Cutting Edge: Bim Is Required for Superantigen-Mediated B Cell Death

Abstract

To impair B cell clonal regulation, the microbial virulence factor, protein A of Staphylococcus aureus, can interact with evolutionarily conserved BCR-binding sites to induce a form of Fas-independent activation-associated B cell death that results in selective immune tolerance. We now show that this in vivo death pathway is associated with induction of increased transcript and protein levels of Bim, a BH3-only proapoptotic Bcl-2 family protein, which is inhibited by excess B cell-activating factor. An absolute requirement for Bim was documented, since Bim-deficient B cells were protected from in vivo superantigen-induced death and instead underwent persistent massive supraclonal expansion without functional impairment. These studies characterize a BCR-dependent negative clonal selection pathway that has been co-opted by a common bacterial pathogen to induce selective defects in host immune defenses.

Host Chemokines Bind to Staphylococcus aureus and Stimulate Protein A Release

“…Although a number of potential mechanisms have been identified, which of these accounts for virulence in vivo has not been clearly delineated. In particular, SPA is best known for its ability to bind IgG (32), but can also bind other host factors, including von Willebrand's factor (33) and the VH3 receptor of B-cells (34). SPA also possesses antiphagocytic activity (35,36), and the ability to activate TNFR1 (37) and to induce apoptosis of naïve B cells (38).…”

Apoptosis and the homeostatic control of immune responses

“…However, the death of some types of activated B cells is affected by the balance of pro and anti-apoptotic members of the Bcl-2 family, for example, Bcl-2 itself (of course! ), Bax and Bak and Bim [22][23][24][25][26][27]. BAFF is the principle survival factor for activated B cells and helps to break the unresponsiveness of autoimmune B cells [25,26].…”

Toward Effective HIV Vaccination

“…Such sites are designated B cell "superantigens" (SAgs) because of their selective and widespread recognition by the comparatively conserved framework regions (FRs) * This work was supported, in whole or in part, by National Institutes of Health of Ab V domains (10,11). Noncovalent SAg binding by preimmune Abs, however, is characterized by low-to-moderate binding strength (12). Most gp120-binding preimmune Abs from humans without infection display poor or no HIV neutralizing activity (13).…”