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研究揭示疫苗诱导免疫血栓性血小板减少症中的抗体表位
2021-07-11 13:27

加拿大麦克马斯特大学Ishac Nazy小组揭示疫苗诱导免疫血栓性血小板减少症中的抗体表位。相关论文于2021年7月7日在线发表在《自然》杂志上。

研究人员表示,疫苗诱导的免疫血栓性血小板减少症(VITT)是COVID-19腺病毒载体疫苗的罕见不良反应。VITT类似于肝素诱导的血小板减少症(HIT),因为它与针对血小板因子 4(PF4)的血小板激活抗体有关;然而,VITT患者在没有肝素暴露的情况下会出现血小板减少和血栓形成。

为了确定来自VITT患者的抗体在PF4上的结合位点,研究人员使用了丙氨酸扫描诱变,并确定了VITT抗PF4抗体(n=5)的结合仅限于8个表面氨基酸,所有这些氨基酸都位于PF上的肝素结合位点内,并且结合被肝素抑制。相比之下,HIT采样(n=10)与对应于PF4上2个不同位点的氨基酸结合。使用生物层干涉仪,研究人员证明VITT抗PF4抗体对PF4和PF4/肝素复合物的结合反应比HIT抗体更强,尽管具有相似的解离率。

这些数据表明,VITT抗体可以通过与PF4上的类似位点结合来模拟肝素的作用,使PF4四聚体聚集并形成免疫复合物,进而导致FcγRIIa依赖性血小板活化。这些结果为可能导致血栓形成的VITT抗体诱导的血小板活化提供了解释。 

附:英文原文

Title: Antibody epitopes in vaccine-induced immune thrombotic thrombocytopenia

Author: Angela Huynh, John G Kelton, Donald M Arnold, Mercy Daka, Ishac Nazy

Issue&Volume: 2021-07-07

Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines1–3. VITT resembles heparin-induced thrombocytopenia (HIT) as it is associated with platelet-activating antibodies against platelet factor 4 (PF4)4; however, patients with VITT develop thrombocytopenia and thrombosis without heparin exposure. The objective of this study was to determine the binding site on PF4 of antibodies from patients with VITT. Using alanine scanning mutagenesis5, we determined the binding of VITT anti-PF4 antibodies (n=5) was restricted to 8 surface amino acids, all of which were located within the heparin binding site on PF4, and the binding was inhibited by heparin. In contrast, HIT sampled (n=10) bound to amino acids corresponding to 2 different sites on PF4. Using biolayer interferometry, we demonstrated VITT anti-PF4 antibodies had a stronger binding response against PF4 and PF4/heparin complexes than HIT antibodies; albeit, with similar dissociation rates. Our data indicates VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4, allowing PF4 tetramers to cluster and form immune complexes, which in turn cause FcγRIIa-dependent platelet activation. These results provide an explanation for VITT antibody-induced platelet activation that could contribute to thrombosis.

DOI: 10.1038/s41586-021-03744-4

Source: https://www.nature.com/articles/s41586-021-03744-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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