Autoreactive B Cell Receptors Mimic Autonomous Pre-B Cell Receptor Signaling and Induce Proliferation of Early B Cells

Abstract

The majority of early immature B cells express autoreactive B cell receptors (BCRs) that are, according to the current view, negatively selected to avoid the production of self-reactive antibodies. Here, we show that polyreactive BCRs, which recognize multiple self-antigens, induced autonomous signaling and selective expansion of B cell precursors in a manner comparable to the pre-BCR. We found that the pre-BCR was capable of recognizing multiple self-antigens and that a signaling-deficient pre-BCR lacking the non-Ig region of the surrogate-light-chain component lambda5 was rescued by the complementarity-determining region 3 derived from heavy chains of polyreactive receptors. Importantly, bone marrow B cells from mice carrying Ig transgenes for an autoreactive BCR showed increased cell-cycle activity, which could not be detected in cells lacking the transgenic BCR. Together, the pre-BCR has evolved to ensure self-recognition because autoreactivity is required for positive selection of B cell precursors.

Tolerance checkpoints in B‐cell development: Johnny B good

“…Whether this leakiness in tolerance induction is mediated directly by the pre-BCR, in that pre-B cells expressing an auto-reactive mH chains are deleted at the pre-BCR positive stage of development, or indirectly, by auto-reactive B cells escaping negative selection more readily in situations of reduced B-cell generation, as is the case in pre-BCR-deficient mice, is still open for clarification. However, the recent findings reported by Köhler et al [30] and van Loo et al [31] would, in our opinion, rather suggest that escape of auto-reactive B cells in surrogate light deficient mice is not directly mediated by the absence of the pre-BCR. Thus, Köhler et al showed that the pre-BCR is auto-reactive and is capable of recognizing multiple self-antigens [30].…”

“…However, the recent findings reported by Köhler et al [30] and van Loo et al [31] would, in our opinion, rather suggest that escape of auto-reactive B cells in surrogate light deficient mice is not directly mediated by the absence of the pre-BCR. Thus, Köhler et al showed that the pre-BCR is auto-reactive and is capable of recognizing multiple self-antigens [30]. This auto-reactivity seems to be mainly mediated by the non-Ig region of the surrogate light chain component l which corresponds to the same region previously shown to mediate cell autonomous pre-BCR signaling [32].…”

“…Recently it was shown that, despite the absence of obvious pathology, surrogate light chain deficient mice have elevated levels of IgG anti-nuclear auto-antibodies in their serum [16] [30]. This auto-reactivity seems to be mainly mediated by the non-Ig region of the surrogate light chain component l which corresponds to the same region previously shown to mediate cell autonomous pre-BCR signaling [32].…”

“…In mice lacking the surrogate light chain components, and thus unable to express the pre-BCR, this selection and expansion process fails to operate, resulting in the generation of fewer immature and mature B cells [1,[12][13][14]29]. Nevertheless, serum antibodies are at normal levels, and moreover, these mice are able to mount T-cell-dependent and -independent humoral immune responses [29].Recently it was shown that, despite the absence of obvious pathology, surrogate light chain deficient mice have elevated levels of IgG anti-nuclear auto-antibodies in their serum [16] [30]. This auto-reactivity seems to be mainly mediated by the non-Ig region of the surrogate light chain component l which corresponds to the same region previously shown to mediate cell autonomous pre-BCR signaling [32].…”

Highly Restricted Usage of Ig H Chain VH14 Family Gene Segments in Slp65-Deficient Pre-B Cell Leukemia in Mice

“…Furthermore, findings of interaction between the pre-BCR and galectin-1 (14) and binding of the non-Ig tail of l5 to stromal cell-associated heparan sulfate (15) would support this notion. The pre-BCR is polyreactive and capable of recognizing multiple (self-)Ags including DNA, LPS, and insulin, via the non-Ig tail of l5 (16). Thus, pre-BCR autoreactivity may serve to clonally expand those cells that produce a functional IgH m chain and ensures that this selection can occur in the absence of foreign Ags.…”