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

Abstract

In response to encounter with self-Ag, autoreactive B cells may undergo secondary L chain gene rearrangement (receptor editing) and change the specificity of their Ag receptor. Knowing at what differentiative stage(s) developing B cells undergo receptor editing is important for understanding how self-reactive B cells are regulated. In this study, in mice with Ig transgenes coding for anti-self (DNA) Ab, we report dsDNA breaks indicative of ongoing secondary L chain rearrangement not only in bone marrow cells with a pre-B/B cell phenotype but also in immature/transitional splenic B cells with little or no surface IgM (sIgM−/low). L chain-edited transgenic B cells were detectable in spleen but not bone marrow and were still found to produce Ab specific for DNA (and apoptotic cells), albeit with lower affinity for DNA than the unedited transgenic Ab. We conclude that L chain editing in anti-DNA-transgenic B cells is not only ongoing in bone marrow but also in spleen. Indeed, transfer of sIgM−/low anti-DNA splenic B cells into SCID mice resulted in the appearance of a L chain editor (Vλx) in the serum of engrafted recipients. Finally, we also report evidence for ongoing L chain editing in sIgMlow transitional splenic B cells of wild-type mice.

Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance

“…Finally, it could be argued that the lack of serum IgM in 2F5 V H +/+ mice is due to the 2F5 HCs inability to pair with LCs similar to the phenotype reported in κ+λ LC-deficient mice, which make no serum IgM but have detectable serum IgG composed of HC dimers (35) gized through receptor engagement (29,30). A similar IgM lo phenotype has also been described in splenic transitional B cells in the various 3H9 mouse lines (21,23,25,26,28), reflecting frequent anergic B cells, or alternatively, cells that have undergone LC editing (28,36,37). Interestingly, 2F5 V H +/+ mature B cells also exhibit lower sIgM densities, similar to anergic anti-Sm transgenic mature B cell fractions (38).…”

Regulation of the B Cell Receptor Repertoire and Self-Reactivity by BAFF

“…2B,C). These subsets have been reported as anergic self reactive B cells (Merrell et al, 2006; Kiefer et al, 2008). On the other hand, BAFF/3H9 mice had a lower proportion of CD93 hi B cells (2.0%) and 44.9% of these cells had a T2 phenotype (B220 + CD93 hi IgM high CD23 high ) (Fig.…”

“…Although Jκbias has been interpreted in the context of receptor editing, it is unclear if BAFF can act directly on editing-competent B cells because they respond poorly to BAFF and have little BAFF-R expression (Rolink et al, 2002; Hsu et al, 2002). Bosma and colleagues working with the 3H9-56R model have suggested that a small splenic B cell subset that they call T3′ might include autoreactive cells in the process of editing (Kiefer et al, 2008). T3′ cells had markers reminiscent of putative natural anergic B cells (T3 cells), though they lacked expression of CD23.…”

Accelerated progression of chronic lymphocytic leukemia in Eμ-TCL1 mice expressing catalytically inactive RAG1

“…33 Receptor editing initiated in response to autoantigen exposure is thought to occur primarily during the immature/transitional T1 stage of B-cell development. 34,35 We speculate that a stochastic mutation which impairs receptor editing induced in response to selfreactivity may enforce B-cell autoreactivity. Based on our previous work showing that dnRAG1 mice accumulate CD5 1 B cells without progressing to overt CLL, 12 we propose that autoreactivity enforced by a receptor editing defect could permit continued autoantigenic stimulation, and thereby promote sustained CD5 expression and persistence of a CD5 1 B-cell clone.…”