Sanquin Research and Landsteiner Laboratory, Department of Immunopathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Sanquin Research and Landsteiner Laboratory, Department of Experimental Immunohematology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Front Immunol. 2020 May 6;11:740. doi: 10.3389/fimmu.2020.00740. eCollection 2020.
Antibody dependent cellular cytotoxicity (ADCC) is an Fc-dependent effector function of IgG important for anti-viral immunity and anti-tumor therapies. NK-cell mediated ADCC is mainly triggered by IgG-subclasses IgG1 and IgG3 through the IgG-Fc-receptor (FcγR) IIIa. Polymorphisms in the immunoglobulin gamma heavy chain gene likely form a layer of variation in the strength of the ADCC-response, but this has never been studied in detail. We produced all 27 known IgG allotypes and assessed FcγRIIIa binding and ADCC activity. While all IgG1, IgG2, and IgG4 allotypes behaved similarly within subclass, large allotype-specific variation was found for IgG3. ADCC capacity was affected by residues 291, 292, and 296 in the CH2 domain through altered affinity or avidity for FcγRIIIa. Furthermore, allotypic variation in hinge length affected ADCC, likely through altered proximity at the immunological synapse. Thus, these functional differences between IgG allotypes have important implications for therapeutic applications and susceptibility to infectious-, allo- or auto-immune diseases.
抗体依赖的细胞毒性 (ADCC) 是 IgG 的一种 Fc 依赖性效应功能，对抗病毒免疫和抗肿瘤治疗很重要。NK 细胞介导的 ADCC 主要通过 IgG 亚类 IgG1 和 IgG3 通过 IgG-Fc 受体 (FcγR) IIIa 触发。免疫球蛋白重链基因中的多态性可能形成 ADCC 反应强度的变异层，但这从未被详细研究过。我们产生了所有 27 种已知的 IgG 同种型，并评估了 FcγRIIIa 结合和 ADCC 活性。虽然所有 IgG1、IgG2 和 IgG4 同种型在亚类内表现相似，但 IgG3 存在很大的同种型特异性变异。ADCC 能力受 CH2 结构域中的残基 291、292 和 296 影响，通过改变与 FcγRIIIa 的亲和力或亲合力。此外，铰链长度的同种型变异影响 ADCC，可能通过免疫突触的改变接近度。因此，这些 IgG 同种型之间的功能差异对治疗应用和对感染、同种异体或自身免疫性疾病的易感性具有重要意义。
