A novel role for the IgG Fc glycan: the anti-inflammatory activity of sialylated IgG Fcs.
IgG antibodies have long been recognized as proinflammatory mediators of the humoral immune response. Antibodies bind and neutralize antigens to promote antibody-dependent cytotoxicity, opsonization of antigens, and the initiation of phagocytosis. Whereas the antigen specificity of antibodies is determined by the antigen-binding Fab portion, the effector functions initiated by antibodies are triggered by the Fc (crystallizable) domain. These effector functions are heavily dependent on the single N-linked, biantennary glycan of the heavy chain, which resides just below the hinge region. This glycan is believed to maintain the two heavy chains of the Fc in an open confirmation required for interactions with activating Fcgamma receptors (FcgammaRs). However, the presence of specific sugar moieties on the glycan has profound implications on Fc effector functions. The addition of terminal sialic acid to the glycan reduces FcgammaR binding and converts IgG antibodies to anti-inflammatory mediators through the acquisition of novel binding activities. Studies from our laboratory demonstrated that these sialylated IgG Fcs are important for the in vivo activity of intravenous immunoglobulin. Instead of binding with FcgammaRs, sialylated Fcs initiate an anti-inflammatory cascade through the lectin receptor SIGN-R1 or DC-SIGN. This leads to upregulated surface expression of the inhibitory FcR, FcgammaRIIb, on inflammatory cells, thereby attenuating autoantibody-initiated inflammation.
Anthony
Robert M
RM
The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
Ravetch
Jeffrey V
JV
D000818:Animals; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000737:chemistry / Q000276:immunology; D001327:Autoimmune Diseases / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000276:immunology; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology* / Q000628:therapy; D037181:Lectins, C-Type / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology; D019158:N-Acetylneuraminic Acid / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000276:immunology; D017452:Receptors, IgG / Q000737:chemistry / Q000276:immunology*; D013329:Structure-Activity Relationship; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D007141:Immunoglobulin Fc Fragments; D007143:Immunoglobulin Heavy Chains; D016756:Immunoglobulins, Intravenous; D037181:Lectins, C-Type; D019158:N-Acetylneuraminic Acid; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C499173:FCGR2B protein, human; C499172:Fcgr2b protein, mouse