IL-1RA Antibodies in Myocarditis after SARS-CoV-2 Vaccination
Lorenz Thurner, Christoph Kessel, Natalie Fadle, et al
N Engl J Med September 21, 2022
DOI: 10.1056/NEJMc2205667
TO THE EDITOR:
Myocarditis associated with messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly affects male adolescents and young male adults (14 to <30 years of age) and typically occurs after receipt of the second vaccine dose.1,2 In adults with critical coronavirus disease 2019 (Covid-19) and in cases of multisystem inflammatory syndrome in children (MIS-C), we recently discovered neutralizing autoantibodies targeting the endogenous interleukin-1 receptor antagonist (IL-1RA), which inhibits interleukin-1 signaling and inflammation.3,4
In this study, we evaluated the prevalence of antibodies neutralizing IL-1RA and progranulin, which inhibits tumor necrosis factor signaling, in 69 patients (14 to 79 years of age) who had clinically suspected myocarditis after SARS-CoV-2 vaccination. A total of 61 patients underwent endomyocardial biopsy.
Figure 1. Autoantibodies Targeting IL-1RA in Myocarditis after SARS-CoV-2 Vaccination.
Myocarditis was confirmed by biopsy in 40 of 61 patients (Figure 1A). Among patients with histologically confirmed myocarditis, anti–IL-1RA antibodies were found in 9 of 12 patients (75%) younger than 21 years of age, as compared with 3 of 28 patients (11%) 21 years of age or older. Anti–IL-1RA antibodies were not detectable in the 21 patients in whom biopsy ruled out the diagnosis of myocarditis (Figure 1B and 1C). IL-1RA antibody–positive patients with biopsy-confirmed myocarditis had an early onset of symptoms, which occurred mostly after receipt of the second vaccine dose, and a milder course of myocarditis than patients with biopsy-confirmed myocarditis but without anti–IL-1RA autoantibodies (Tables S1 through S6 and Figs. S1 through S6 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).1,2
IL-1RA antibodies were observed in 2 of 214 vaccinated control participants (1%) and in 2 of 125 participants (2%) who had histologically proven myocarditis that had been diagnosed before the Covid-19 pandemic. Previous data that had been obtained from patients with critical Covid-19 did not support the cross-reactivity of purified IL-1RA antibodies with structural proteins of SARS-CoV-2, including the spike protein,3 which argues against virus- or vaccine-driven molecular mimicry.
Current evidence points toward a transient hyperphosphorylation of IL-1RA preceding a breakdown of peripheral immune tolerance.3,4 In Western blots of total plasma protein, antibodies to IL-1RA coincided with weaker bands of free IL-1RA, but prominent immune (IgM or IgG)–complexed protein with an atypical IL-1RA isoform occurred exclusively in patients who were seropositive for anti–IL-1RA antibodies (Figure 1D). This additional IL-1RA isoform was hyperphosphorylated at threonine position 111, which had been observed previously in adult patients with critical Covid-19 and in patients with MIS-C.3,4 In contrast to our observations in patients with myocarditis after SARS-CoV-2 vaccination, IL-1RA was not hyperphosphorylated in any of the samples that had been obtained from control participants.
At the time of acute myocarditis, the mean (±SD) free IL-1RA plasma level in 15 patients who were seropositive for anti–IL-1RA antibodies was 236±82 pg per milliliter, whereas the level was 1736±312 pg per milliliter in 33 patients without anti–IL-1RA antibodies and 1599±277 pg per milliliter in 21 patients in whom histologic testing ruled out the diagnosis of myocarditis (Figure 1F). IL-1RA plasma levels correlated with markers of cardiac damage (troponin T, creatine kinase, creatine kinase MB, or pro–B-type natriuretic peptide), cardiac-tissue infiltration of CD3+ T cells and CD68+ macrophages, and systemic inflammation (C-reactive protein). There was a negative correlation between markers of cardiac damage and IL-1RA plasma levels in patients with anti–IL-1RA antibodies (Figure 1E). Interleukin-1 signaling reporter assay experiments showed direct impairment of IL-1RA bioactivity after the addition of anti–IL-1RA antibodies from patients’ plasma (Figure 1G).
Our study of SARS-CoV-2 vaccination–associated myocarditis and anti–IL-1RA antibodies should be interpreted within the context that the transiency of hyperphosphorylation (as previously reported in patients with critical Covid-19 or MIS-C3,4) and patients’ HLA haplotypes were not known. In our study, neutralizing antibodies against IL-1RA and a hyperphosphorylated IL-1RA isoform were observed in young male patients with biopsy-confirmed myocarditis after the receipt of SARS-CoV-2 mRNA vaccine. These antibodies impaired IL-1RA bioactivity in vitro, were associated with low circulating levels of IL-1RA, and were found in patients with biomarker evidence of cardiac damage and inflammation.
