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CUTTING EDGE |
Rheumatic Diseases Core Center, University of California, San Diego, La Jolla, CA 92093
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants CA104815 from the National Cancer Institute and National Blood Foundation (to C.S.G.), Grants AI40305, AR47360, AR50659, and AI46637 from the National Institutes of Health, and grants from the Alliance for Lupus Research (to G.J.S.).
2 Current address: Division of Clinical Neurosciences, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, G12 8TA, UK.
3 Address correspondence and reprint requests to Dr. Carl S. Goodyear, at the current address: Glasgow Biomedical Research Centre, B329, University of Glasgow, 120 University Place, Glasgow, G12 8TA, U.K. or Dr. Gregg J. Silverman, Rheumatic Diseases Core Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663. E-mail addresses: C.Goodyear{at}clinmed.gla.ac.uk or gsilverman{at}ucsd.edu
4 Abbreviations used in this paper: SpA, protein A of Staphylococcus aureus; AICD, activation-induced cell death; BAFF, B cell activation-induced factor of the TNF family; LN, lymph node; 
m, mitochondrial membrane potential; SAg, superantigen.
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