Monomeric IgG in intravenous Ig preparations is a functional antagonist of FcgammaRII and FcgammaRIIIb.
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 FcgammaR antagonist and sought experimental evidence for this hypothesis. Human neutrophils as well FcgammaRIIa-transfected IIA1.6 cells were used as FcgammaR-positive cells and aggregated IgG (aIgG) or stable dimeric IgG as FcgammaR-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 FcgammaRIIa transfectants, reduced aIgG-induced influx of Ca(2+) 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 FcgammaR antagonist. Moreover, FcgammaR antagonism constitutes an immunomodulatory effect of IVIg.
van Mirre
Edwin
E
Department of Immunopathology, Sanquin Research, PO Box 9190, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. e.vanmirre@sanquin.nl
Teeling
Jessica L
JL
van der Meer
Jos W M
JW
Bleeker
Wim K
WK
Hack
C Erik
CE
D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D002460:Cell Line; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology*; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D009504:Neutrophils / Q000276:immunology / Q000502:physiology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000502:physiology
C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; C485700:Fcgr3 protein, mouse; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D017452:Receptors, IgG; D002118:Calcium