doi: 10.1056/NEJMc2205667.
Epub 2022 Sep 21.
IL-1RA Antibodies in Myocarditis after SARS-CoV-2 Vaccination
Affiliations
- PMID: 36130012
- PMCID: PMC9513854
- DOI: 10.1056/NEJMc2205667
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IL-1RA Antibodies in Myocarditis after SARS-CoV-2 Vaccination
N Engl J Med.
.
No abstract available
Figures
Blood plasma samples were obtained from 69 patients with suspected myocarditis after receipt of vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In 61 patients, endomyocardial biopsy (EMB) was performed, and myocarditis was confirmed on EMB in 40 patients (Panel A). Plasma samples that were obtained from 8 patients with no confirmatory investigation on EMB, from 21 patients in whom the diagnosis of myocarditis was ruled out, and from 40 patients in whom myocarditis was confirmed on EMB were analyzed for antibodies against endogenous interleukin-1 receptor antagonist (IL-1RA) and progranulin by enzyme-linked immunosorbent assay (ELISA). Data are shown sorted according to the age of the study participants (Panel B). OD490 denotes optical density as measured at a wavelength of 490 nm. The frequency of anti–IL-1RA antibodies in plasma samples from patients with vaccine-associated myocarditis was confirmed or ruled out on EMB and was sorted according to age. Control participants were 214 healthy adults who had samples obtained 1 week after receipt of the second dose of SARS-CoV-2 vaccine and 127 patients with myocarditis whose samples were obtained before 2020 (Panel C). Western blots of native gradient polyacrylamide gel electrophoresis (PAGE) revealed immune-complexed IL-1RA and weakened bands resembling free IL-1RA (16 kDa) in plasma samples seropositive for anti–IL-1RA. In identical samples, isoelectric focusing of IL-1RA revealed a differentially charged IL-1RA isoform (Panel D). Multiple Spearman’s correlation analyses were conducted of IL-1RA plasma levels in anti–IL-1RA–positive patients (left graph) and autoantibody-negative patients (right graph) with the use of troponin T (Trop T; in units per milliliter), creatine kinase (CK and CK-MB; in picograms per milliliter), pro–B-type natriuretic peptide (pro-BNP; in units per milliliter), and CD3+ cells (normal value, <7 per square millimeter) and CD68+ cells (per square millimeter) infiltrating the tissue of the right or left ventricle, respectively, as well as C-reactive protein (CRP; in milligrams per deciliter). Numbers indicate the respective Spearman’s r (*P<0.05, and **P<0.01) (Panel E). IL-1RA plasma levels were determined by ELISA in patients with vaccination-associated myocarditis. Data are shown as violin plots; in each plot, dots indicate individual samples, the solid horizontal line the median, dotted horizontal lines the upper and lower quartiles, and the shaded area the probability density. Data were analyzed by Brown-Forsythe and Welch analysis of variance and Dunnett’s T3 multiple comparisons test (Panel F). Human embryonic kidney IL-1 reporter cells (releasing secreted embryonic alkaline phosphatase on IL-1β signaling) were incubated with tumor necrosis factor α (TNF-α), IL-1β , and IL-1β with anakinra or recombinant human IL-1RA (rec hIL-1RA). Plasma from adult patients with critical coronavirus disease 2019, without and with IL-1RA antibodies, and from patients with myocarditis after SARS-CoV-2 vaccination, without or with IL-1RA antibodies, were added (all plasma in 1:20 dilution). Recombinant anti–IL-1RA antibody and recombinant anti–stomatin-like protein 2 antibody were used as positive and negative controls, respectively (Panel G). 𝙸 bars indicate the standard deviation of the mean. OD650 denotes optical density as measured at a wavelength of 650 nm, and VAM vaccination-associated myocarditis.
References
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- Thurner L, Fadle N, Bewarder M, et al. Autoantibodies against progranulin and IL-1 receptor antagonist in critically ill COVID-19. April 26, 2021. (https://www.biorxiv.org/content/10.1101/2021.04.23.441188v1). preprint.