Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia;
J Immunol. 2014 Jan 15;192(2):792-803. doi: 10.4049/jimmunol.1301554. Epub 2013 Dec 16.
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.
关于 Fc 受体（FcR）多态性对人类 IgG 结合的影响，人们知之甚少，而对于在临床前疫苗和治疗性抗体评估中使用的猪尾猕猴（Macaca nemestrina）中这种相互作用则一无所知。我们确定了 M. nemestrina 激活型 FcγRIIa（mnFcγRIIa）和抑制型 FcγRIIb（mnFcγRIIb）的序列和与人 IgG 的结合特征，并使用 huIgGFc/huFcγRIIa 晶体结构对其结构进行了预测。与人类 FcR 相比，mnFcγRIIa 和 mnFcγRIIb 对 huIgG 的结合存在很大差异。与 huFcγRIIa（His（131））相比，mnFcγRIIa 对 huIgG1 和 huIgG2 免疫复合物的结合明显受损。相比之下，mnFcγRIIb 对 huIgG1 的结合增强，特异性更广，因为与 huFcγRIIb 不同，它能强烈结合 IgG2。mnFcγRIIa 的突变和分子建模表明，Pro（159）和 Tyr（160）破坏了 FG 环与 huIgG 的关键相互作用。mnFcγRIIb 对 huIgG1 和 huIgG2 的增强结合依赖于 His（131）和 Met（132）。重要的是，FcγRIIb 在恒河猴和食蟹猴中均保守 His（131）和 Met（132）。我们发现 mnFcγRIIa 的功能显著多态性，其位置 131 的脯氨酸也是 huFcγRIIa 的一个重要多态性位点，与 mnFcγRIIa His（131）相比，几乎完全消除了 huIgG2 和 huIgG1 的结合，并降低了 huIgG3 的结合。人类和猕猴 FcR 之间 IgG 结合的这些显著种间差异以及种内多态性，对猕猴中抗体和疫苗的临床前评估具有重要意义。
