title: IgG4 can induce an M2-like phenotype in human monocyte-derived macrophages through FcγRI.
abstract: Antibodies evoke cellular responses through the binding of their Fc region to Fc receptors, most of which contain immunoreceptor tyrosine-based activation motif domains and are thus considered "activating." However, there is a growing appreciation of these receptors for their ability to deliver an inhibitory signal as well. We previously described one such phenomenon whereby interferon (IFN)γ signaling is inhibited by immune complex signaling through FcγRI. To understand the implications of this in the context of therapeutic antibodies, we assessed individual IgG subclasses to determine their ability to deliver this anti-inflammatory signal in monocyte-derived macrophages. Like IgG1, we found that IgG4 is fully capable of inhibiting IFNγ-mediated events. In addition, F(ab')2 fragments that interfere with FcγRI signaling reversed this effect. For mAbs developed with either an IgG1 or an IgG4 constant region for indications where inflammation is undesirable, further examination of a potential Fc-dependent contribution to their mechanism of action is warranted.
authors.affiliation: a Laboratory of Molecular and Developmental Immunology; Division of Monoclonal Antibodies; Office of Biotechnology Products; Center for Drug Evaluation and Research; Food and Drug Administration ; Bethesda , MD USA.
authors.forename: Jennifer F A
authors.initials: JF
authors.lastname: Swisher
authors.forename: Devin A
authors.initials: DA
authors.lastname: Haddad
authors.forename: Anna G
authors.initials: AG
authors.lastname: McGrath
authors.forename: Gunther H
authors.initials: GH
authors.lastname: Boekhoudt
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Feldman
mesh_terms: D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG; D007371:Interferon-gamma
keywords: Fc gamma receptors; IC, immune complexes; IP-10, Interferon Inducible Protein-10; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; IgG4; TLR, Toll Like Receptor; alternatively activated M2 macrophage; immune complex; monocyte-derived macrophage