A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy
A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy
复制标题
DOI：
10.1182/blood-2013-09-527978
复制
发表时间：
2014-01-23
期刊：
影响因子：
20.3
通讯作者：
Vidarsson, Gestur
中科院分区：
文献类型：
--
作者：
Kapur, Rick;Kustiawan, Iwan;Vidarsson, Gestur
妊娠期间针对胎儿的人血小板抗原 (HPA) 形成的免疫球蛋白 G (IgG) 介导胎儿或新生儿同种免疫性血小板减少症 (FNAIT)。由于抗体滴度或同种型与疾病严重程度并不严格相关，因此我们通过质谱研究了 IgG Fc 中 Asn297 糖基化的变化，因为该聚糖的组成可能高度可变，影响与吞噬细胞 IgG-Fc 受体 (Fc gamma R) 的结合。我们发现 FNAIT 患者 (n = 48) 的抗 HPA-1a 特异性 IgG1 的核心岩藻糖基化水平显着降低，但血清总 IgG1 没有显着降低。与具有高含量 Fc 岩藻糖的抗体相比，具有低含量岩藻糖的抗体对 Fc γ RIIIa 和 Fc γ RIIIb 显示出更高的结合亲和力，但对 Fc γ RIIa 则不然。因此，使用 Fc γ RIIIb(+) 多形核细胞或 Fc γ RIIIa 1 单核细胞作为效应细胞时，这些含有少量 Fc 岩藻糖的抗体显示出增强的血小板吞噬作用，但使用 Fc γ RIIIa(-) 单核细胞时则不然。此外，抗HPA-1a岩藻糖基化程度与FNAIT中的新生儿血小板计数呈正相关，与临床疾病严重程度呈负相关。与 FNAIT 患者相反，在难治性血小板减少症（血小板输注后）中，未观察到抗 HLA 抗体的核心岩藻糖基化变化，这表明岩藻糖基化水平可能是抗原依赖性的和/或与妊娠定义的免疫环境相关。
Immunoglobulin G (IgG) formed during pregnancy against human platelet antigens (HPAs) of the fetus mediates fetal or neonatal alloimmune thrombocytopenia (FNAIT). Because antibody titer or isotype does not strictly correlate with disease severity, we investigated by mass spectrometry variations in the glycosylation at Asn297 in the IgG Fc because the composition of this glycan can be highly variable, affecting binding to phagocyte IgG-Fc receptors (Fc gamma R). We found markedly decreased levels of core fucosylation of anti-HPA-1a-specific IgG1 from FNAIT patients (n = 48), but not in total serum IgG1. Antibodies with a low amount of fucose displayed higher binding affinity to Fc gamma RIIIa and Fc gamma RIIIb, but not to Fc gamma RIIa, comparedwith antibodieswith a high amount of Fc fucose. Consequently, these antibodies with a low amount of Fc fucose showed enhanced phagocytosis of platelets using Fc gamma RIIIb(+) polymorphonuclear cells or Fc gamma RIIIa 1 monocytes as effector cells, but not with Fc gamma RIIIa(-) monocytes. In addition, the degree of anti-HPA-1a fucosylation correlated positively with the neonatal platelet counts in FNAIT, and negatively to the clinical disease severity. In contrast to the FNAIT patients, no changes in core fucosylation were observed for anti-HLA antibodies in refractory thrombocytopenia (post platelet transfusion), indicating that the level of fucosylation may be antigen dependent and/or related to the immune milieu defined by pregnancy.