Crucial Role of Aspartic Acid at Position 265 in the CH2 Domain for Murine IgG2a and IgG2b Fc-Associated Effector Functions
Crucial Role of Aspartic Acid at Position 265 in the CH2 Domain for Murine IgG2a and IgG2b Fc-Associated Effector Functions
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DOI：
10.4049/jimmunol.181.9.6664
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发表时间：
2008-11-01
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;Shinohara, Yasuro;Izui, Shozo
小鼠IgG 1中265位（D265 A）的天冬氨酸被丙氨酸取代导致该同种型与低亲和力IgG Fc受体（Fc γ RIIB和Fc γ RIII）之间的相互作用完全丧失。然而，尚未确定D265 A置换是否对与其他两种Fc γ R（Fc γ RI和Fc γ RIV）的相互作用以及对补体激活表现出相似的影响。为了解决这个问题，产生了带有D265 A突变的34-3C抗RBC IgG 2a和IgG 2b开关变体，并将它们的效应器功能和体内致病性与相应的野生型Ab进行了比较。D265 A突变的引入几乎完全消除了34-3C IgG 2a和IgG 2b与所有四类Fc γ R的结合以及补体的激活。因此，这些突变体几乎没有致病性。尽管发现这些突变体的寡糖侧链含有比野生型Ab更高水平的唾液酸，但酶促去唾液酸化D265 A变体的分析排除了D265 A突变体的非常差的Fc相关效应子功能是由于突变体Fc唾液酸化水平增加的可能性。因此，我们的研究结果表明，天冬氨酸在位置265是一个残基，可能是通过定义一个关键的三维结构的Fc区触发Fc相关的效应功能的IgG。免疫学杂志，2008，181：6664-6669.
Replacement of aspartic acid by alanine at position 265 (D265A) in mouse IgG1 results in a complete loss of interaction between this isotype and low-affinity IgG Fc receptors (Fc gamma RIIB and Fc gamma RIII). However, it has not yet been defined whether the D265A substitution could exhibit similar effects on the interaction with two other Fc gamma R (Fc gamma RI and Fc gamma RIV) and on the activation of complement. To address this question, 34-3C anti-RBC IgG2a and IgG2b switch variants bearing the D265A mutation were generated, and their effector functions and in vivo pathogenicity were compared with those of the respective wild-type Abs. The introduction of the D265A mutation almost completely abolished the binding of 34-3C IgG2a and IgG2b to all four classes of Fc gamma R and the activation of complement. Consequently, these mutants were hardly pathogenic. Although oligosaccharide side chains of these mutants were found to contain higher levels of sialic acids than those of wild-type Abs, the analysis of enzymatically desialylated D265A variants ruled out the possibility that very poor Fc-associated effector functions of the D265A mutants were due to an increased level of the mutant Fc sialylation. Thus, our results demonstrate that aspartic acid at position 265 is a residue critically implicated in triggering the Fc-associated effector functions of IgG, probably by defining a crucial three-dimensional structure of the Fc region. The Journal of Immunology, 2008, 181: 6664-6669.