Mouse model recapitulating human Fcγ receptor structural and functional diversity
Mouse model recapitulating human Fcγ receptor structural and functional diversity
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DOI：
10.1073/pnas.1203954109
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发表时间：
2012-04-17
影响因子：
11.1
通讯作者：
Ravetch, Jeffrey V.
中科院分区：
文献类型：
--
作者：
Smith, Patrick;DiLillo, David J.;Ravetch, Jeffrey V.
IgG抗体的体内生物活性源于其双功能性质，其中Fab的抗原识别与Fc结构域中发现的效应子和免疫调节多样性偶联。由氨基酸和聚糖异质性引起的这种多样性通过Fc γ受体（Fc γ R）转化为细胞应答，Fc γ R是在整个免疫系统中发现的结构和功能多样的细胞表面受体家族。尽管该系统的许多总体特征在整个哺乳动物进化过程中得以保持，但物种多样性已经排除了在动物物种中对人抗体的直接分析，因此，对人IgG抗体及其Fc γ R的独特特征的详细研究受到限制。我们现在报告了小鼠模型的开发，其中所有鼠Fc γ R均已缺失，人Fc γ R（编码为转基因）已插入小鼠基因组中，导致重现人Fc γ R表达的独特特征。这些人Fc γ R显示具有介导人IgG抗体和Fc工程化变体的免疫调节、炎症和细胞毒性活性的功能，并为治疗性和致病性IgG抗体的详细机制分析提供了平台。
The in vivo biological activities of IgG antibodies result from their bifunctional nature, in which antigen recognition by the Fab is coupled to the effector and immunomodulatory diversity found in the Fc domain. This diversity, resulting from both amino acid and glycan heterogeneity, is translated into cellular responses through Fc gamma receptors (Fc gamma Rs), a structurally and functionally diverse family of cell surface receptors found throughout the immune system. Although many of the overall features of this system are maintained throughout mammalian evolution, species diversity has precluded direct analysis of human antibodies in animal species, and, thus, detailed investigations into the unique features of the human IgG antibodies and their Fc gamma Rs have been limited. We now report the development of a mouse model in which all murine Fc gamma Rs have been deleted and human Fc gamma Rs, encoded as transgenes, have been inserted into the mouse genome resulting in recapitulation of the unique profile of human Fc gamma R expression. These human Fc gamma Rs are shown to function to mediate the immunomodulatory, inflammatory, and cytotoxic activities of human IgG antibodies and Fc engineered variants and provide a platform for the detailed mechanistic analysis of therapeutic and pathogenic IgG antibodies.