Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia.
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Front Immunol. 2018 Aug 20;9:1809. doi: 10.3389/fimmu.2018.01809. eCollection 2018.
FcγRIIa is an activating FcγR, unique to humans and non-human primates. It induces antibody-dependent proinflammatory responses and exists predominantly as FcγRIIa1. A unique splice variant, we designated FcγRIIa3, has been reported to be associated with anaphylactic reactions to intravenous immunoglobulins (IVIg) therapy. We aim to define the functional consequences of this FcγRIIa variant associated with adverse responses to IVIg therapy and evaluate the frequency of associated SNPs. FcγRIIa forms from macaque and human PBMCs were investigated for IgG-subclass specificity, biochemistry, membrane localization, and functional activity. Disease-associated SNPs were analyzed by sequencing genomic DNA from 224 individuals with immunodeficiency or autoimmune disease. FcγRIIa3 was identified in macaque and human PBMC. The FcγRIIa3 is distinguished from the canonical FcγRIIa1 by a unique 19-amino acid cytoplasmic insertion and these two FcγRIIa forms responded distinctly to antibody ligation. Whereas FcγRIIa1 was rapidly internalized, FcγRIIa3 was retained longer at the membrane, inducing greater calcium mobilization and cell degranulation. Four SNPs were identified including the previously reported intronic SNP associated with anaphylaxis, but in only 1 of 224 individuals. The unique cytoplasmic element of FcγRIIa3 delays internalization and is associated with enhanced cellular activation. The frequency of the immunodeficiency-associated SNP varies between disease populations but interestingly occurred at a lower frequency than previously reported. None-the-less enhanced FcγRIIa3 function may promote a proinflammatory environment and predispose to pathological inflammatory responses.
FcγRIIa 是一种激活型 FcγR，仅存在于人类和非人类灵长类动物中。它诱导抗体依赖的促炎反应，主要以 FcγRIIa1 的形式存在。一种独特的剪接变体，我们称为 FcγRIIa3，已被报道与静脉注射免疫球蛋白 (IVIg) 治疗的过敏反应有关。我们旨在确定与 IVIg 治疗不良反应相关的 FcγRIIa 变体的功能后果，并评估相关单核苷酸多态性的频率。研究了来自猕猴和人 PBMC 的 FcγRIIa 形成物的 IgG 亚类特异性、生物化学、膜定位和功能活性。通过对 224 名免疫缺陷或自身免疫性疾病个体的基因组 DNA 进行测序，分析了与疾病相关的 SNPs。在猕猴和人 PBMC 中鉴定出了 FcγRIIa3。FcγRIIa3 与经典的 FcγRIIa1 不同，其细胞质中插入了独特的 19 个氨基酸，这两种 FcγRIIa 形式对抗体连接的反应明显不同。虽然 FcγRIIa1 迅速内化，但 FcγRIIa3 在膜上的保留时间更长，诱导更大的钙动员和细胞脱颗粒。鉴定出了 4 个 SNPs，包括先前报道的与过敏反应相关的内含子 SNP，但在 224 名个体中仅发现了 1 个。FcγRIIa3 的独特细胞质元件延迟内化，并与增强的细胞激活有关。与免疫缺陷相关的 SNP 的频率在疾病人群中有所不同，但有趣的是，其频率低于先前报道的频率。然而，增强的 FcγRIIa3 功能可能会促进促炎环境，并易患病理性炎症反应。
