Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor.
The molecular basis for the anti-inflammatory property of intravenous gamma globulin (IVIG) was investigated in a murine model of immune thrombocytopenia. Administration of clinically protective doses of intact antibody or monomeric Fc fragments to wild-type or Fcgamma receptor-humanized mice prevented platelet consumption triggered by a pathogenic autoantibody. The inhibitory Fc receptor, FcgammaRIIB, was required for protection, because disruption either by genetic deletion or with a blocking monoclonal antibody reversed the therapeutic effect of IVIG. Protection was associated with the ability of IVIG administration to induce surface expression of FcgammaRIIB on splenic macrophages. Modulation of inhibitory signaling is thus a potent therapeutic strategy for attenuating autoantibody-triggered inflammatory diseases.
Samuelsson
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Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Towers
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Ravetch
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology / Q000627:therapeutic use; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009895:Opsonin Proteins; D010587:Phagocytosis; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology / Q000517:prevention & control*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D001323:Autoantibodies; C080571:Fc gamma receptor IIB; D007141:Immunoglobulin Fc Fragments; D016756:Immunoglobulins, Intravenous; D009895:Opsonin Proteins; D018129:Phosphatidylinositol Phosphates; D017452:Receptors, IgG; C060974:phosphatidylinositol 3,4,5-triphosphate; D003165:Complement System Proteins; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases