ReviewBAFF, APRIL and human B cell disorders
Section snippets
Overview
The generation of the mature B cell pool involves the step-wise development of hematopoietic stem cells into pro-B cells, which mature into pre-B cells and then immature B cells [1], [2], [3]. Immature B cells are then exported to the periphery as transitional B cells which undergo further selection and developmental events, represented as discrete subsets of transitional cells (type 1 [T1], type 2 [T2], type 3 [T3]) to yield mature B cells [4], [5]. When mature B cells encounter T-cell
BAFF: B cell activating factor belonging to the TNF family
BAFF (also known as BLyS, TALL-1, zTNF4, THANK; TNFSF13B) was independently identified in 1999 by several research groups based on its homology to the TNF superfamily [13], [14], [15], [16]. BAFF exhibits greatest homology to another member of the TNF family, a proliferation-inducing ligand (APRIL) [17]. BAFF is produced predominantly by myeloid cells (monocytes, macrophages, DCs, astrocytes) [18], [19], [20], [21] and neutrophils [22], [23]. The amount of BAFF produced in vitro can be
B cell survival
Initial studies found that treating mice with BAFF increased the numbers of splenic B cells, particularly transitional B cells, and enhanced humoral immune responses to both T-cell independent (TI) and TD Ag [14], [31], [32]. Consistent with this was the ability of BAFF to augment proliferation and Ig secretion by B cells activated through the B cell receptor (BcR) [13], [14] (Fig. 2). Although early studies proposed that BAFF improved B cell responses by acting as a co-stimulator of
Identification and expression of BAFF receptors
BAFF binds three receptors, which all belong to the TNF-R superfamily—BAFF receptor (BAFF-R/BR3) [64], [65], transmembrane activator of and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), and B cell maturation antigen (BCMA) [60], [61], [66], [67], [68]; the latter two receptors also bind APRIL.
The expression of BAFF receptors has been characterised by two approaches—first, soluble BAFF was used as a probe, which does not discriminate between expression of BAFF-R, TACI and
BAFF-R, TACI and BCMA have distinct functions on B cells
The functions of the different BAFF receptors, as well as of BAFF and APRIL, have been investigated by examining mice harbouring mutations in the genes encoding these molecules. Analysis of these strains has revealed that each receptor has a distinct role following interaction with BAFF (summarised in Table 1).
Aberrant expression of BAFF, APRIL and BAFF receptors in human disease
The findings that (a) BAFF Tg mice develop symptoms typical of several human autoimmune diseases, such as systemic lupus erythematosus (SLE) and Sjogren's syndrome (SjS) [58], [59], [60], [90], (b) the level of BAFF is elevated in the serum of autoimmune-prone mice [60], and (c) some BAFF Tg mice develop lymphomas [91] led to the suggestion that dysregulated expression and/or function of BAFF or its receptors may result in different human disease states. A wealth of information has been
Differences in the BAFF/APRIL system in humans and mice
Excessive production of BAFF in both humans and mice results in B cell mediated disease—consequently, the therapeutic utility of BAFF inhibitors is enormous, a fact that has not been underestimated by pharmaceutical companies. However, it is important to appreciate important differences that may exist between human diseases and murine models. Several of these are outlined below.
Conclusion
Since its discovery in 1999, a wealth of information regarding the role of BAFF in B cell development and differentiation has been reported. These findings have shed new light on some basic processes of immunology. More importantly, these studies have revealed potential mechanisms that underlie the pathogenesis of a diverse array of diseases characterised by perturbed B cell behaviour. With this knowledge, it should now be possible to improve treatment of antibody-mediated systemic autoimmune
Note added in proof
Since the submission of this review, another patient with CVID and a TACI mutation has been reported [133], while another study examining a BAFF neutralising mAb (Belimumab) also found that B-cell numbers in the lymphoid tissues of cynomolgus monkeys was reduced approximately two-fold when treated with this reagent for 26 weeks [134].
Acknowledgements
We thank Danielle Avery for providing the data presented in Fig. 2; VLB and KLG are recipients of Postgraduate Research Awards; SGT is the recipient of an RD Wright Career Development Award from the National Health and Medical Research Council (NHMRC) of Australia. Research performed in the Tangye Lab is supported by the NHMRC, Cancer Council New South Wales and the NSW Cancer Institute.
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