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Monomeric IgG in Intravenous Ig Preparations Is a Functional Antagonist of FcRII and FcRIIIb

Edwin van Mirre^1,*, Jessica L. Teeling^*, Jos W. M. van der Meer, Wim K. Bleeker^* and C. Erik Hack^*,

^* Department of Immunopathology, Sanquin Research, Amsterdam, Department of Internal Medicine, University Medical Center St. Radboud, Nijmegen, and Department of Clinical Chemistry, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

Intravenous Ig preparations (IVIg), originally developed as a substitution therapy for patients with low plasma IgG, are nowadays frequently used in the treatment of various immune diseases. However, the mechanism of action of IVIg in these diseases remains elusive and is often referred to as "immunomodulatory." We hypothesized that monomeric IgG may act as a low-affinity FcR antagonist and sought experimental evidence for this hypothesis. Human neutrophils as well FcRIIa-transfected IIA1.6 cells were used as FcR-positive cells and aggregated IgG (aIgG) or stable dimeric IgG as FcR-specific agonists for these cells. We found that monomeric IgG purified from IVIg at concentrations similar to that of IgG in plasma, diminished the binding of stable dimeric IgG to FcRIIa transfectants, reduced aIgG-induced influx of Ca²⁺ ions into the cytosol of neutrophils, and attenuated the aIgG-induced release of elastase. Notably, monomeric IgG by itself did not elicit these responses, nor did it affect these processes in response to fMLP. Absorption of IgG from normal plasma revealed that plasma IgG exerted similar effects as monomeric IgG in IVIg. In addition, adding monomeric IgG to blood of healthy volunteers showed a dose-dependent decrease of aIgG-induced elastase release. Finally, we observed decreased aIgG-induced polymorphonuclear neutrophil responses in two hypogammaglobulinemic patients upon treatment with IVIg. We conclude that monomeric IgG at physiological levels acts as a low-affinity FcR antagonist. Moreover, FcR antagonism constitutes an immunomodulatory effect of IVIg.

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