4.8 Article

High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages

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SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 596, 页码 -

出版社

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abf8654

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资金

  1. ZonMw [10430 01 201 0008, 09120011910025, 10430 01 201 0012]
  2. Amsterdam Infection and Immunity COVID-19 grant [24184]
  3. AMC Fellowship
  4. European Union [847551]
  5. Innovative Medicines Initiative 2 Joint Undertaking grant [831434]
  6. Netherlands Heart Foundation
  7. Spark-Holding BV [2015B002, 2019B016]
  8. European Union (ITN-grant EPIMAC)
  9. Fondation Leducq (LEAN-Transatlantic Network Grant)
  10. Amsterdam UMC
  11. Amsterdam Cardiovascular Sciences
  12. LSBR [1908]
  13. Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation
  14. Dutch Federation of University Medical Centers
  15. The Netherlands Organization for Health Research and Development
  16. Royal Netherlands Academy of Sciences (CVON-PHAEDRA IMPACT)
  17. Sanquin Blood Supply Foundation
  18. NWO VICI [91818627]
  19. Bill and Melinda Gates Foundation
  20. European Commission [101015756]

向作者/读者索取更多资源

Patients diagnosed with COVID-19 tend to become critically ill around the activation of the adaptive immune response. Evidence shows that antibodies in serum may worsen the disease during seroconversion. High anti-spike IgG levels in critically ill patients with severe COVID-19 induce excessive inflammatory responses and may lead to pulmonary complications such as microvascular thrombosis.
Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fc gamma receptor (Fc gamma R) Ila and FeyRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.

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