Polymorphisms and interspecies differences of the activating and inhibitory Fc{gamma}RII of Macaca nemestrina influence the binding of human IgG subclasses

Halina Trist, Peckszee Tan, Bruce D Wines, Paul Allen Ramsland, Eva Orlowski, Janine Stubbs, Elizabeth Ellen Gardiner, Geoffrey A Pietersz, Stephen J Kent, Ivan Stratov, Dennis Burton, Phillip Mark Hogarth

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

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 Fc?RIIa (mnFc?RIIa) and inhibitory Fc?RIIb (mnFc?RIIb) and predicted their structures using the huIgGFc/huFc?RIIa crystal structure. Large differences were observed in the binding of huIgG by mnFc?RIIa and mnFc?RIIb compared with their human FcR counterparts. MnFc?RIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFc?RIIa (His131). In contrast, mnFc?RIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFc?RIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFc?RIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFc?RIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across Fc?RIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFc?RIIa wherein proline at position 131, also an important polymorphic site in huFc?RIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFc?RIIa 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. Copyright ? 2014 by The American Association of Immunologists, Inc.
Original languageEnglish
Pages (from-to)792 - 803
Number of pages12
JournalJournal of Immunology
Volume192
Issue number2
DOIs
Publication statusPublished - 2014

Cite this

@article{71b6530ac876431f98b378cbc2fc2383,
title = "Polymorphisms and interspecies differences of the activating and inhibitory Fc{gamma}RII 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 Fc?RIIa (mnFc?RIIa) and inhibitory Fc?RIIb (mnFc?RIIb) and predicted their structures using the huIgGFc/huFc?RIIa crystal structure. Large differences were observed in the binding of huIgG by mnFc?RIIa and mnFc?RIIb compared with their human FcR counterparts. MnFc?RIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFc?RIIa (His131). In contrast, mnFc?RIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFc?RIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFc?RIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFc?RIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across Fc?RIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFc?RIIa wherein proline at position 131, also an important polymorphic site in huFc?RIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFc?RIIa 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. Copyright ? 2014 by The American Association of Immunologists, Inc.",
author = "Halina Trist and Peckszee Tan and Wines, {Bruce D} and Ramsland, {Paul Allen} and Eva Orlowski and Janine Stubbs and Gardiner, {Elizabeth Ellen} and Pietersz, {Geoffrey A} and Kent, {Stephen J} and Ivan Stratov and Dennis Burton and Hogarth, {Phillip Mark}",
year = "2014",
doi = "10.4049/jimmunol.1301554",
language = "English",
volume = "192",
pages = "792 -- 803",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "2",

}

Polymorphisms and interspecies differences of the activating and inhibitory Fc{gamma}RII of Macaca nemestrina influence the binding of human IgG subclasses. / Trist, Halina; Tan, Peckszee; Wines, Bruce D; Ramsland, Paul Allen; Orlowski, Eva; Stubbs, Janine; Gardiner, Elizabeth Ellen; Pietersz, Geoffrey A; Kent, Stephen J; Stratov, Ivan; Burton, Dennis; Hogarth, Phillip Mark.

In: Journal of Immunology, Vol. 192, No. 2, 2014, p. 792 - 803.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Polymorphisms and interspecies differences of the activating and inhibitory Fc{gamma}RII of Macaca nemestrina influence the binding of human IgG subclasses

AU - Trist, Halina

AU - Tan, Peckszee

AU - Wines, Bruce D

AU - Ramsland, Paul Allen

AU - Orlowski, Eva

AU - Stubbs, Janine

AU - Gardiner, Elizabeth Ellen

AU - Pietersz, Geoffrey A

AU - Kent, Stephen J

AU - Stratov, Ivan

AU - Burton, Dennis

AU - Hogarth, Phillip Mark

PY - 2014

Y1 - 2014

N2 - 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 Fc?RIIa (mnFc?RIIa) and inhibitory Fc?RIIb (mnFc?RIIb) and predicted their structures using the huIgGFc/huFc?RIIa crystal structure. Large differences were observed in the binding of huIgG by mnFc?RIIa and mnFc?RIIb compared with their human FcR counterparts. MnFc?RIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFc?RIIa (His131). In contrast, mnFc?RIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFc?RIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFc?RIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFc?RIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across Fc?RIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFc?RIIa wherein proline at position 131, also an important polymorphic site in huFc?RIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFc?RIIa 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. Copyright ? 2014 by The American Association of Immunologists, Inc.

AB - 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 Fc?RIIa (mnFc?RIIa) and inhibitory Fc?RIIb (mnFc?RIIb) and predicted their structures using the huIgGFc/huFc?RIIa crystal structure. Large differences were observed in the binding of huIgG by mnFc?RIIa and mnFc?RIIb compared with their human FcR counterparts. MnFc?RIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFc?RIIa (His131). In contrast, mnFc?RIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFc?RIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFc?RIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFc?RIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across Fc?RIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFc?RIIa wherein proline at position 131, also an important polymorphic site in huFc?RIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFc?RIIa 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. Copyright ? 2014 by The American Association of Immunologists, Inc.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080885/pdf/nihms595807.pdf

U2 - 10.4049/jimmunol.1301554

DO - 10.4049/jimmunol.1301554

M3 - Article

VL - 192

SP - 792

EP - 803

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 2

ER -