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RIIb in human macrophages γ sialylation and Fc R-mediated phagocytosis by IVIg is independent of IgG-Fc γ Inhibition of Fc

Abstract In immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA), circulating IgG-opsonized blood cells are cleared from the circulation by macrophages. Administration of intravenous immunoglobulin (IVIg) can prevent uptake, but the exact working mechanism is not known. The prevailing theory from murine studies, which states that Fc-sialylated IgG alters the balance between activating and inhibitory Fc-gamma receptors (Fc Rs) by inducing upregulation of the inhibitory Fc RIIb on effector macrophages, is currently debated. We studied phagocytosis of IgG-opsonized blood cells in a human system, assessing the effect of IVIg and blocking anti-Fc R F(ab’) 2 fragments on uptake by monocyte-derived macrophages (both M1 and M2 macrophages). Phagocytosis was remarkably sensitive to administration of IVIg but unexpectedly, recombinant Fc-sialylated IgG or sialic acid-enriched IVIg were equally active as unsialylated IgG fractions in mediating this inhibition - independent of Fc RIIb expression. Instead, IVIg inhibited phagocytosis by direct blockade of Fc Rs. IgG fractions enriched for IgG-dimers with enhanced avidity for Fc Rs showed increased inhibition compared to monomeric IgG fractions. Together, our data demonstrate that inhibition of IgG-mediated phagocytosis in human macrophages by IVIg is dependent on the capacity to directly bind Fc Rs but independent of Fc RIIb or sialylation of the Fc fragment in the human setting.