Baff Mediates Survival of Peripheral Immature B Lymphocytes

Abstract

B cell maturation is a very selective process that requires finely tuned differentiation and survival signals. B cell activation factor from the TNF family (BAFF) is a TNF family member that binds to B cells and potentiates B cell receptor (BCR)-mediated proliferation. A role for BAFF in B cell survival was suggested by the observation of reduced peripheral B cell numbers in mice treated with reagents blocking BAFF, and high Bcl-2 levels detected in B cells from BAFF transgenic (Tg) mice. We tested in vitro the survival effect of BAFF on lymphocytes derived from primary and secondary lymphoid organs. BAFF induced survival of a subset of splenic immature B cells, referred to as transitional type 2 (T2) B cells. BAFF treatment allowed T2 B cells to survive and differentiate into mature B cells in response to signals through the BCR. The T2 and the marginal zone (MZ) B cell compartments were particularly enlarged in BAFF Tg mice. Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance. These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment. This work provides new clues on mechanisms regulating B cell maturation and tolerance.

NF-κB and the immune response

“…A requirement for both the canonical and non-canonical NF-kB pathways may explain why deletion of p50 and p52 produces a more complete block in B-cell development than loss of RelA and c-Rel. Although both canonical and noncanonical NF-kB pathways are functional during B-cell development, recent work (Batten et al, 2000;Schiemann et al, 2001;Claudio et al, 2002) has underscored the importance of BAFF ligation in selectively activating the non-canonical NF-kB pathway and the consequent expression of antiapoptotic Bcl-2 family members in transitional B cells (see Mackay et al, 2003). Indeed, BAFF knockout mice exhibit a complete failure of transitional B-cell maturation, which mirrors that seen in Bcl-X L knockout mice (Motoyama et al, 1995;Gross et al, 2001;Schiemann et al, 2001).…”

Tolerance checkpoints in B‐cell development: Johnny B good

“…However, BAFF-BAFF-R signaling not only plays a crucial role in B-cell homeostasis, but also in B-cell tolerance. Thus, it has been shown that mice over-expressing BAFF develop a lupus-like disease [72,[78][79][80]. Moreover, elevated BAFF serum levels have been found in patients with autoimmune diseases in which B cells play an important role [81,82].…”

Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis

“…[1][2][3][4][5] BLyS is a potent B cell co-stimulator, and promotes B cell differentiation, proliferation and survival. 1,2,[6][7][8][9][10] In BLyS deficient mice, the number of B cells, serum IgG and IgM levels were decreased, and B cell development was blocked at the transitional T1 stage. 11 BLyS and a proliferation-inducing ligand (APRIL) bind to B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), 4,12,13 which belong to the tumor necrosis factor receptor superfamily and are mainly expressed in B cells.…”