Evaluating IL1RA-Autoantibodies Across SARS-CoV-2-Related Diseases

Anish Behere¹, Pär Hallberg², Axel Cederholm¹, Marco Cavalli^{2

3}, Ahmet Yalcinkaya^{1

4}; COVID‐HGE; Paul Bastard^{5

6

7

8}, Anne Puel^{6

7

8}, Jean-Laurent Casanova^{6

7

8

9

10}, Mia Wadelius², Petter Brodin^{11

12

13}, Nils Landegren¹

Affiliations

¹ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
² Department of Medical Sciences, Clinical Pharmacogenomics, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
³ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁴ Department of Medical Biochemistry, Hacettepe University Hospital, Ankara, Turkey.
⁵ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, (Assistance Publique-Hôpitaux de Paris) AP-HP, Paris Cité University, Paris, France.
⁶ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
⁷ Imagine Institute, Paris Cité University, Paris, France.
⁸ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
⁹ Howard Hughes Medical Institute, New York, New York, USA.
¹⁰ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
¹¹ Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
¹² Department of Immunology and Inflammation, Imperial College London, London, UK.
¹³ Medical Research Council London Institute of Medical Sciences (LMS), Imperial College Hammersmith Campus, London, UK.

PMID: 40556349
PMCID: PMC12188108
DOI: 10.1111/sji.70039

Evaluating IL1RA-Autoantibodies Across SARS-CoV-2-Related Diseases

Anish Behere et al. Scand J Immunol. 2025 Jul.

. 2025 Jul;102(1):e70039.

doi: 10.1111/sji.70039.

Authors

Affiliations

¹ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
² Department of Medical Sciences, Clinical Pharmacogenomics, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
³ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁴ Department of Medical Biochemistry, Hacettepe University Hospital, Ankara, Turkey.
⁵ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, (Assistance Publique-Hôpitaux de Paris) AP-HP, Paris Cité University, Paris, France.
⁶ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
⁷ Imagine Institute, Paris Cité University, Paris, France.
⁸ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
⁹ Howard Hughes Medical Institute, New York, New York, USA.
¹⁰ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
¹¹ Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
¹² Department of Immunology and Inflammation, Imperial College London, London, UK.
¹³ Medical Research Council London Institute of Medical Sciences (LMS), Imperial College Hammersmith Campus, London, UK.

PMID: 40556349
PMCID: PMC12188108
DOI: 10.1111/sji.70039

No abstract available

Keywords: COVID‐19; IL1RA; MIS‐C; adverse events following immunisation; autoantibodies; myocarditis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**FIGURE 1**
Patients with multisystem inflammatory syndrome in children (MIS‐C, n = 28), COVID‐19 vaccine‐associated myocarditis and perimyocarditis (Cardiac AEFI, n = 47), severe COVID‐19 pneumonia (n = 48), COVID‐19 vaccine‐associated thrombosis (Non‐cardiac AEFI, n = 47) plasma samples and blood donor samples were tested for autoantibodies against IL1RA. (A) A heatmap showing the unique antigen‐specific reactivities with log2 fold‐change above the pre‐pandemic blood donor group (grey, n = 38), from a multiplex bead assay experiment. Elevated and shared immunoreactivity against multiple type‐I interferons was observed in the severe COVID‐19 pneumonia patient group. However, none of the disease groups showed elevated immunoreactivity against IL1RA (HEK293T cell‐expression system) (B) In the same experiment, IL1RA protein from three sources, as well as technical controls in the form of a representative type‐I interferon (IFNA16), SARS‐CoV‐2 Spike protein and Epstein–Barr virus Nuclear Antigen (EBNA1) were included. The red‐dotted threshold line indicates mean + 5 SD over MFI value of pre‐pandemic blood donor group, while blue‐dotted line indicates lower limit of detection of the bead assay. (C) IL1RA autoantibodies were measured using a sandwich ELISA with human IL1RA protein. The red‐dotted threshold line indicates mean + 7 SD over OD value at 450 nm of pre‐pandemic blood donors' group. (D) Samples were tested for IL1RA neutralisation using a cell‐based IL1 reporter assay. HEK‐Blue IL‐1β cells were stimulated with recombinant IL‐1β in the presence of IL1RA, with or without rabbit anti‐IL1RA antibody or samples. The resultant release of SEAP in proportion with IL1R‐mediated cell stimulation was measured at 650 nm using manufacturer reagents. The red‐dotted threshold line indicates IC₅₀ threshold calculated based on IL‐1β sole stimulation versus IL‐1β + IL1RA co‐stimulation. IC₅₀, half maximal inhibitory concentration; MFI, Mean Fluorescence Intensity; OD, optical density; SD, standard deviation; SEAP, Secreted Embryonic Alkaline Phosphatase.

See this image and copyright information in PMC

References

1. Bastard P., Rosen L. B., Zhang Q., et al., “Autoantibodies Against Type I IFNs in Patients With Life‐Threatening COVID‐19,” Science 370 (2020): eabd4585. - PMC - PubMed
1. Pfeifer J., Thurner B., Kessel C., et al., “Autoantibodies Against Interleukin‐1 Receptor Antagonist in Multisystem Inflammatory Syndrome in Children: A Multicentre, Retrospective, Cohort Study,” Lancet Rheumatology 4 (2022): e329–e337. - PMC - PubMed
1. Thurner L., Fadle N., Bewarder M., et al., “Autoantibodies Against Progranulin and IL‐1 Receptor Antagonist in Critically Ill COVID‐19,” (2021), 2021.04.23.441188.
1. Thurner L., Kessel C., Fadle N., et al., “IL‐1RA Antibodies in Myocarditis After SARS‐CoV‐2 Vaccination,” New England Journal of Medicine 387 (2022): NEJMc2205667. - PMC - PubMed
1. Solanich X., Rigo‐Bonnin R., Gumucio V.‐D., et al., “Pre‐Existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID‐19 Patients Admitted to Intensive Care in Barcelona,” Journal of Clinical Immunology 41 (2021): 1733–1744. - PMC - PubMed

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Evaluating IL1RA-Autoantibodies Across SARS-CoV-2-Related Diseases

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Evaluating IL1RA-Autoantibodies Across SARS-CoV-2-Related Diseases

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Conflict of interest statement

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