BAFF and the regulation of B cell survival
Introduction
Most cell die in the absence of appropriate growth and survival signals. This default death pathway provides efficient protection against potentially dangerous processes such as autoimmunity and cellular transformation. In the immune system, where expansion of cell population in response to pathogens and subsequent down-regulation of the response occurs permanently, homeostasis is critically dependent on the balance between survival and death. In the recent years, much attention has been drawn to elements that affect lymphocyte survival. A cytokine called BAFF (or BLyS, TALL-1, THANK, zTNF4 or TNFSF13b), was identified in 1999 and was rapidly recognized as a potent survival factor for most B cells [1], [2], [3], [4], [5].
Section snippets
Cloning, structure and expression of BAFF
BAFF cDNA was identified in EST databases because of its homology with TNF family members. Subsequent structural studies confirmed that it adopts the β-sheet-rich homotrimeric structure that earmarks members of this family [6], [7], [8] (Fig. 1). Two magnesium atoms coordinated in the center of the trimer are believed to stabilize the protein, as previously reported for a zinc atom in the related ligand TRAIL [7], [9]. BAFF is a type II transmembrane protein that is released in a soluble form
Receptors interacting with BAFF
Knowledge-based and expression screening approaches have led to the identification of three distinct receptors for BAFF, namely BCMA, TACI and BAFF-R (also known as BR3), that are predominantly or exclusively expressed in B cells [2], [18], [19], [20] (Fig. 2). All three belong to a relatively distant branch of the TNF receptor family, and all three bind to BAFF through relatively small domains [21]. In the case of BAFF-R, the binding domain can be reduced down to 26 aa [22]. Binding of BAFF to
Function of BAFF and of its receptors
One of the most spectacular functions of BAFF is undoubtedly to allow survival of transitional B cells during B cell maturation in the spleen. The bone marrow of BAFF−/− mice generates and releases immature B cells normally, but these B cells fail to proceed from the transitional type 1 (T1) to the transitional type 2 (T2) stage in the spleen [28], [29]. As a result, BAFF−/− animals are virtually devoid of mature B cells and of marginal zone B cells, and are severely deficient in mounting
Signaling through the different BAFF receptors
As discussed above, BAFF-R is required for the survival of transitional B cells in the spleen. It is therefore of particular interest to identify the intracellular mediators of this response. Genetic studies have demonstrated the implication of the alternative NF-κB pathway in this process [22], [42]. In the classical NF-κB pathway, the transcription factor NF-κB is usually activated following proteasome-mediated degradation of its inhibitor Iκ-B following phosphorylation by the Iκ-B kinase
BAFF and diseases
A potential implication of BAFF in autoimmune diseases was first suggested by the phenotype of BAFF transgenic mice. In these mice, B lymphoplasia and hyperglobulinemia is often accompanied by production of autoantibodies, the development of glomerulonephritis and the destruction of salivary gland tissues [2], [54], [55], [56]. This suggests a possible implication of elevated BAFF levels in autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis and Sjögren's
Conclusions
Genetic and biochemical studies on the BAFF system have provided a clear picture of a non-redundant survival signal for maturating, and, most probably, for fully differentiated B cells too. This provides a basis for the study of how B cells integrate signals provided by the BCR, co-stimulatory signals and BAFF itself, and how they respond to them. Exploration of BAFF regulation will help understand how B cells can survive in various environments under normal and pathologic conditions.
It is
Acknowledgements
We thank Stuart G. Tangye for sharing unpublished results and Fabienne Mackay for useful comments. This work was supported by grants from the Swiss National Science Foundation and the NCCR.
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