Publications & Reports

Polymorphisms and Interspecies Differences of the Activating and Inhibitory FcgammaRII of Macaca nemestrina Influence the Binding of Human IgG Subclasses.

Trist HM, Tan PS, Wines BD, Ramsland PA, Orlowski E, Stubbs J, Gardiner EE, Pietersz GA, Kent SJ, Stratov I, Burton DR, Hogarth PM
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia;

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 FcgammaRIIa (mnFcgammaRIIa) and inhibitory FcgammaRIIb (mnFcgammaRIIb) and predicted their structures using the huIgGFc/huFcgammaRIIa crystal structure. Large differences were observed in the binding of huIgG by mnFcgammaRIIa and mnFcgammaRIIb compared with their human FcR counterparts. MnFcgammaRIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFcgammaRIIa (His131). In contrast, mnFcgammaRIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFcgammaRIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFcgammaRIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFcgammaRIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across FcgammaRIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFcgammaRIIa wherein proline at position 131, also an important polymorphic site in huFcgammaRIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFcgammaRIIa His131. 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.

This work was supported by National Health and Medical Research Council Fellowship and Project Grant 1002270 and Program Grant 510448, as well as by the Victorian Operational Infrastructure Support Program.

Full text of this article can be obtined at the publisher’s web site at

http://www.jimmunol.org/content/192/2/792.long

Publication

  • Journal: Journal of Immunology
  • Published: 15/01/2014
  • Volume: 192
  • Issue: 2
  • Pagination: 892-903

Authors