The antiinflammatory activity of IgG: the intravenous IgG paradox

Abstract

How high doses of intravenous IgG (IVIG) suppress autoimmune diseases remains unresolved. We have recently shown that the antiinflammatory activity of IVIG can be attributed to a minor species of IgGs that is modified with terminal sialic acids on their Fc-linked glycans. Here we propose that these Fc-sialylated IgGs engage a unique receptor on macrophages that, in turn, leads to the upregulation of an inhibitory Fcgamma receptor (FcgammaR), thereby protecting against autoantibody-mediated pathology.

Figure 1.

Models for the mechanism of IVIG-mediated antiinflammatory activity. (A) During an inflammatory response immune complexes consisting of autoantibodies (brown) and self-antigens (green) activate innate immune effector cells (e.g., macrophages) by cross-linking cell surface FcγRs, which can lead to the destruction of self-tissues. Serum antibody half-life of normal (light brown) and autoreactive antibodies is regulated by FcRn (purple) expressed on endothelial cells. (B) Three models have been proposed to explain the antiinflammatory activity of IVIG. In the first model, IVIG (consisting of a mixture of sialic acid–rich [red] and sialic acid–low [blue] antibodies) binds to activating FcγRs on immune effector cells, thereby blocking access of immune complexes to these receptors and inhibiting cell activation. The second model proposes that IVIG competes with serum IgG (including autoreactive antibodies) for recycling mediated by FcRn. Thus, serum and autoreactive antibodies would be cleared more rapidly and not reach the threshold level for initiating tissue destruction. In the third model, IVIG leads to up-regulation of the inhibitory FcγRIIB on immune effector cells, thus increasing the threshold level for cell activation by immune complexes.

Figure 2.

Two-cell model for the mechanism of IVIG activity. Sialic acid–rich antibodies (red) in the IVIG preparation bind to an as yet unknown IVIG receptor on CSF-1–dependent regulatory macrophages. This induces the up-regulation of the inhibitory FcγRIIB on effector macrophages, thereby increasing the threshold for cell activation in response to the binding of immune complexes and inhibiting the release of destructive inflammatory and cytotoxic mediators.