Elsevier

Seminars in Immunology

Volume 18, Issue 5, October 2006, Pages 305-317
Seminars in Immunology

Review
BAFF, APRIL and human B cell disorders

https://doi.org/10.1016/j.smim.2006.04.004Get rights and content

Abstract

B cells require signals from multiple sources for their development from precursor cells, and differentiation into effector cells. BAFF has been identified as a critical regulator of B cell development and differentiation. Defects in the production of BAFF and/or expression of its receptors have been associated with a diverse array of human immunopathologies characterised by perturbed B cell function and behaviour, including autoimmunity, malignancy, and immunodeficiency. This review will discuss the role of BAFF in the pathogenesis of these human immune disorders. It will also highlight relevant differences between the function of BAFF in humans and mice and the impact of this on the therapeutic utility of BAFF antagonists in the treatment of different human diseases.

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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