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

Abstract

SummaryTo 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/Ipr 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. B cells expressing autoreactive Ig receptors are thought to be negatively regulated through inactivation or deletion. Inactivation was observed by Pike and Nossal (reviewed in reference 1), who demonstrated that low doses of antigen could render B cells specifically unresponsive to antigen and mitogen stimulation. This type of tolerance was shown in amplified form using mice with transgenes (tgs) 1 coding for an anti-hen egg lysozyme (HEL) antibody (reviewed in reference 2). These mice, when crossed with mice with a tg coding for HEL, yielded double-tg progeny whose B cells were refractory to antigenic or mitogenic stimulation. Deletion was dramatically demonstrated using a tg system in which genes of an anti-H-2 k antibody were introduced into mice of the H-2 k haplotype (reviewed in reference 3). These mice showed a great reduction in B cell number and absence of the tg idiotype on the remaining peripheral B cells.These types of negative regulation operate at the cellular level through uncoupling signaling pathways or by initiating cell death. Another level at which regulation might occur 1Abbreviations used in this paper: ANA, anti-nuclear antigen; ds, double stranded; tg, transgene.is by changing the specificity of antiself receptors (4). Such "editing" might occur at the genetic level by replacing V genes coding for antiself receptors with V genes coding for "harmless" receptors. Mechanisms are available at both the H and L chain g loci for V gene replacement. Here we describe another way of editing receptors. In this case, the L ...

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

“…2B, bottom right panel). Immature 3-83 + B cells that encounter auto-antigen in the bone marrow continue L chain rearrangement, a process known as receptor editing [21,22]. This can be clearly seen in the syksufficient chimeras, when comparing non-deleting (H-2 d ) to deleting (H-2 k ) mice, where the fraction of Q + 3-83 -B cells increases to 4% (Fig.…”

Tolerance checkpoints in B‐cell development: Johnny B good

“…According to this hypothesis, recognition of foreign antigen by mature B cells induces clonal expansion and antibody secretion, and thus yields an antigen specific immune response and the induction of memory, whereas newly formed immature B cells with an auto-reactive receptor will die upon encounter with their auto-antigen. That death was inevitable for an immature B cell that had had its BCR triggered was challenged about 15 years ago by findings reported by Nemazee and colleagues [43] and Weigert and colleagues [44,45] and reviewed in [46,47]. The groups of Nemazee and Weigert independently showed that auto-reactive immature B cells upon encounter of their auto-antigen do not have to automatically die, but rather can eliminate their auto-reactive specificity and express a novel non-auto-reactive receptor by secondary V to D-J recombination events [43][44][45][46][47].…”

“…The groups of Nemazee and Weigert independently showed that auto-reactive immature B cells upon encounter of their auto-antigen do not have to automatically die, but rather can eliminate their auto-reactive specificity and express a novel non-auto-reactive receptor by secondary V to D-J recombination events [43][44][45][46][47]. This process of receptor revision was then called receptor editing [43][44][45][46][47]. Figure 2 shows a schematic representation of the various newly formed B cells in the bone marrow and which of them will be receptor edited.…”

“…That death was inevitable for an immature B cell that had had its BCR triggered was challenged about 15 years ago by findings reported by Nemazee and colleagues [43] and Weigert and colleagues [44,45] and reviewed in [46,47]. The groups of Nemazee and Weigert independently showed that auto-reactive immature B cells upon encounter of their auto-antigen do not have to automatically die, but rather can eliminate their auto-reactive specificity and express a novel non-auto-reactive receptor by secondary V to D-J recombination events [43][44][45][46][47]. This process of receptor revision was then called receptor editing [43][44][45][46][47].…”

CD25+ Treg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

“…The first checkpoint incapacitates B cells of high affinity to autoantigen in the bone marrow, by receptor editing [1,2] or central deletion [1][2][3][4]. Self-reactive low-affinity B cells enter the periphery and can constitute up to 5-20% of circulating mature B cells in healthy individuals [5,6].…”