Inhibition of FcγR-mediated phagocytosis by IVIg is independent of IgG-Fc sialylation and FcγRIIb in human macrophages

S.Q. Nagelkerke, G. Dekkers, I. Kustiawan, F.S. van de Bovenkamp, J. Geissler, R. Plomp, M. Wuhrer, G. Vidarsson, T. Rispens, T.K. van den Berg, T.W. Kuijpers

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84 Citations (Scopus)


In immune thrombocytopenia and warm autoimmune hemolytic anemia, circulating immunoglobulin G (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 (FcγRs) by inducing upregulation of the inhibitory FcγRIIb 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-FcγR 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 FcγRIIb expression. Instead, IVIg inhibited phagocytosis by direct blockade of FcγRs. IgG fractions enriched for IgG dimers with enhanced avidity for FcγRs showed increased inhibition compared with 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 FcγRs but is independent of FcγRIIb or sialylation of the Fc fragment in the human setting.

Original languageEnglish
Pages (from-to)3709-18
Number of pages10
Issue number25
Publication statusPublished - 11 Dec 2014


  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Erythrocytes/immunology
  • Flow Cytometry
  • Granulocyte-Macrophage Colony-Stimulating Factor/immunology
  • Humans
  • Immunoglobulin Fc Fragments/immunology
  • Immunoglobulin G/immunology
  • Immunoglobulins, Intravenous/immunology
  • Macrophage Colony-Stimulating Factor/immunology
  • Macrophages/drug effects
  • N-Acetylneuraminic Acid/immunology
  • Phagocytosis/drug effects
  • Receptors, IgG/immunology

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