title: Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity.
abstract: IgG molecules exert both pro- and antiinflammatory effector functions based on the composition of the fragment crystallizable (Fc) domain glycan. Sialylated IgG Fc domains have antiinflammatory properties that are attributed to their ability to increase the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory Fcγ receptor IIB (FcγRIIB). Here, we report that IgG Fc sialylation of human monoclonal IgG1 molecules impairs their efficacy to induce complement-mediated cytotoxicity (CDC). Fc sialylation of a CD20-targeting antibody had no impact on antibody-dependent cellular cytotoxicity and did not change the affinity of the antibody for activating Fcγ receptors. In contrast, the presence of sialic acid abrogated the increased binding of C1q to Fc-galactosylated IgG1 and resulted in decreased levels of C3b deposition on the cell surface. Similar to monoclonal antibodies, sialic acid inhibited the increased C1q binding to galactosylated Fc fragments in human polyclonal IgG. In sera derived from patients with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system in which humoral immune responses mediate tissue damage, induction of IgG Fc sialylation was associated with clinical disease remission. Thus, impairment of CDC represents an FcγR-independent mechanism by which Fc-sialylated glycovariants might limit proinflammatory IgG effector functions.
authors.forename: Isaak
authors.initials: I
authors.lastname: Quast
authors.forename: Christian W
authors.initials: CW
authors.lastname: Keller
authors.forename: Michael A
authors.initials: MA
authors.lastname: Maurer
authors.forename: John P
authors.initials: JP
authors.lastname: Giddens
authors.forename: Björn
authors.initials: B
authors.lastname: Tackenberg
authors.forename: Lai-Xi
authors.initials: LX
authors.lastname: Wang
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Marinos C
authors.initials: MC
authors.lastname: Dalakas
authors.forename: Jan D
authors.initials: JD
authors.lastname: Lünemann
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000473:pathology; D045744:Cell Line, Tumor; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism; D003171:Complement Pathway, Classical; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology; D007142:Immunoglobulin gamma-Chains / Q000737:chemistry* / Q000276:immunology; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / Q000276:immunology / Q000628:therapy; D011499:Protein Processing, Post-Translational; D017452:Receptors, IgG / Q000276:immunology; D000069283:Rituximab / Q000737:chemistry* / Q000276:immunology
chemical_list: D018951:Antigens, CD20; D007074:Immunoglobulin G; D007142:Immunoglobulin gamma-Chains; D016756:Immunoglobulins, Intravenous; D063308:Myelin-Oligodendrocyte Glycoprotein; D017452:Receptors, IgG; D000069283:Rituximab; D015922:Complement C1q; D003165:Complement System Proteins; D019158:N-Acetylneuraminic Acid