The TNF family members BAFF and APRIL: the growing complexity
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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2020, Journal of Clinical NeuroscienceCitation 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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