B-cell response and thrombotic complications in COVID-19

COVID-19 中的 B 细胞反应和血栓并发症

基本信息

  • 批准号:
    10552034
  • 负责人:
  • 金额:
    $ 65.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2026-01-31
  • 项目状态:
    未结题

项目摘要

Abstract COVID-19 severity/lethality is associated with a dysfunctional inflammatory immune response and a hyper- engagement of pathways driving hemostasis and thrombosis, but the link between the two manifestations is not understood. Compared to patients with mild symptoms, severe COVID-19 patients have stronger IgG reactivity to SARS-CoV-2 virus and its spike protein receptor binding domain (RBD) and a robust B-cell response with a marked increase of the CD11c+CD21- B cells and plasmablast compartments. The incidence of thrombosis and inflammatory disease in severe COVID-19 is unprecedented, manifested by increased plasma inflammatory markers, such as IL-6, tumor necrosis factor alpha, C-reactive protein, and activation of compliment pathway etc., and dysregulated activation of cellular components participating in inflammatory and coagulation responses that include platelets, endothelial, monocytes, and neutrophils. The thrombotic manifestation ranges from arterial, venous, and tissue micro thrombosis to thromboembolism and is predominated by venous thromboembolism. Similar manifestations are observed in catastrophic thrombosis associated with heparin- induced thrombocytopenia and thrombosis (HIT). Patients with catastrophic HIT have the sudden onset of multiple arterial and venous thrombi with, but sometime without, heparin exposure, due to prothrombotic platelet- activating IgGs that recognize platelet factor 4 complexed with heparin polysaccharide (PF4/H). Using methods employed in previous studies of HIT, we studied patients with severe COVID-19 patients and identified PF4/H- reactive, pro-thrombotic IgG antibodies that closely resemble pathogenic antibodies found in patients with HIT in their ability to activate platelets. Surprisingly, levels of PF4/H antibodies in the patient plasma correlated with levels of antibodies specific for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. We cloned RBD-specific antibodies that are able to activate platelets. Compared to those that recognize RBD alone, significantly more B cells recognizing both RBD and PF4/H were CD11c+, CD21- and CXCR3+, which mark a subset of extrafollicular B cells robustly expanded in severe COVID-19. Based on these findings, we hypothesize that SARS-CoV-2 infection drives a subset of RBD-specific B cells to respond via an extrafollicular pathway and generate platelet-activating antibodies that contribute to thrombotic complications but not virus neutralization in severe COVID-19. To test our hypothesis, we will 1) investigate the prothrombotic activity of RBD-specific antibodies in the plasma of hospitalized COVID-19 patients; 2) investigate the expansion of B cells that make RBD-specific platelet-activating antibodies in severe COVID-19; 3) investigate the developmental pathway that governs affinity maturation of RBD and PF4/H cross-reactive B cells. Our proposal studies a novel B-cell/platelet axis in thrombotic complications in COVID-19 and should unravel a large portion of the complex pathogenesis of morbidity/mortality in this disease and suggest new treatment.
摘要 新冠肺炎的严重程度/致命性与炎性免疫反应紊乱和高血压有关 驱动止血和血栓形成的通路的参与,但这两种表现之间的联系不是 明白了。与症状较轻的患者相比,重度新冠肺炎患者的免疫球蛋白反应性更强 对SARS-CoV-2病毒及其刺激性蛋白受体结合域(RBD)和强大的B细胞应答 CD11c+CD21-B细胞和浆母细胞明显增多。血栓形成的发生率和 严重新冠肺炎的炎症性疾病是前所未有的,表现为血浆炎症增加 白介素6、肿瘤坏死因子α、C反应蛋白等标志物与补体信号通路的激活 等,以及参与炎症和凝血反应的细胞成分的异常激活 包括血小板、内皮细胞、单核细胞和中性粒细胞。血栓的表现范围从 动脉、静脉和组织微血栓形成到血栓栓塞症,以静脉为主 血栓栓塞症。在与肝素相关的灾难性血栓形成中也观察到类似的表现。 诱发性血小板减少和血栓形成(HIT)。遭受灾难性打击的患者突然发作 多发性动脉和静脉血栓,有,但有时没有,肝素暴露,由于血栓前血小板- 活化识别血小板因子4的免疫球蛋白与肝素多糖(PF4/H)的复合体。使用方法 在先前的HIT研究中,我们研究了重症新冠肺炎患者,并鉴定出pF4/H- 反应性促血栓形成抗体,与HIT患者中发现的致病抗体非常相似 它们激活血小板的能力。令人惊讶的是,患者血浆中的PF4/H抗体水平与 SARS-CoV-2刺突蛋白受体结合域(RBD)的特异性抗体水平。我们克隆了 能够激活血小板的RBD特异性抗体。与那些只识别RBD的人相比, 识别RBD和PF4/H的B细胞明显更多的是CD11c+、CD21-和CXCR3+,这标志着a 重度新冠肺炎患者卵泡外B细胞亚群明显增多。基于这些发现,我们假设 SARS-CoV-2感染驱动RBD特异性B细胞亚群通过卵泡外 途径并产生导致血栓并发症的血小板激活抗体,但不是 病毒中和重度新冠肺炎。为了验证我们的假设,我们将1)研究血栓前病变 住院新冠肺炎患者血浆中RBD特异性抗体活性2)扩张性调查 重症新冠肺炎患者产生RBD特异性血小板活化抗体的B细胞;3)研究 调控RBD和PF4/H交叉反应B细胞亲和力成熟的发育途径。我们的建议 新冠肺炎血栓并发症中新的B细胞/血小板轴的研究应该会揭开很大一部分 研究这种疾病发病率/死亡率的复杂发病机制,并提出新的治疗方法。

项目成果

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Renren Wen其他文献

Renren Wen的其他文献

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{{ truncateString('Renren Wen', 18)}}的其他基金

B-cell response and thrombotic complications in COVID-19
COVID-19 中的 B 细胞反应和血栓并发症
  • 批准号:
    10343238
  • 财政年份:
    2022
  • 资助金额:
    $ 65.99万
  • 项目类别:
Molecular Basis of the Humoral Immune Response in Heparin-Induced Thrombocytopenia
肝素诱导的血小板减少症体液免疫反应的分子基础
  • 批准号:
    10176180
  • 财政年份:
    2019
  • 资助金额:
    $ 65.99万
  • 项目类别:
Molecular Basis of the Humoral Immune Response in Heparin-Induced Thrombocytopenia
肝素诱导的血小板减少症体液免疫反应的分子基础
  • 批准号:
    10491676
  • 财政年份:
    2019
  • 资助金额:
    $ 65.99万
  • 项目类别:
Functions of Bcl10 in Lymphocytes
Bcl10 在淋巴细胞中的功能
  • 批准号:
    7929077
  • 财政年份:
    2009
  • 资助金额:
    $ 65.99万
  • 项目类别:
Individual and Collaborative Roles in T Cell Activation
T 细胞激活中的个体和协作作用
  • 批准号:
    6653204
  • 财政年份:
    2002
  • 资助金额:
    $ 65.99万
  • 项目类别:
Individual and Collaborative Roles in T Cell Activation
T 细胞激活中的个体和协作作用
  • 批准号:
    6532033
  • 财政年份:
    2002
  • 资助金额:
    $ 65.99万
  • 项目类别:
Individual and Collaborative Roles in T Cell Activation
T 细胞激活中的个体和协作作用
  • 批准号:
    6703689
  • 财政年份:
    2002
  • 资助金额:
    $ 65.99万
  • 项目类别:
Individual and Collaborative Roles in T Cell Activation
T 细胞激活中的个体和协作作用
  • 批准号:
    6845115
  • 财政年份:
    2002
  • 资助金额:
    $ 65.99万
  • 项目类别:

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