Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells

Abstract

Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear antibodies. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remains unclear. We now report that, whereas surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACIhi transitional cells from BAFF-Tg mice are characterized by an activated, cycling phenotype; and the TACIhi cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase (AID) and T-bet and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACIhi transitional B cells from BAFF-Tg mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism whereby BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells.

BAFF overexpression increases lymphocytic infiltration in Sjögren's target tissue, but only inefficiently promotes ectopic B-cell differentiation

“…As an alternative explanation, it is also possible that the mechanism by which BAFF induces autoimmunity and GC B cell formation in BAFF Tg mice does not rely on effects on follicular B cells. Supporting this hypothesis, several recent reports indicate that autoimmunity in BAFF Tg mice is T-cell independent [30] and relies on the activation of transitional B cells [45] and/or on the innate activation of B cells via the upregulation of TLRs by TACI expressed preferentially on marginal zone and B1 B cells [31,46]. The latter result is in agreement with the phenotype of expanded B cells in BAFF Tg mice which are mostly of a marginal zone-like phenotype in spleen and salivary glands [25,26].…”

Altered B cell signalling in autoimmunity

“…78) and promotes T cell-independent antibody responses 79 , suggesting a role for TACI in this process. Consistent with this idea, two independent studies demonstrated the surprising finding that BAFF-driven autoimmunity is abrogated by Taci deletion 80,81 .…”

Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation

“…In support of this idea, Taci −/− mice have lower serum IgM levels suggesting that lack of TACI may decrease the formation of atheroprotective IgM against oxidized lipid epitopes. Further, while TACI was initially hypothesized to act as a negative regulator of BAFF-mediated signals, recent independent studies, including one from our laboratory, demonstrate that TACI signals are required for class-switched autoantibody formation in BAFF-Tg mice (30, 44). …”

“…Ab ELISAs were performed on 96 well Immuno plates (Nunc) were coated with: MDA-LDL (Academy Bio-Medical; 20P-MD-L110) or phosphorylcholine PC(10)–BSA (10 µg/ml; Biosearch Technologies PC-1011-10), as described (30)…”