Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19

Florian Tran^{1

2}, Danielle M M Harris^{1

3}, Alena Scharmacher¹, Hanna Graßhoff⁴, Kristina Sterner⁴, Susanne Schinke⁴, Nadja Käding⁵, Jens Y Humrich⁴, Otávio Cabral-Marques^{6

7

8

9

10}, Joana P Bernardes¹, Neha Mishra¹, Thomas Bahmer^{2

11}, Jeanette Franzenburg^{1

12}, Bimba F Hoyer¹³, Andreas Glück², Martina Guggeis^{1

2}, Alexander Ossysek¹, Andre Küller¹⁴, Derk Frank^{14

15}, Christoph Lange^{16

17

18

19}, Jan Rupp⁵, Jan Heyckendorf^{2

16

17

20}, Karoline I Gaede^{16

17

20

21}, Howard Amital²², Philip Rosenstiel¹, Yehuda Shoenfeld^{22

23

24}, Gilad Halpert²², Avi Z Rosenberg²⁵, Kai Schulze-Forster²⁶, Harald Heidecke²⁶, Gabriela Riemekasten^{3

27

28}, Stefan Schreiber^{1

2

28}

Affiliations

¹ Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
² Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
³ Institute for Human Nutrition and Food Science, University Medical Center Schleswig-Holstein, Kiel, Germany.
⁴ Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein, Lübeck, Germany.
⁵ Department of Infectious Diseases and Microbiology, University Medical Center Schleswig-Holstein, Lübeck, Germany.
⁶ Department of Immunology, Instituto de Ciencias Biomedicas, Universidade de São Paulo, São Paulo, SP, Brazil.
⁷ Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
⁸ Network of Immunity in Infection, Malignancy, and Autoimmunity, Universal Scientific Education and Research Network, Sao Paulo, SP, Brazil.
⁹ Department of Medicine, Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
¹⁰ Laboratory of Medical Investigation 29, University of São Paulo School of Medicine, São Paulo, Brazil.
¹¹ LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany.
¹² Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹³ Section for Rheumatology, Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹⁴ Department of Internal Medicine III, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹⁵ German Centre for Cardiovascular Research (DZHK), partner site Hamburg, Kiel, Lübeck, Germany.
¹⁶ Research Center Borstel, Borstel, Germany.
¹⁷ German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Borstel, Germany.
¹⁸ Respiratory Medicine and International Health, University of Lübeck, Lübeck, Germany.
¹⁹ Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
²⁰ Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany.
²¹ BioMaterialBank Nord, Borstel, Germany.
²² Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat-Gan, Israel.
²³ Ariel University, Ariel, Israel.
²⁴ Laboratory of the Mosaic of Autoimmunity, Saint Petersburg State University, Saint-Petersburg, Russia.
²⁵ Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
²⁶ CellTrend GmbH, Luckenwalde, Germany.
²⁷ Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany.
²⁸ These authors contributed equally.

PMID: 36575710
PMCID: PMC9571165
DOI: 10.1183/23120541.00379-2022

Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19

Florian Tran et al. ERJ Open Res. 2022.

. 2022 Dec 27;8(4):00379-2022.

doi: 10.1183/23120541.00379-2022. eCollection 2022 Oct.

Authors

Affiliations

¹ Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
² Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
³ Institute for Human Nutrition and Food Science, University Medical Center Schleswig-Holstein, Kiel, Germany.
⁴ Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein, Lübeck, Germany.
⁵ Department of Infectious Diseases and Microbiology, University Medical Center Schleswig-Holstein, Lübeck, Germany.
⁶ Department of Immunology, Instituto de Ciencias Biomedicas, Universidade de São Paulo, São Paulo, SP, Brazil.
⁷ Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
⁸ Network of Immunity in Infection, Malignancy, and Autoimmunity, Universal Scientific Education and Research Network, Sao Paulo, SP, Brazil.
⁹ Department of Medicine, Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
¹⁰ Laboratory of Medical Investigation 29, University of São Paulo School of Medicine, São Paulo, Brazil.
¹¹ LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany.
¹² Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹³ Section for Rheumatology, Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹⁴ Department of Internal Medicine III, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹⁵ German Centre for Cardiovascular Research (DZHK), partner site Hamburg, Kiel, Lübeck, Germany.
¹⁶ Research Center Borstel, Borstel, Germany.
¹⁷ German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Borstel, Germany.
¹⁸ Respiratory Medicine and International Health, University of Lübeck, Lübeck, Germany.
¹⁹ Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
²⁰ Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany.
²¹ BioMaterialBank Nord, Borstel, Germany.
²² Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat-Gan, Israel.
²³ Ariel University, Ariel, Israel.
²⁴ Laboratory of the Mosaic of Autoimmunity, Saint Petersburg State University, Saint-Petersburg, Russia.
²⁵ Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
²⁶ CellTrend GmbH, Luckenwalde, Germany.
²⁷ Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany.
²⁸ These authors contributed equally.

PMID: 36575710
PMCID: PMC9571165
DOI: 10.1183/23120541.00379-2022

Abstract

In patients with severe #COVID19, increased levels of autoantibodies against PAR1 were found. These might serve as allosteric agonists of PAR1 on endothelial cells and platelets, and thus might contribute to the pathogenesis of microthrombosis in COVID-19. https://bit.ly/3pqM9Vv.

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Conflict of interest statement

Conflict of Interest: T. Bahmer reports grants from BMBF (unrestricted research grant for the German Center for Lung Research (DZL) and National Pandemic Cohort Network (NAPKON) – Coordinating Study Site for population-based cohort platform); lecture fees from Novartis, AstraZeneca, and Chiesi; support for attending the American Thoracic Society Conference from Chiesi; and advisory board participation with GlaxoSmithKline, Boehringer Ingelheim, Roche and AstraZeneca, outside the submitted work. D. Frank reports grants from DFG (467267736), BMBF and DZHK; consulting fees and support for attending meetings from Edwards Lifesciences and Medtronic; lecture honoraria from Edwards Lifesciences, Medtronic, Astra Zeneca, Pfizer, BMS, Novartis, Bayer and Abbott; and participation on advisory boards with BMS, Boehringer Ingelheim, Daiichi Sankyo, outside the submitted work. A.Z. Rosenberg reports grants from the NIH (NIDDK and NHLBI) outside the submitted work. CellTrend is owned by K. Schulze-Forster; CellTrend produces ELISA kits for the determination of antibodies against GPCR. G. Riemekasten reports consulting fees from CellTrend GmbH outside the submitted work. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk, outside the submitted work. All other authors have nothing to disclose.

Figures

**FIGURE 1**
Anti-protease-activated receptor 1 (PAR1) antibodies (abs) correlated with disease severity and survival. a) anti-PAR1 ab levels in serum samples from healthy controls (HC) (29 samples, 29 individuals) and patients with coronavirus disease 2019 (COVID-19), either hospitalised/non-intensive care unit (ICU) (59 samples, 45 individuals) or ICU treatment (52 samples, 29 individuals); linear mixed model (LMM) p=0.092 and 3.36×10⁻⁵, respectively; b) anti-PAR1 ab levels in serum samples from ICU-treated COVID-19 patients in the cohort (29 patients), stratified by the outcome thrombotic events and survival (LMM p=0.0062 and 0.0319, respectively); c) correlation analysis for anti-PAR1 abs in COVID-19 patients against D-dimers. The linear regression line with confidence interval is displayed; statistical analysis is based on LMM (p=0.0010); d) receiver operating characteristic (ROC) analysis of anti-PAR1 abs, D-dimers and combined (upper panels) as well as anti-PAR1 abs, interleukin (IL)-6 and combined (lower panels) for the clinical outcomes “thrombotic events” (left panels) and “survival” (right panels). Areas under the ROC curve (AUC) are indicated in the panels.

See this image and copyright information in PMC

References

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Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19

Affiliations

Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources