Receptor Editing Can Lead to Allelic Inclusion and Development of B Cells That Retain Antibodies Reacting with High Avidity Autoantigens

Abstract

Receptor editing is a major B cell tolerance mechanism that operates by secondary Ig gene rearrangements to change the specificity of autoreactive developing B cells. In the 3-83Igi mouse model, receptor editing operates in every autoreactive anti-H-2Kb B cell, providing a novel receptor without additional cell loss. Despite the efficiency of receptor editing in generating nonautoreactive Ag receptors, we show in this study that this process does not inactivate the autoantibody-encoding gene(s) in every autoreactive B cell. In fact, receptor editing can generate allelically and isotypically included B cells that simultaneously express the original autoreactive and a novel nonautoreactive Ag receptors. Such dual Ab-expressing B cells differentiate into transitional and mature B cells retaining the expression of the autoantibody despite the high avidity interaction between the autoantibody and the self-Ag in this system. Moreover, we find that these high avidity autoreactive B cells retain the autoreactive Ag receptor within the cell as a consequence of autoantigen engagement and through a Src family kinase-dependent process. Finally, anti-H-2Kb IgM autoantibodies are found in the sera of older 3-83Igi mice, indicating that dual Ab-expressing autoreactive B cells are potentially functional and capable of differentiating into IgM autoantibody-secreting plasma cells under certain circumstances. These results demonstrate that autoreactive B cells reacting with ubiquitous membrane bound autoantigens can bypass mechanisms of central tolerance by coexpressing nonautoreactive Abs. These dual Ab-expressing autoreactive B cells conceal their autoantibodies within the cell manifesting a superficially tolerant phenotype that can be partially overcome to secrete IgM autoantibodies.

Editing and escape from editing in anti-DNA B cells

“…7). Clearly, alternative explanations for the reduced levels of surface Ig in IgM a B cells may apply, e.g., L chain editing and/or surface Ig downregulation (7,11,26,27).…”

“…The autoreactive H/L combination escapes central tolerance and gains access to the periphery because, we presume, the nonautoreactive H/L pair dilutes the expression of the autoreactive pair. Since we discovered this type of partially edited B cell, many examples of allelic or isotypic inclusion have been observed (15,(22)(23)(24)(25), including additional transgenic (Tg)-encoded autoreactivities (26,27) and autoreactivities present within an unperturbed repertoire (11,28). Such B cells have been referred to as ''Trojan horses'' and may, if activated in the periphery, pose a risk of autoimmunity.…”

Tolerance checkpoints in B‐cell development: Johnny B good

“…In fact, it has recently been shown that about half the peripheral mature B cells derived from immature B cells that had undergone receptor editing express two IgL chains [62]. Moreover, several studies have indicated that dual IgL chain expressing auto-reactive immature B cells can escape deletion by being positively selected by the non-auto-reactive IgL and IgH chain combination [63][64][65]. …”

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

“…However, and in contrast with this previous report, more than a half of included ͞ B cells showed a mature follicular phenotype (CD23 high ͞CD21 int ) and demonstrated that such cells are not necessarily trapped in the MZ. It has also been hypothesized that dual BCR expression resulted from receptor editing of an autoreactive primary Ig HC͞LC combination (22,23,25,26). In such models of LC inclusion, the expression of multiple antigen receptors was thought to dilute the autoreactive BCR and permit autoreactive cells to escape deletion.…”

“…Receptor editing also occurs in normal mice during the selection of immature B cells and may be a major pathway of tolerance induction by rescuing cells with autoreactive BCR from deletion (or anergy) provided that they express a new receptor (20,21). Nevertheless, this editing process intrinsically bears the risk of generating B cell clones that will migrate toward peripheral lymphoid organs while carrying dual or multiple antigen receptors, one of those potentially being autoreactive (22)(23)(24)(25)(26). Moreover, autoreactivity may not be the only way to promote receptor editing because some non-autoreactive knockin mice also showed extensive secondary rearrangements, likely due to a low expression of the knockin gene (27,28).…”