Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway

RM Anthony, T Kobayashi, F Wermeling, JV Ravetch - Nature, 2011 - nature.com
Nature, 2011nature.com
High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly
purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1–2 grams per
kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical
settings. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a
minor population of IgG crystallizable fragments (Fcs), with glycans terminating in α2, 6 sialic
acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific …
Abstract
High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1–2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in α2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209),,. Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC-SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc-treated hDC-SIGN+ macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor FcγRIIB on effector macrophages. Systemic administration of the TH2 cytokines IL-33 or IL-4 upregulates FcγRIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN–TH2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases.
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