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FcRIIb Balances Efficient Pathogen Clearance and the Cytokine-mediated Consequences of Sepsis

The Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2XY, United Kingdom

Address correspondence to Kenneth G.C. Smith, University of Cambridge School of Clinical Medicine, Lab 5.15, Box 139, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. Phone: 44-1223-762645; Fax: 44-1223-762640; email: kgcs2{at}cam.ac.uk

The immune response to infection must be controlled to ensure it is optimal for defense while avoiding the consequences of excessive inflammation, which include fatal septic shock. Mice deficient in FcRIIb, an inhibitory immunoglobulin G Fc receptor, have enhanced immune responses. Therefore, we examined whether FcRIIb controls the response to Streptococcus pneumoniae. Macrophages from FcRIIb-deficient mice showed increased antibody-dependent phagocytosis of pneumococci in vitro, and consistent with this infected FcRIIb-deficient mice demonstrated increased bacterial clearance and survival. In contrast, previously immunized FcRIIb-deficient mice challenged with large inocula showed reduced survival. This correlated with increased production of the sepsis-associated cytokines tumor necrosis factor and interleukin 6. We propose that FcRIIb controls the balance between efficient pathogen clearance and the cytokine-mediated consequences of sepsis, with potential therapeutic implications.

Key Words: FcRIIb • Streptococcus pneumoniae • septic shock • tumor necrosis factor • interleukin 6

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