Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody.
Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody.
复制标题
补体激活有选择地增强高亲和力抗雄激素自身抗体的IgG2b和IgG3同种型的致病性。
DOI：
10.1084/jem.20012024
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发表时间：
2002-03-18
影响因子：
15.3
通讯作者：
Izui, Shozo
中科院分区：
文献类型：
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作者：
Azeredo da Silveira, Samareh;Kikuchi, Shuichi;Fossati-Jimack, Liliane;Moll, Thomas;Saito, Takashi;Verbeek, J Sjef;Botto, Marina;Walport, Mark J;Carroll, Michael;Izui, Shozo
通过生成高亲和力34-3C抗红细胞自身抗体的四种IgG同型开关变体，并将其与我们之前研究的低亲和力4C8抗红细胞自身抗体的IgG变体进行比较，我们在本研究中评估了与红细胞的高亲和力结合如何影响每个IgG同型的致病性，以及Fcγ受体（Fcγ r）和补体各自的贡献。34-3C自身抗体可广泛活化循环红细胞，除IgG1同型外，可有效激活体内补体（IgG2a = IgG2b > IgG3），而4C8 IgG自身抗体不能激活补体。IgG2b和IgG3同型的34-3C自身抗体的致病性显著高于4C8抗体的相应同型（约200倍）。这种增强的活性高度（IgG2b）或完全（IgG3）依赖于补体。相比之下，红细胞结合亲和力仅在34-3C和4C8抗体的IgG1和IgG2a同型的体内溶血活性中发挥次要作用，补体分别不参与或仅部分参与。四种不同的低亲和力和高亲和力的抗红细胞自身抗体的IgG同型在体内激活fc γ r承载效应细胞和补体的能力显著不同，证明了自身抗体亲和成熟和IgG同型转换在自身抗体介导的病理中的作用。
By generating four IgG isotype-switch variants of the high affinity 34–3C anti-erythrocyte autoantibody, and comparing them to the IgG variants of the low affinity 4C8 anti-erythrocyte autoantibody that we have previously studied, we evaluated in this study how high affinity binding to erythrocytes influences the pathogenicity of each IgG isotype in relation to the respective contributions of Fcγ receptor (FcγR) and complement. The 34–3C autoantibody opsonizing extensively circulating erythrocytes efficiently activated complement in vivo (IgG2a = IgG2b > IgG3), except for the IgG1 isotype, while the 4C8 IgG autoantibody failed to activate complement. The pathogenicity of the 34–3C autoantibody of IgG2b and IgG3 isotypes was dramatically higher (>200-fold) than that of the corresponding isotypes of the 4C8 antibody. This enhanced activity was highly (IgG2b) or totally (IgG3) dependent on complement. In contrast, erythrocyte-binding affinities only played a minor role in in vivo hemolytic activities of the IgG1 and IgG2a isotypes of 34–3C and 4C8 antibodies, where complement was not or only partially involved, respectively. The remarkably different capacities of four different IgG isotypes of low and high affinity anti-erythrocyte autoantibodies to activate FcγR-bearing effector cells and complement in vivo demonstrate the role of autoantibody affinity maturation and of IgG isotype switching in autoantibody-mediated pathology.