title: Polymorphisms and interspecies differences of the activating and inhibitory FcγRII of Macaca nemestrina influence the binding of human IgG subclasses.
abstract: Little is known of the impact of Fc receptor (FcR) polymorphism in macaques on the binding of human (hu)IgG, and nothing is known of this interaction in the pig-tailed macaque (Macaca nemestrina), which is used in preclinical evaluation of vaccines and therapeutic Abs. We defined the sequence and huIgG binding characteristics of the M. nemestrina activating FcγRIIa (mnFcγRIIa) and inhibitory FcγRIIb (mnFcγRIIb) and predicted their structures using the huIgGFc/huFcγRIIa crystal structure. Large differences were observed in the binding of huIgG by mnFcγRIIa and mnFcγRIIb compared with their human FcR counterparts. MnFcγRIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFcγRIIa (His(131)). In contrast, mnFcγRIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFcγRIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFcγRIIa showed that Pro(159) and Tyr(160) impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFcγRIIb was shown to be dependent on His(131) and Met(132). Significantly, both His(131) and Met(132) are conserved across FcγRIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFcγRIIa wherein proline at position 131, also an important polymorphic site in huFcγRIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFcγRIIa His(131). These marked interspecies differences in IgG binding between human and macaque FcRs and polymorphisms within species have implications for preclinical evaluation of Abs and vaccines in macaques.
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Halina M
authors.initials: HM
authors.lastname: Trist
authors.forename: Peck Szee
authors.initials: PS
authors.lastname: Tan
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wines
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
authors.forename: Eva
authors.initials: E
authors.lastname: Orlowski
authors.forename: Janine
authors.initials: J
authors.lastname: Stubbs
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gardiner
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Pietersz
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
authors.forename: Ivan
authors.initials: I
authors.lastname: Stratov
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: P Mark
authors.initials: PM
authors.lastname: Hogarth
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008254:Macaca nemestrina / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D017452:Receptors, IgG