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  • Review Article
  • Published:

Cracking the BAFF code

Nature Reviews Immunology volume 9, pages 491–502 (2009)Cite this article

Key Points

  • Studies examining the binding of B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) to their receptors have revealed additional layers of complexity. Trimeric forms of both BAFF and APRIL bind to the receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), but only multimeric forms of these ligands can signal through this receptor.

  • Recent work has provided a more detailed roadmap of BAFF-induced survival signalling. The activation of the alternative nuclear factor-κB2 (NF-κB2) pathway and of the phosphoinositide 3-kinase–AKT1–mammalian target of rapamycin pathway, and the upregulation of expression of myeloid cell leukaemia sequence 1 (MCL1) provide a rational basis for the effects of BAFF on B cell survival and metabolic fitness.

  • The role of BAFF is no longer restricted to B cells. BAFF is also produced by non-haematopoietic cells and affects B cells as well as T cells, macrophages and dendritic cells.

  • The role of BAFF in B cell tolerance is not what it seems. BAFF does not markedly affect the negative selection of high-affinity self-reactive B cells but instead increases the proliferation of positively selected low-affinity self-reactive B cells.

  • BAFF mediates a unique form of autoimmune disease, which is independent of T cell involvement but requires the activation of innate immune mechanisms such as Toll-like receptor activation.

  • BAFF and/or APRIL inhibitors have shown some benefits in the clinic, but there are many remaining challenges and possible future options in the form of combined therapies.

Abstract

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting.

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Figure 1: BAFF, APRIL and their receptors.
Figure 2: The role of TRAF molecules in BAFFR signalling.
Figure 3: BAFF-dependent maturation of mouse B cells.
Figure 4: Signal transduction through BAFF receptors.
Figure 5: The potential role of excess BAFF in B cell tolerance and activation of self-reactive B cells.

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Acknowledgements

We thank S. Gardam for assistance with the design of Fig. 2. This work was funded by grants from The National Health and Medical Research Council (NHMRC) of Australia, the New South Wales Lupus association and the Nancy E. Pendergast Charitable Trust Fund Perpetual (to F.M.), and the Swiss National Science Foundation (to P.S.). We apologise to the many authors who have contributed to this field but have not been cited in this manuscript owing to referencing restrictions.

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  1. Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges, CH-1066, Switzerland.

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  1. Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Alfred Hospital, 86 Commercial Road, Melbourne, 3004, Victoria, Australia

    Fabienne Mackay & Pascal Schneider

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  1. Fabienne Mackay
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Correspondence to Fabienne Mackay.

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Glossary

B cell receptor (BCR) editing

The process of inducing somatic mutations that selectively alter the sequence and specificity of the B cell receptor.

Trans-splicing

Splicing of a pre-mRNA spanning two adjacent genes.

Classical NF-κB pathway

An IKKγ (inhibitor of nuclear factor-κB (NF-κB) kinase-γ)-dependent signalling pathway that activates the transcription factor NF-κB, which usually contains the p50 subunit derived from the p105 NF-κB1 precursor.

Alternative NF-κB pathway

A signalling cascade resulting in the IKKγ (inhibitor of nuclear factor-κB (NF-κB) kinase-γ)-independent activation of the transcription factor NF-κB. Hallmarks of this pathway are the activation of NF-κB-inducing kinase and the processing of NF-κB2 from a p100 precursor to a p52 fragment.

Cytotrophoblast

A cell of the inner layer of the trophoblast, which is the outermost layer in an embryo that functions to anchor the embryo to the maternal endometrium.

Marginal zone B cell

A B cell that resides in the marginal zone, a region at the interface between the non-lymphoid red pulp and the lymphoid white pulp of the spleen.

B1 B cell

A cell belonging to a sub-class of B cells that reside mainly in the peritoneal and pleural cavities, that express IgM in greater quantities than IgG and the receptors of which are polyspecific (that is, they have low affinities for many different antigens).

Class switching

The somatic recombination process by which immunoglobulin isotypes are switched from IgM to IgG, IgA or IgE. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of these antibody classes to activate the appropriate downstream effector mechanisms.

Heparitinase

An enzyme that catalyses the eliminative cleavage of glycosidic bonds in heparan sulphate.

T cell-independent type II humoral immune response

Type of B cell activation in which several of the same antigen are presented in a way that causes cross-linking of antibodies on the surface of B cells, without requiring T cell help.

mTOR complex 1

A multiprotein complex containing mammalian target of rapamycin (mTOR), which functions as a nutrient, energy and redox sensor and controls protein synthesis. The activity of this complex is stimulated, among others, by insulin, growth factors and amino acids.

Atrophy

Cellular wasting resulting in volume loss and decreased protein content. It is the opposite of cell growth.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, particularly in the kidney. Patients with SLE generally have abnormal B and T cell function.

Vascular sinusoid

A specialized blood vessel in haematopoietic tissues through which venous circulation occurs and that has thin walls formed by a discontinuous, irregularly shaped endothelium that allows cells to pass in and out of the circulation.

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Mackay, F., Schneider, P. Cracking the BAFF code. Nat Rev Immunol 9, 491–502 (2009). https://doi.org/10.1038/nri2572

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