近日，加拿大麦克马斯特大学Theodore E. Warkentin团队报道了腺病毒刺激抗原与VITT的体细胞超突变。该项研究成果发表在2026年2月12日出版的《新英格兰医学杂志》上。

疫苗诱导的免疫性血小板减少症和血栓形成（VITT）是一种罕见的促血栓形成并发症，发生在基于腺病毒载体的冠状病毒疫苗接种后；在极少数情况下，也可能发生在自然腺病毒感染之后。VITT 是由针对高阳离子蛋白血小板因子4（PF4）的血小板活化抗体介导的。其潜在的诱发抗原触发因素和免疫发病机制尚不清楚。

研究组使用抗体蛋白质组学方法，确定了来自21名VITT患者的抗PF4抗体的氨基酸序列，并对来自100名VITT患者的免疫球蛋白轻链高变区编码基因进行了测序。为确定腺病毒触发因素，利用抗PF4抗体和抗腺病毒蛋白抗体的抗原结合指纹图谱来识别共享的血清克隆型，随后使用腺病毒蛋白肽和重组抗PF4 VITT抗体来定位模拟的线性表位。

VITT抗体的基因组和蛋白质组学分析揭示了一个共享的免疫球蛋白轻链等位基因 IGLV3-21*02 或 *03，该基因携带一个关键的体细胞高频突变 K31E。只有针对腺病毒核心蛋白 VII（pVII）纯化的抗体含有与VITT指纹图谱匹配的抗PF4抗体种类；针对完整病毒颗粒或其他腺病毒蛋白的抗体则不含有。交叉反应性IgG被定位到pVII上的一个碱性线性表位。将一种致病性抗PF4 VITT抗体回复突变为胚系型（K31）后，其在体外和体内的促血栓形成活性均丧失，并且优先结合pVII，这一发现直接支持了该高频突变在从腺病毒pVII到PF4的抗原转换中的作用。

该研究结果表明，当携带免疫球蛋白轻链等位基因 IGLV3-21*02 或 *03 的个体中，针对腺病毒核心蛋白pVII上特定表位的抗体发生特定的体细胞高频突变，导致抗体靶向错误地指向PF4时，就会发生VITT。

附：英文原文

Title: Adenoviral Inciting Antigen and Somatic Hypermutation in VITT

Author: Jing Jing Wang, Linda Schnborn, Theodore E. Warkentin, Luisa Müller, Thomas Thiele, Lena Ulm, Uwe Vlker, Sabine Ameling, Sren Franzenburg, Lars Kaderali, Ana Tzvetkova, Alex Colella, Tim Chataway, Chee Wee Tan, Bridie Armour, Alexander Troelnikov, Lucy Rutten, James McCluskey, Roland Zahn, Tom P. Gordon, Andreas Greinacher

Issue&Volume: 2026-02-12

Abstract:

Background

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare prothrombotic complication that occurs after adenoviral vector–based vaccination against coronavirus disease 2019; in rare cases, it can also occur after natural adenovirus infection. VITT is mediated by platelet-activating antibodies against the highly cationic protein platelet factor 4 (PF4). The underlying inciting antigen trigger and immunopathogenesis remain unknown.

Methods

We used antibody proteomics to determine the amino acid sequences of anti-PF4 antibodies from 21 patients with VITT and sequenced the genes encoding the immunoglobulin light-chain hypervariable region from 100 patients with VITT. To identify an adenoviral trigger, we used the antigen-binding fingerprints of anti-PF4 and anti–adenovirus protein antibodies to identify a shared serum clonotype and subsequently used adenovirus protein peptides and recombinant anti-PF4 VITT antibodies to map the mimicking linear epitope.

Results

Genomic and proteomic profiling of VITT antibodies revealed a shared immunoglobulin light-chain allele, IGLV3-21*02 or *03, harboring a critical somatic hypermutation, K31E. Only antibodies purified against adenoviral core protein VII (pVII) contained anti-PF4 species matching the VITT fingerprint; antibodies against intact virions or other adenoviral proteins did not. Cross-reactive IgGs were mapped to a basic linear epitope on pVII. A pathogenic anti-PF4 VITT antibody, back-mutated to germline (K31), lost its prothrombotic activity in vitro and in vivo and preferentially bound pVII, a finding that directly supported the role of the hypermutation in the antigenic shift from adenovirus pVII to PF4.

Conclusions

The results of our study indicate that VITT occurs when, in persons with immunoglobulin light-chain allele IGLV3-21*02 or *03, a specific somatic hypermutation develops that affects antibodies that recognize a specific epitope on the adenoviral core protein pVII, which results in misdirection of antibody targeting toward PF4.

DOI: NJ202602123940710

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2514824