title: General mechanism for modulating immunoglobulin effector function.
abstract: Immunoglobulins recognize and clear microbial pathogens and toxins through the coupling of variable region specificity to Fc-triggered cellular activation. These proinflammatory activities are regulated, thus avoiding the pathogenic sequelae of uncontrolled inflammation by modulating the composition of the Fc-linked glycan. Upon sialylation, the affinities for Fcγ receptors are reduced, whereas those for alternative cellular receptors, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)/CD23, are increased. We demonstrate that sialylation induces significant structural alterations in the Cγ2 domain and propose a model that explains the observed changes in ligand specificity and biological activity. By analogy to related complexes formed by IgE and its evolutionarily related Fc receptors, we conclude that this mechanism is general for the modulation of antibody-triggered immune responses, characterized by a shift between an "open" activating conformation and a "closed" anti-inflammatory state of antibody Fc fragments. This common mechanism has been targeted by pathogens to avoid host defense and offers targets for therapeutic intervention in allergic and autoimmune disorders.
authors.affiliation: SuppreMol GmbH, 82152 Martinsried, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sondermann
authors.forename: Andrew
authors.initials: A
authors.lastname: Pincetic
authors.forename: Jad
authors.initials: J
authors.lastname: Maamary
authors.forename: Katja
authors.initials: K
authors.lastname: Lammens
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D007141:Immunoglobulin Fc Fragments; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D017455:Receptors, IgE; D017452:Receptors, IgG; D012794:Sialic Acids; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
keywords: conformational change; sialylated IgG Fc