Endothelial Cell–Activating Antibodies in COVID‐19

  1. Hui Shi
  2. Yu Zuo
  3. Sherwin Navaz
  4. Alyssa Harbaugh
  5. Claire K. Hoy
  6. Alex A. Gandhi
  7. Gautam Sule
  8. Srilakshmi Yalavarthi
  9. Kelsey Gockman
  10. Jacqueline A. Madison
  11. Jintao Wang
  12. Melanie Zuo
  13. Yue Shi
  14. Michael D. Maile
  15. Jason S. Knight
  16. Yogendra Kanthi

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Abstract

While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID‐19, the upstream mediators of endotheliopathy remain, for the most part, unknown. This study was undertaken to identify circulating factors contributing to endothelial cell activation and dysfunction in COVID‐19.

Methods

Human endothelial cells were cultured in the presence of serum or plasma from 244 patients hospitalized with COVID‐19 and plasma from 100 patients with non–COVID‐19–related sepsis. Cell adhesion molecules (E‐selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 [ICAM‐1]) were quantified using in‐cell enzyme‐linked immunosorbent assay.

Results

Serum and plasma from COVID‐19 patients increased surface expression of cell adhesion molecules. Furthermore, levels of soluble ICAM‐1 and E‐selectin were elevated in patient serum and correlated with disease severity. The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID‐19 serum to activate endothelium. Depletion of total IgG from antiphospholipid antibody–positive serum markedly reduced the up‐regulation of cell adhesion molecules. Conversely, supplementation of control serum with patient IgG was sufficient to trigger endothelial activation.

Conclusion

These data are the first to indicate that some COVID‐19 patients have potentially diverse antibodies that drive endotheliopathy, providing important context regarding thromboinflammatory effects of autoantibodies in severe COVID‐19.

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  1. Version published to 10.1002/art.42094
  2. ScreenIT

    SciScore for 10.1101/2021.01.18.21250041: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Patient consent for publication: N/A Ethics approval: This study complied with all relevant ethical regulations, and was approved by the University of Michigan Institutional Review Board (HUM00179409).
    IRB: Patient consent for publication: N/A Ethics approval: This study complied with all relevant ethical regulations, and was approved by the University of Michigan Institutional Review Board (HUM00179409).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe average age was 62, while 47% were female and 42% were Black/African American (Supplemental Table 1); 35% were receiving mechanical ventilation.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.01.18.21250041 on medRxiv