B lymphocytes may escape tolerance by revising their antigen receptors.

Abstract

SlllllmsryTo explore mechanisms that prevent autoreactivity in nonautoimmune mice, endogenous immunoglobulin (Ig) light (L) chains that associate with a transgenic anti-DNA heavy chain were analyzed. The antibodies from splenic B cell hybridomas of such mice did not bind doublestranded DNA (dsDNA) and their L chain sequences showed a biased use of V~ and J~ gene segments. The 44 L chains in this survey were coded for by just 18 germline genes. Six of the genes, each belonging to a different V~ group, were used more than once and accounted for three fourths of all sequences. Based on the distribution of V~ genes, the L chain repertoire in this line of transgenic mice was estimated at 37 V~ genes. The most frequently observed gene, a member of the V~ 12/13 group, was identified in 16 hybrids. In addition, the majority of V~ genes used J~5. We interpret the skewed representation of V~ and J~ gene segments to result from negative selection. Based on the data, we suggest that V~ rearrangements giving rise to anti-dsDNA reactivity are removed from the repertoire by a corrective mechanism capable of editing self-reactive Ig.T olerance to self has been studied in Ig transgenic models of autoreactivity. By using Ig transgenes against facultative self-antigens, it has been shown that self-reactive B cells are selected against by anergy or deletion (1, 2). We have constructed mice with transgenes that code for anti-DNA antibodies and obtained similar results. The majority of splenic B lymphocytes from mice with the V,3H9 and V~8 genes express anti-single-stranded DNA (ssDNA) 1 antibodies on their surface, but we do not detect them in the serum (3). By analogy to Goodnow et al. (1), anti-ssDNA B cells in those mice appear to be anergic.Analysis of splenic B cells from mice containing just the V,3H9 transgene suggested a second feature of tolerance to DNA. No anti-double-stranded DNA (dsDNA) activity was detected among hybridomas from these mice. This was surprising, since previous studies have established that the 3H9 H chain can combine with a diverse range of L chains to yield antibodies capable of binding to both ssDNA and dsDNA (4, 5). The absence of hybrids producing anti-dsDNA suggested that dsDNA-spedfic B cells are functionally deleted.Nevertheless, V.3H9 mice have near normal numbers of splenic B cells, and hybridomas can be readily obtained (3). Some of the antibodies produced by these hybridomas bound ssDNA, whereas others did not bind DNA at all. We have now examined the V~ and J~ gene segment use of hybrids obtained from two of these mice. The mAbs were characterized by a sharply reduced repertoire of L chains. L chains that are found among spontaneous anti-DNA antibodies from MLR/lpr (4) or NZB x NZW (6) mice were absent from our sample. In addition, J~5 was overutilized. The data suggested that the major driving force shaping the L chain use in V.3H9 mice is selection against dsDNA-binding B cells. Furthermore, the data are consistent with the notion that B cells can escape deletion if their autoreactive surf...

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].…”

“…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].…”

“…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.…”

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

“…D eveloping bone marrow (BM) 4 B cells that are strongly autoreactive may avoid elimination by changing the specificity of their Ag receptor (1)(2)(3). This process is referred to as receptor editing and usually involves secondary L chain gene rearrangement and expression of a new or additional L chain (4,5).…”

“…This process is referred to as receptor editing and usually involves secondary L chain gene rearrangement and expression of a new or additional L chain (4,5). L chain editing was first demonstrated in mice containing Ig transgenes (tgs) that code for Abs with anti-self specificity (1)(2)(3). Subsequent studies have indicated that L chain editing may occur frequently and help shape the Ab repertoire (6,7).…”