BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway

Abstract

The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)–induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3–only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector–mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal–regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim−/− mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim.

Correlations of TNF-α gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis in a northern Chinese Han population

“…22 The B-cell-activating factor belongs to the TNF family (BAFF), which is crucial to B-cell survival and maturation. 23,24 Excess BAFF can result in the development of autoimmune disorders and has been detected in various autoimmune conditions. 25 Therefore, we speculated that TNF-α might be involved in the susceptibility of T-MG through its correlation with T cells and B cells.…”

BAFF and the plasticity of peripheral B cell tolerance

“…Clearly, BAFF thwarts death mechanisms driven by strong BCR signals. For example, BCR-driven Bim dephosphorylation and consequent caspase-mediated cell death [30] is blocked by BAFF. While these findings disclose distal events through which BAFF opposes BCR-driven death at the TR stages, the reason why BCR signals are also necessary for BAFF-mediated survival remains unclear.…”

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

“…The TNF family-related cytokine BAFF is an important survival factor for B lymphocytes (Cancro, 2004;Craxton et al, 2005;Crowley et al, 2005;Schneider 2005). BAFF binds to three receptors: BAFF-R, transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA).…”