Impact of a three amino acid deletion in the CH2 domain of murine IgG1 on Fc-associated effector functions
Impact of a three amino acid deletion in the CH2 domain of murine IgG1 on Fc-associated effector functions
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DOI：
10.4049/jimmunol.181.6.4107
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发表时间：
2008-09-15
影响因子：
4.4
通讯作者：
Izui, Shozo
中科院分区：
文献类型：
--
作者：
Baudino, Lucie;Nimmerjahn, Falk;Izui, Shozo
四种鼠 IgG 亚类表现出明显不同的 Fc 相关效应器功能，因为它们与三种激活 IgG Fc 受体（Fc gamma RI、Fc gamma RIII 和 Fc gamma RIV）和 C1q 的结合存在差异。先前对 34-3C 抗红细胞单克隆自身抗体的 IgG 亚类转换变体的分析表明，仅与 Fc gamma RIII 结合且无法激活补体的 IgG1 亚类表现出最差的致病潜力。这可能与该亚类中独特发现的 CH2 结构域中第 233-235 位的三个氨基酸缺失有关。为了解决这个问题，在 34-3C 抗红细胞抗体的 233-235 位产生了 IgG1 插入和 IgG2b 缺失突变体，并将它们启动效应子功能的能力及其致病性与各自的野生型抗体进行了比较。在位置 233-235 插入氨基酸残基使 IgG1 亚类能够结合 Fc gamma RIV，但没有改善与 C1q 的结合。因此，其致病性有所增强，但仍不如IgG2b。相反，IgG2b 缺失突变体失去了与 Fc gamma RIV 结合并激活补体的能力。因此，其致病性显着降低至与IgG1相当的水平。我们的结果表明，IgG2b 的 Fc gamma R 和补体介导的效应功能的启动受到 233-235 位三个氨基酸缺失的深刻影响，但是这种天然的三个氨基酸缺失只能部分解释 IgG1 与 Fc gamma RIV 和 C1q 的不良结合。这表明 IgG1 亚类中缺乏尚未知的基序，可促进与 Fc gamma RIV 和 C1q 的有效相互作用。
Four murine IgG subclasses display markedly different Fc-associated effector functions because of their differential binding to three activating IgG Fc receptors (Fc gamma RI, Fc gamma RIII, and Fc gamma RIV) and C1q. Previous analysis of IgG subclass switch variants of 34-3C anti-RBC monoclonal autoantibodies revealed that the IgG1 subclass, which binds only to Fc gamma RIII and fails to activate complement, displayed the poorest pathogenic potential. This could be related to the presence of a three amino acid deletion at positions 233-235 in the CH2 domain uniquely found in this subclass. To address this question, IgG1 insertion and IgG2b deletion mutants at positions 233-235 of 34-3C anti-RBC Abs were generated, and their ability to initiate effector functions and their pathogenicity were compared with those of the respective wild-type Abs. The insertion of amino acid residues at positions 233-235 enabled the IgG1 subclass to bind Fc gamma RIV but did not improve the binding to C1q. Accordingly, its pathogenicity was enhanced but still inferior to that of IgG2b. In contrast, the IgG2b deletion mutant lost its ability to bind to Fc gamma RIV and activate complement. Consequently, its pathogenicity was markedly diminished to a level comparable to that of lgG1. Our results demonstrated that the initiation of Fc gamma R- and complement-mediated effector functions of IgG2b was profoundly affected by the three amino acid deletion at positions 233-235, but that this natural three amino acid deletion could only partially explain the poor binding of IgG1 to Fc gamma RIV and C1q. This indicates the lack in the IgG1 subclass of as yet unknown motifs promoting efficient interaction with Fc gamma RIV and C1q.