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Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia

机译：疫苗诱导的免疫血栓形成血小板减少症的抗体表位

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Vaccine-induced immune thrombotic thrombocytopaenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines~(1-3). VITT resembles heparin-induced thrombocytopaenia (HIT) in that it is associated with platelet-activating antibodies against platelet factor 4 (PF4)~(4); however, patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin. Here we sought to determine the binding site on PF4 of antibodies from patients with VITT. Using alanine-scanning mutagenesis~(5), we found that the binding of anti-PF4 antibodies from patients with VITT (n = 5) was restricted to eight surface amino acids on PF4, all of which were located within the heparin-binding site, and that the binding was inhibited by heparin. By contrast, antibodies from patients with HIT (n = 10) bound to amino acids that corresponded to two different sites on PF4. Biolayer interferometry experiments also revealed that VITT anti-PF4 antibodies had a stronger binding response to PF4 and PF4-heparin complexes than did HIT anti-PF4 antibodies, albeit with similar dissociation rates. Our data indicate that VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4; this allows PF4 tetramers to cluster and form immune complexes, which in turn causes Fcγ receptor IIa (FcγRIIa; also known as CD32a)-dependent platelet activation. These results provide an explanation for VITT-antibody-induced platelet activation that could contribute to thrombosis.
机译：疫苗诱导的免疫血栓形成血小板减少症（VITT）是Covid-19腺病毒载体疫苗〜（1-3）的罕见不良影响。 vitt类似于肝素诱导的血小板减少（命中），因为它与针对血小板因子4的血小板活化抗体（pf4）〜（4）有关;然而，VITT患者发育血小板减少症和血栓形成而不会暴露于肝素。在这里，我们试图确定来自Vitt患者的抗体PF4上的结合位点。使用丙氨酸扫描诱变〜（5），我们发现，抗PF4抗体与Vitt（n = 5）患者的结合仅限于PF4上的八个表面氨基酸，所有这些都位于肝素结合位点内，并且肝素抑制了结合。相比之下，来自患者的抗体（n = 10）与氨基酸结合，所述氨基酸对应于PF4上的两个不同位点。 Biolayer干涉测量实验还显示Vitt抗PF4抗体对PF4和PF4-肝素复合物具有更强的结合反应，而不是抗PF4抗体，尽管具有类似的解离速率。我们的数据表明，Vitt抗体可以通过与PF4上的类似部位结合而模拟肝素的作用;这允许PF4四聚体簇形成并形成免疫复合物，这反过来导致FCγ受体IIa（FCγRIIA;也称为CD32A） - 依赖性血小板活化。这些结果为Vitt-抗体诱导的血小板活化提供了可能导致血栓形成的解释。

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  • 来源
    《Nature》 |2021年第7873期|565-569|共5页
  • 作者

    Angela Huynh; John G Kelton; Donald M Arnold; Mercy Daka; Ishac Nazy;

  • 作者单位

    Department of Medicine Michael G. DeGroote School of Medicine McMaster University;

    Department of Medicine Michael G. DeGroote School of Medicine McMaster University|McMaster Centre for Transfusion Research McMaster University;

    Department of Medicine Michael G. DeGroote School of Medicine McMaster University|McMaster Centre for Transfusion Research McMaster University;

    Department of Biochemistry and Biomedical Sciences Faculty of Health Sciences McMaster University;

    Department of Medicine Michael G. DeGroote School of Medicine McMaster University|McMaster Centre for Transfusion Research McMaster University;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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