Tolerance checkpoints in B‐cell development: Johnny B good

Abstract

B-cell development up to the immature B-cell stage takes place in the bone marrow, while final maturation into mature B cells occurs in the spleen. During differentiation, the precursor and immature B cells have to pass several checkpoints, including those in which they are censored for being auto-reactive, and therefore being potentially dangerous. Numerous studies have shown that the immature B-cell stage in the bone marrow and the transitional B-cell stages in the spleen comprise distinct checkpoints at which autoreactivity is censored. Recently, evidence has been provided that the large pre-BII stage in the bone marrow, at which the pre-BCR is expressed, is yet another B-cell tolerance checkpoint. Here, we review these findings and speculate on directions for possible further experimentation.Key words: B cells . Negative selection . Positive selection . Receptor editing . Tolerance Introduction B-cell development, as it takes place in the bone marrow and spleen, can be subdivided into various stages based on the expression of different cell-surface and intra-cellular markers, the cell cycle profile and the rearrangement status of the cell's Ig-heavy (IgH) and Ig-light (IgL) chains [1][2][3][4]. In Fig. 1, the different stages of B-cell development in the bone marrow and spleen and the most important cell-surface markers by which different subpopulations can be distinguished are depicted. Moreover, the stages in which censoring for auto-reactivity takes place are shown in gray.The earliest B-lineage cell type found in the bone marrow is the pro/pre-BI cell. This cell type is characterized by the expression of CD19 and CD117 (c-kit) and the IgH chain loci are in a rearranged D-J configuration [4][5][6]. Under physiological conditions, these cells are already committed to the B-cell lineage. However, their commitment can be reversed by the ablation of the B-cell identity gene Pax5 [7][8][9]. Pro/pre-BI cells are the direct precursors of large pre-BII cells, which have lost CD117 expression and gained the expression of CD25 [3]. At this stage of differentiation, the IgH chain loci are V to D-J rearranged and those that have done this successfully (synthesized a m-heavy (mH) chain) are positively selected within this compartment. This positive selection is mediated by the pre-BCR, which is composed of the mH chain and the surrogate light chain proteins . Moreover, the pre-BCR induces a strong proliferation of these positively selected pre-B cells [12,13]. A very recent report indicates that the pre-BCR might also be involved in the censoring of B-cell auto-reactivity [16]. These findings will be discussed in the section Large pre-BII cells.Pre-BCR signaling down-modulates transcription of the surrogate light chain genes , and thereby extinguishes its own expression. Upon down-modulation of surface pre-BCR expression, cells stop proliferating and enter the small pre-BII compartment [3]. At this developmental stage, [18][19][20]. It is at this stage of development that, for the first time, cells are censored for t...

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

“…Even though this in itself is not sufficient to tip the balance to overt autoimmunity, it could potentially result in the production of pathogenic autoantibodies. In current models of B-cell development, some degree of autoreactivity displayed by the pre-BCR appears to be critical for downstream signalling events at the pre-B-cell stage [24][25][26][27]51 . This is provided by the l5-tail that interacts with molecules on stromal cells and with neighbouring mH chains 24,26,52,53 .…”

“…A characteristic of a majority of anti-DNA and ANAs is a H-CDR3 with one, or more, basic amino acid (aa) residues (ANA H-CDR3) that is critical to antigen binding 15,21 . Also the non-Ig portion of l5 (l5-tail) contains basic amino acid residues that are critical to pre-BCR signalling [24][25][26][27] . Moreover, some of the pre-B cells that develop in both mice and humans with a dysfunctional SL chain 28,29 express mH chains characterized by a prototypic ANA H-CDR3 (refs 24,25).…”

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease–associated dysgammaglobulinemia

“…39 A first checkpoint for the detection and elimination of such autoreactive B cells represents the pre-B-cell receptor stage, at which surrogate lightchain facilitated B-cell receptor signaling contributes to censoring the development of autoantibody-producing cells. 40,41 Immature B cells migrate to the periphery at the transitional B-cell stage, when they are still short-lived and functionally immature. Besides the immature B-cell stage, in the BM the transition between newly emigrant and mature B cells in the periphery is a checkpoint for selection against autoreactive antibodies in humans.…”

Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

“…In autoimmunity, probably the most important effector action of B cells is the production of autoantibodies by plasma cells that have evaded the self-tolerance check points [38]. Although in some neurological diseases autoantibodies are directly pathogenic [i.e., antiacetylcholine receptor (AChR) in myasthenia gravis (MG), antimyelin-associated glycoprotein (MAG) in IgM paraproteinemic neuropathy, anti-N-methyl-D-aspartate receptor (NMDAR) in limbic encephalitis, antiaquaporin 4 (AQP4) in neuromyelitis optica (NMO)], in most others autoantibodies [like those seen in paraneoplastic neuropathies, multifocal motor neuropathy, or stiff person syndrome (SPS)] do not exert a direct effect on self-antigens and may only be disease markers.…”