Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity

Abstract

B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (TNF) superfamily. BLyS stimulates proliferation of, and immunoglobulin production by, B cells. However, the relative importance of BLyS in physiological B cell activation is unclear. We identified a B cell receptor for BLyS through expression cloning as TACI, an orphan TNF receptor homologue of unknown function. Binding of BLyS to TACI activated signaling by nuclear factor-kappa B (NF-kappa B). In vitro soluble TACI-Fc fusion protein blocked BLyS-induced NF-kappa B activation in B lymphoma cells and IgM production in peripheral blood B cells. In vivo treatment of immunized mice with TACI-Fc inhibited production of antigen-specific IgM and IgGI antibodies and abolished splenic germinal center (GC) formation. Thus, BLyS activity must play a critical role in the humoral immune response.

Cutting Edge: Germinal Centers Formed in the Absence of B Cell-Activating Factor Belonging to the TNF Family Exhibit Impaired Maturation and Function

“…4, right panel). These data are consistent with previously published reports using BAFF inhibitors (19,22).…”

“…A single study using the BAFF receptor decoy, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI)-Fc, reported a complete absence of GCs in treated mice (19). However, this same report also noted the presence of high-affinity anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) Ab, albeit at low levels.…”

“…Yan et al (19) dosed with TACI-Fc daily for 14 days following Ag priming with NP-CGG. Spleens were examined for GCs at only a single time point, day 14 postimmunization.…”

BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas‐mediated cell death

“…Among these factors, BAFF has a relatively well-defined role in the survival of immature and naïve B cells and in promoting Ab responses [32][33][34].…”

TNFR-Associated Factor-3 Is Associated With BAFF-R and Negatively Regulates BAFF-R-Mediated NF-κB Activation and IL-10 Production

“…It is now believed that sTALL-1 promotes either differentiation of B cells or survival of mature B cells (25)(26)(27)(28). Administration of recombinant sTALL-1 or overexpression of sTALL-1 in mice leads to increased numbers of mature B lymphocytes, splenomegaly, anti-DNA Abs, proteinuria, and glomerulonephritis, phenotypes that mimic those of systemic lupus erythemia (3,5,14,29,30). Conversely, it has been shown that recombinant soluble TACI-Ig fusion proteins can significantly inhibit progression of lupus-like autoimmune syndrome and collagen-induced arthritis in animal models (27,31).…”