The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity

Abstract

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

Keywords: A proliferation inducing ligand (APRIL); ACR; ALL; ANA; APRIL; American College of Rheumatology; Autoimmunity; B cell activating factor from the TNF family; B cell activating factor from the tumor necrosis factor family (TNF) (BAFF); B cell maturation antigen; B cell receptor; BAFF; BAFF-R; BAFF-receptor; BCMA; BCR; BOS; CIDP; CLL; CNS; CVID; Cancer; DCs; EBV; ECP; EULAR; Epstein–Barr virus; European League Against Rheumatism; FDA; Food and Drug Administration; GC; HIV; HSCT; HSPGs; ICOS; IFN; IL; Ig; LN; MMF; MS; MTX; MVECS; MZ; MyD88; NK; NZB; NZW; New-Zealand black; New-Zealand white; NgR; Nogo-66 receptor; PC; PFS; RF; RSV; SAEs; SCF; SLE; SLE Disease Activity Index; SLEDAI; SNPs; SS; Sjögren's syndrome; Systemic lupus erythematosus (SLE); T-helper; TACI; TGF-β; TLR; TNF; Tg; Th; Treg; a proliferation inducing ligand; acute lymphoblastic leukemia; anti-nuclear autoantibodies; bronchiolitis obliterans syndrome; cGVHD; central nervous system; chronic graft versus host disease; chronic lymphocytic leukemia; chronic-inflammatory demyelinating polyneuropathy; common variable immunodeficiency; dentritic cells; double stranded deoxyribonucleic acid; dsDNA; extracorporeal photopheresis; germinal center; hematopoietic stem cell transplantation; heparan sulfate proteoglycans; human immunodeficiency virus; immunoglobulin; inducible costimulatory; interferon; interleukin; lupus nephritis; mRNA; marginal zone; messenger ribonucleic acid; methotrexate; microvacular endothelial cells; multiple sclerosis; mycophenolate mofetil; myeloid differentiation primary response gene 88; natural killer; plasma cell; progression-free survival; regulatory T cells; respiratory syncytial virus; rheumatoid factor; serious adverse events; single nucleotide polymorphisms; stem cell factor; systemic lupus erythematosus; toll-like receptor; transforming growth factor-β; transgenic; transmembrane activator and cyclophilin ligand interactor; tumor necrosis factor.

Fig. 1

BAFF and APRIL signaling. BAFF is expressed as a membrane-bound trimer, which is proteolytically cleaved to form a soluble trimer. BAFF also exists in the circulation as a 60-mer. BAFF binds strongly to BAFF-R and TACI, and weakly to BCMA (as indicated by thick or thin arrows, respectively). BAFF trimers do not activate TACI efficiently and BAFF multimers are required for this. BAFF has also recently been described to bind to a receptor on astrocytes and neurons called Nogo-66 receptor (NgR). APRIL is cleaved intracellularly (with the exception of APRIL-δ), and is found in the circulation as a trimer, and as a multimer in association with heparin sulfate proteoglycans (HSPGs). APRIL binds strongly to BCMA, weakly to TACI, which also binds to HSPGs. BAFF-R is primarily expressed on all B cells, TACI on innate-like B cells, and BCMA on plasmablasts and plasma cells. However, these receptors can be found on other cell types, such as BAFF-R on activated T cells.