The anti-inflammatory activity of IgG requires the co-engagement of types I and II Fc receptors
Jones, A. T.; Martynyuk, T.; Marino, A. E.; Bournazos, S.; Ravetch, J. V.
Show abstract
Intravenous immunoglobulin administered at high doses has been used for decades as an effective anti-inflammatory preparation to treat a wide array of autoimmune diseases. Studies in murine models have found this activity to be dependent on 1) sialylation of the N-linked glycan on the CH2 domain of IgG, 2) the type I IgG inhibitory Fc receptor Fc{gamma}RIIB, and 3) the type II Fc receptor DC-SIGN. Here, we demonstrate that the ectodomain glycan on Fc{gamma}RIIB interacts with the lectin domain of DC-SIGN to form a cell surface complex, thereby enabling the binding of sialylated IgG1. We have exploited this observation to Fc-engineer sialylated IgG1 to enhance its affinity for Fc{gamma}RIIB and demonstrate that the resulting molecule is at least 100-fold more potent in reducing the inflammatory sequelae of antibody or T cell mediated autoimmune diseases, providing the basis for a new class of anti-inflammatory therapeutics.
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