The TNF family members BAFF and APRIL: the growing complexity

doi:10.1016/S1359-6101(03)00023-6

Cytokine & Growth Factor Reviews

Volume 14, Issues 3–4, June–August 2003, Pages 311-324

https://doi.org/10.1016/S1359-6101(03)00023-6 Get rights and content

Abstract

B cell activating factor belonging to the TNF family (BAFF) and apoptosis-inducing ligand (APRIL) are two related members of the TNF ligand superfamily. Although they share two receptors, TACI and BCMA, transgenic and knockout mice in this system reveal that their functions are not redundant. BAFF is a critical survival/maturation factor for peripheral B cells and this activity is mediated through a BAFF-specific receptor, BAFF-R. Overexpression of BAFF has been linked to autoimmune disease and aspects of B cell neoplasia. APRIL appears to play a role in T-independent type II antigen responses and T cell survival, but can also induce proliferation/survival of non-lymphoid cells. Elevated expression of APRIL has been found in some tumor cell lines and in tumor tissue libraries. Therapies designed to inhibit the BAFF and APRIL pathways holds great promise for the future.

Section snippets

The structure of BAFF and APRIL

B cell activating factor belonging to the TNF family (BAFF, also named BLyS, TALL-1, THANK, zTNF-4 and TNFSF-13B) and apoptosis-inducing ligand (APRIL also named TALL-2, TRDL-1 and TNFSF-13) are relatively new members of the TNF family of ligands [1], [2], [3], [4], [5], [6]. In the past few years, the biology of BAFF, in particular, has been widely studied and reviewed [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. TNF ligands are type II membrane proteins, but many of these

B cell survival, maturation and activation

Various in vitro assays revealed that addition of recombinant BAFF prolongs survival of B cells in culture [63], [64], [65]. Furthermore, injection of BCMA-Ig in mice used as a decoy, rapidly leads to B cell loss from all secondary lymphoid organs [36]. In contrast, in BAFF Tg mice, numbers of B cells were dramatically increased and levels of the pro-survival oncogene Bcl-2 were elevated in these cells [5], [19], [66]. These results indicated that BAFF acts as a powerful survival factor for B

BAFF signaling

The study of BAFF signaling is complicated by the fact that it binds three receptors and that B cells may express one or more of these receptors. A comprehensive study of receptor expression on the surface of all B cell types has not been published. Examination of the B cells from BAFF transgenic mice indicated that the anti-apoptotic factor, Bcl-2, was up-regulated, suggesting a mechanism for the B cell survival activity of BAFF [19]. Supporting this finding, it was shown that splenic B cells

Role in autoimmune disease

The maintenance of immune tolerance that prevents autoimmune responses relies, in part, on the strict control of lymphocyte survival. Dysregulated lymphocyte survival as seen in mice Tg for the survival oncogene Bcl-2 leads to autoimmune disorders [87]. Similar to Bcl-2 Tg mice, BAFF Tg mice have elevated numbers of B cells, secrete high levels of immunoglobulins, in particular autoantibodies such as rheumatoid factors, anti-double stranded and single stranded DNA, anti-histones and

Strategies for therapeutic intervention

The apparent role of BAFF in autoimmune disorders and cancer is accumulating and the development of reagents neutralizing BAFF is the main focus of several pharmaceutical laboratories. Experiments using mouse models of RA and SLE have already shown the protective effect of TACI-Ig treatment used as a BAFF/APRIL-neutralizing agent [5], [35], [105]. In the NZBWF1 lupus mouse model and the autoimmune mouse model MRL-lpr/lpr, mice have been shown to produce elevated levels of serum BAFF [5].

Conclusions and perspectives

In recent years, few ligand-receptor systems have received as much attention as the BAFF/APRIL system. The wealth of information recently accumulated on BAFF has enriched our understanding of B cell survival, maturation and homeostasis and the role played by BAFF in controlling these various functions. Some of the unique functions of BAFF are associated with the ability of this factor to trigger specific signalling pathways through BAFF-R, such as processing and activation of the NFκB-2

Acknowledgements

We thank Yen-Ming Hsu, Susan Kalled, Jeffrey Browning, Charles Mackay and Pascal Schneider for critical comments on the manuscript.

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B cells play a pivotal role in the pathogenesis of autoimmune disease (AD) by the production of autoantibodies, secretion of cytokines and presentation of autoantigens. As a pro-survival factor mainly produced by myeloid cells, B cell-activating factor (BAFF) maintains B cell maturation and homeostasis at various B cell differentiation stages. Under autoimmune conditions, BAFF acts on autoreactive B cells that have escaped checkpoint apoptosis from negative selection. Numerous studies have shown increased levels of BAFF in patients with ADs and in mouse models with ADs wherein the production of autoantibodies is a prominent feature of immunopathology. Compelling evidence has indicated a key function of BAFF in driving autoreactive B cell response during autoimmune progression. Recent clinical studies have demonstrated BAFF as a therapeutic target in various ADs. Here, we review recent findings on BAFF expression and its effector mechanisms in autoimmune pathogenesis as well as newly developed therapeutic targeting of BAFF in the treatment of ADs.
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Citation Excerpt :
Besides, the affinity of receptor which is expressed on the tumor cells might impact on the predominance of BAFF. BAFF and APRIL share the receptor of B cell maturation antigen (BCMA), whereas APRIL has stronger avidity to BCMA than BAFF [10]. On the other hand, BAFF robustly binds to BAFF receptor (BAFF-R) which has no affinity to APRIL.
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The TNF family members BAFF and APRIL: the growing complexity

Abstract

Section snippets

The structure of BAFF and APRIL

B cell survival, maturation and activation

BAFF signaling

Role in autoimmune disease

Strategies for therapeutic intervention

Conclusions and perspectives

Acknowledgements

J. Biol. Chem.

Trends Immunol.

Curr. Opin. Immunol.

Curr. Biol.

Cytokine Growth Factor Rev.

Immunity

Trends Biochem. Sci.

Cytokine

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

Cell

Blood

Immunity

Immunity

Cell Signal

Trends Biochem. Sci.

Curr. Biol.

Curr. Biol.

Immunity

J. Biol. Chem.

Immunity

Immunity

Cell

Mol. Cell

J. Biol. Chem.

Immunity

Exp. Hematol.

Blood

Genomics

BAFF, a novel ligand of the tumor necrosis factor (TNF) family, stimulates B cell growth

J. Exp. Med.

BlyS: member of the tumor necrosis factor family and B lymphocyte stimulator

Science

TALL-1 is a novel member of the TNF family that is down-regulated by mitogens

J. Leuk. Biol.

TACI and BCMA are receptors for a TNF homologue implicated in B cell autoimmune disease

Nature

APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor growth

J. Exp. Med.

BAFF and APRIL: a tutorial on B cell survival

Ann. Rev. Immunol.

BAFF: a fundamental survival factor for B cells

Nat. Rev. Immunol.

BAFF: a novel therapeutic target for autoimmunity

Curr. Opin. Investig. Drugs

Systemic lupus erythematosus: a blissless disease of too much BLyS (B lymphocyte stimulator) protein

Curr. Opin. Rheumatol.

APRIL and BAFF connect autoimmunity and cancer

J. Exp. Med.

To B or not to B: TNF family signalling in lymphocytes

Nat. Immunol.

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations

J. Exp. Med.

Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases

Arthr. Rheum.

A role for B lymphocyte stimulator in Systemic Lupus Erythematosus

J. Immunol.

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome

J. Clin. Invest.

Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase

EMBO J.

BLyS and APRIL form biologically active heteromers that are expressed in patients with systemic immune-based rheumatic diseases

J. Immunol.

An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein

EMBO J.

Structural basis of BLyS receptor recognition

Nat. Struct. Biol.

BAFF-R, a novel TNF receptor that specifically interacts with BAFF

Science