BAFF/BLyS Receptor 3 Binds the B Cell Survival Factor BAFF Ligand through a Discrete Surface Loop and Promotes Processing of NF-κB2

Abstract

The TNF-like ligand BAFF/BLyS is a potent survival factor for B cells. It binds three receptors: TACI, BCMA, and BR3. We show that BR3 signaling promotes processing of the transcription factor NF-kappaB2/p100 to p52. NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells. Furthermore, wild-type mice injected with BAFF-neutralizing BR3-Fc protein showed reduced basal NF-kappaB2 activation. BR3-Fc treatment of NZB/WF1 mice, which develop a fatal lupus-like syndrome, inhibited NF-kappaB2 processing and attenuated the disease process. Since inhibiting the BR3-BAFF interaction has therapeutic ramifications, the ligand binding interface of BR3 was investigated and found to reside within a 26 residue core domain. When stabilized within a structured beta-hairpin peptide, six of these residues were sufficient to confer binding to BAFF.

Intrarenal production of B-cell survival factors in human lupus nephritis

“…13 In lupus mouse models, circulating BLyS levels were found to be elevated 12 and interventions into the APRIL/BLyS system ameliorated proteinuria and renal inflammation. 12,14,15 Consistently in human systemic lupus erythematosus, serum as well as blood mRNA levels of APRIL and BLyS were found to be elevated. [16][17][18] Although depleting B cells by an anti-CD20 antibody, eg, by rituximab, surprisingly failed to show significant benefit in patients with renal and non-renal systemic lupus erythematosus, 19 phase II/III clinical trials investigating the blockade of the APRIL/ BLyS system in systemic lupus erythematosus have been initiated (LBSLO2/99 NCT00071487 and NCT 00583362; BLISS-76/NCT00410384 and BLISS-52/ NCT00424476; NCT00624338) and promising results have been reported.…”

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

“…Despite the profound effects on morbidity and mortality, none of these interventions had appreciable effects on circulating levels of anti-dsDNA antibodies (49). Third, treatment of NZB/NZW mice with one BAFF antagonist (TACI-Ig) had a dramatic salutary effect on renal disease and survival without measurable effects on circulating anti-dsDNA antibody levels (6) (although treatment of such mice with another BAFF antagonist [BAFF-R-Ig] did reduce circulating levels of anti-dsDNA antibodies in parallel with clinical improvement [50]). …”

Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF

“…In particular, both receptors are able to signal CSR to IgG 1 and IgE, but the switch to IgA is controlled by TACI only (Litinskiy et al, 2002;Castigli et al, 2005b). These receptors have been described to be able to induce nuclear translocation of NFkB (Litinskiy et al, 2002;Castigli et al, 2005a;Kayagaki et al, 2002), which activates Iγ1 and Iε promoters by cooperating with IL-4-induced signal transducer and activator of transcription (STAT)-6, and Iα promoter by cooperating with TGF-β-induced Smad proteins (Stavnezer, 1996).…”