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Polymorphisms and interspecies differences of the activating and inhibitory Fc?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 (His(131)). 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 Pro(159) and Tyr(160) impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFc?RIIb was shown to be dependent on His(131) and Met(132). Significantly, both His(131) and Met(132) 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 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.

SUBMITTER: Trist HM

PROVIDER: S-EPMC4080885 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Polymorphisms and interspecies differences of the activating and inhibitory FcγRII of Macaca nemestrina influence the binding of human IgG subclasses.

Trist Halina M HM Tan Peck Szee PS Wines Bruce D BD Ramsland Paul A PA Orlowski Eva E Stubbs Janine J Gardiner Elizabeth E EE Pietersz Geoffrey A GA Kent Stephen J SJ Stratov Ivan I Burton Dennis R DR Hogarth P Mark PM

Journal of immunology (Baltimore, Md. : 1950) 20131216 2

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 d ...[more]

PMID: 24342805

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Project description:The Fc-glycan profile of IgG1 anti-citrullinated peptide antibodies (ACPA) in rheumatoid arthritis (RA) patients has recently been reported to be different from non-ACPA IgG1, a phenomenon which likely plays a role in RA pathogenesis. Herein we investigate the Fc-glycosylation pattern of all ACPA-IgG isotypes and simultaneously investigate in detail the IgG protein-chain sequence repertoire. IgG from serum or plasma (S/P, n = 14) and synovial fluid (SF, n = 4) from 18 ACPA-positive RA-patients was enriched using Protein G columns followed by ACPA-purification on cyclic citrullinated peptide-2 (CCP2)-coupled columns. Paired ACPA (anti-CCP2 eluted IgG) and IgG flow through (FT) fractions were analyzed by LC-MS/MS-proteomics. IgG peptides, isotypes and corresponding Fc-glycopeptides were quantified and interrogated using uni- and multivariate statistics. The Fc-glycans from the IgG4 peptide EEQFNSTYR was validated using protein A column purification. Relative to FT-IgG4, the ACPA-IgG4 Fc-glycan-profile contained lower amounts (p = 0.002) of the agalacto and asialylated core-fucosylated biantennary form (FA2) and higher content (p = 0.001) of sialylated glycans. Novel differences in the Fc-glycan-profile of ACPA-IgG1 compared to FT-IgG1 were observed in the distribution of bisected forms (n = 5, p = 0.0001, decrease) and mono-antennnary forms (n = 3, p = 0.02, increase). Our study also confirmed higher abundance of FA2 (p = 0.002) and lower abundance of afucosylated forms (n = 4, p = 0.001) in ACPA-IgG1 relative to FT-IgG1 as well as lower content of IgG2 (p = 0.0000001) and elevated content of IgG4 (p = 0.004) in ACPA compared to FT. One λ-variable peptide sequence was significantly increased in ACPA (p = 0.0001). In conclusion, the Fc-glycan profile of both ACPA-IgG1 and ACPA-IgG4 are distinct. Given that IgG1 and IgG4 have different Fc-receptor and complement binding affinities, this phenomenon likely affects ACPA effector- and immune-regulatory functions in an IgG isotype-specific manner. These findings further highlight the importance of antibody characterization in relation to functional in vivo and in vitro studies.

Dataset Information

Polymorphisms and interspecies differences of the activating and inhibitory Fc?RII of Macaca nemestrina influence the binding of human IgG subclasses.

Publications

Polymorphisms and interspecies differences of the activating and inhibitory FcγRII of Macaca nemestrina influence the binding of human IgG subclasses.

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