cells to escape tolerance.

Abstract

To determine the fate of anti-DNA antibody-bearing B cells in normal mice, we generated transgenic mice bearing the heavy (H) and light (L) chain genes of a well-characterized anti-double-stranded DNA antibody. This antibody was originally isolated from a diseased MRL/lpr mouse and has characteristics common to spontaneously arising anti-DNA antibodies. Results show that the H/L transgene (tg) immunoglobulin receptor is not expressed by animals bearing both tgs, although single tg animals (H or L) express their transgenes. Young H/L tg animals express few B cells, whereas adult H/L tg animals maintain almost normal B cell numbers. Analysis of the immunoglobulin receptors used by adult B cells shows that all contain the tg H chain in association with endogenous L chains. These B cells transcribe the L tg as well as the rearranged endogenous L chain gene, and loss of endogenous L chain gene transcription results in resurrection of the 3H9 H/L tg product. Examination of the endogenous L chains used by these cells shows that they represent a highly restricted subset of V genes. Taken together, these data suggest that autoreactive transgenic B cells can rearrange endogenous L chain genes to alter surface receptors. Those L chains that compete successfully with the L tg for H chain binding, and that create a nonautoreactive receptor, allow the B cell to escape deletion. We suggest that this receptor editing is a mechanism used by immature autoreactive B cells to escape tolerance.