title: Structural basis for Fc gammaRIIa recognition of human IgG and formation of inflammatory signaling complexes.
abstract: The interaction of Abs with their specific FcRs is of primary importance in host immune effector systems involved in infection and inflammation, and are the target for immune evasion by pathogens. FcγRIIa is a unique and the most widespread activating FcR in humans that through avid binding of immune complexes potently triggers inflammation. Polymorphisms of FcγRIIa (high responder/low responder [HR/LR]) are linked to susceptibility to infections, autoimmune diseases, and the efficacy of therapeutic Abs. In this article, we define the three-dimensional structure of the complex between the HR (arginine, R134) allele of FcγRIIa (FcγRIIa-HR) and the Fc region of a humanized IgG1 Ab, hu3S193. The structure suggests how the HR/LR polymorphism may influence FcγRIIa interactions with different IgG subclasses and glycoforms. In addition, mutagenesis defined the basis of the epitopes detected by FcR blocking mAbs specific for FcγRIIa (IV.3), FcγRIIb (X63-21), and a pan FcγRII Ab (8.7). The epitopes detected by these Abs are distinct, but all overlap with residues defined by crystallography to contact IgG. Finally, crystal structures of LR (histidine, H134) allele of FcγRIIa and FcγRIIa-HR reveal two distinct receptor dimers that may represent quaternary states on the cell surface. A model is presented whereby a dimer of FcγRIIa-HR binds Ag-Ab complexes in an arrangement that possibly occurs on the cell membrane as part of a larger signaling assembly.
authors.affiliation: Centre for Immunology, Burnet Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
authors.forename: William
authors.initials: W
authors.lastname: Farrugia
authors.forename: Tessa M
authors.initials: TM
authors.lastname: Bradford
authors.forename: Caroline Tan
authors.initials: CT
authors.lastname: Sardjono
authors.forename: Sandra
authors.initials: S
authors.lastname: Esparon
authors.forename: Halina M
authors.initials: HM
authors.lastname: Trist
authors.forename: Maree S
authors.initials: MS
authors.lastname: Powell
authors.forename: Peck Szee
authors.initials: PS
authors.lastname: Tan
authors.forename: Angela C
authors.initials: AC
authors.lastname: Cendron
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wines
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: P Mark
authors.initials: PM
authors.lastname: Hogarth
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D020836:Protein Structure, Quaternary; D017452:Receptors, IgG / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D020349:Surface Plasmon Resonance
chemical_list: D000936:Antigen-Antibody Complex; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D017452:Receptors, IgG; D011994:Recombinant Proteins