BAFF and selection of autoreactive B cells - PubMed (original) (raw)
Review
BAFF and selection of autoreactive B cells
Zheng Liu et al. Trends Immunol. 2011 Aug.
Abstract
B cell activating factor (BAFF) is a crucial survival factor for transitional and mature B cells, and is a promising therapeutic target for systemic lupus erythematosus (SLE). A BAFF inhibitor, belimumab, is the first new drug in 50 years to be approved for the treatment of SLE. However, the mechanism of action of this drug is not entirely clear. In this review we will focus on the role of the BAFF-APRIL signaling pathway in the selection of autoreactive B cells, and discuss whether altered selection is the mechanism for the therapeutic efficacy of BAFF inhibition in SLE.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Figures
Figure 1
The effects of various factors on the negative selection of autoreactive B cells: The fate of autoreactive B cells is determined by the strength of the BCR signal induced by self antigens and is different for early transitional and antigen activated mature B cells. A. In immature bone marrow cells and early transitional B cells, if the strength of the BCR signal reaches a certain threshold (purple dashed line), autoreactive B cells are eliminated through deletion or anergy (grey area); otherwise they continue to differentiate into mature cells. Diminished BCR signals associated with genetic variants of PTPN22 or BLK increase the threshold for elimination (red dashed line), allowing more autoreactive B cells to escape immune tolerance. Conversely, enhanced BCR signals conferred by upregulation of CD19, or augmented TLR signals, may lower the threshold for elimination (green dashed line), leading to more stringent regulation of autoreactive B cells. *BAFF appears to have little role in the bone marrow but regulates the threshold for selection of early transitional B cells in the directions shown. B. In antigen activated mature B cells the threshold for deletion of autoreactive B cells is increased (red dashed line) by a number of factors such as increased T cell help and costimulation, enhanced BCR signals via CD19 upregulation, increased TLR signals, or impaired negative signals mediated through FcγRIIB and CD22, leading to differentiation of autoreactive effector cells. Further studies are needed to investigate the role of BAFF in tolerance of antigen activated autoreactive B cells.
Figure 2
The BAFF–APRIL family and their receptors: BAFF can be expressed by a wide range of cells including B and T cells, neutrophils, macrophages, other myeloid cells, stroma l cells as a type II transmembrane protein that is cleaved by a furin protease to yield soluble homotrimers. BAFF is also expressed on the cell membrane as an alternatively spliced form missing 57 bp (ΔBAFF) that is inefficiently cleaved from the cell surface, does not bind receptors and limits BAFF availability by forming heterotrimers with full length BAFF [67]. BAFF and APRIL can heterotrimerize; small amounts of heterotrimers are found in the sera of patients with autoimmune diseases [68]. APRIL, like BAFF, is expressed by multiple cell types and even some tumor cells. APRIL is expressed on the cell membrane if it is fused to the transmembrane and cytoplasmic portion of TWEAK (TWE-PRIL) [69]. Other splice variants of various family members and their receptors have been identified [–72]. Soluble BAFF can multimerize into a 20 trimer structure that is the preferential activating ligand for TACI and BMCA [73]. Similarly, APRIL is multimerized by binding to proteoglycans [19] and only the oligermeric form activates TACI [73]. TACI can also bind to proteoglycans such as syndecan [19]. Inhibitors block either BAFF alone or both BAFF and APRIL (see Table 2). Abbreviations: APRIL, A proliferation inducing ligand; BAFF, B cell activating factor belonging to the TNF family; TACI, Transmembrane activator and calcium modulator ligand interactor; BCMA, B cell maturation antigen; BAFF-R, BAFF receptor; HSPG, heparan sulfate proteoglycan. Abbreviations: APRIL, A proliferation inducing ligand; BAFF, B cell activating factor belonging to the TNF family; TACI, Transmembrane activator and calcium modulator ligand interactor; BCMA, B cell maturation antigen; BAFF-R, BAFF receptor; HSPG, heparan sulfate proteoglycan.
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