IL-1RA Antibodies in Myocarditis after SARS-CoV-2 Vaccination

This observational study investigated the prevalence and effects of neutralizing autoantibodies against interleukin-1 receptor antagonist (IL-1RA) in patients with myocarditis following SARS-CoV-2 mRNA vaccination. Among 69 individuals (14–79 years) with suspected myocarditis, biopsy-confirmed cases showed anti-IL-1RA autoantibodies predominantly in younger males (75% under age 21 vs. 11% in older patients). No antibodies were detected in biopsy-negative cases. A hyperphosphorylated IL-1RA isoform (threonine position 111) was found only in antibody-positive patients and was associated with reduced IL-1RA plasma levels and increased inflammatory markers (e.g., troponin T, CK-MB, CRP). Functional assays demonstrated impaired IL-1RA activity, suggesting the autoantibodies contribute directly to immune dysregulation. Controls including vaccinated individuals without myocarditis and pre-pandemic myocarditis cases—rarely exhibited IL-1RA antibodies. The study argues against molecular mimicry with the SARS-CoV-2 spike protein, implicating transient post-vaccine modifications in IL-1RA as a trigger. These findings offer mechanistic insight into a subset of vaccine-associated myocarditis with distinct immunologic features.

This observational study investigated the prevalence and effects of neutralizing autoantibodies against interleukin-1 receptor antagonist (IL-1RA) in patients with myocarditis following SARS-CoV-2 mRNA vaccination. Among 69 individuals (14–79 years) with suspected myocarditis, biopsy-confirmed cases showed anti-IL-1RA autoantibodies predominantly in younger males (75% under age 21 vs. 11% in older patients). No antibodies were detected in biopsy-negative cases. A hyperphosphorylated IL-1RA isoform (threonine position 111) was found only in antibody-positive patients and was associated with reduced IL-1RA plasma levels and increased inflammatory markers (e.g., troponin T, CK-MB, CRP). Functional assays demonstrated impaired IL-1RA activity, suggesting the autoantibodies contribute directly to immune dysregulation. Controls including vaccinated individuals without myocarditis and pre-pandemic myocarditis cases—rarely exhibited IL-1RA antibodies. The study argues against molecular mimicry with the SARS-CoV-2 spike protein, implicating transient post-vaccine modifications in IL-1RA as a trigger. These findings offer mechanistic insight into a subset of vaccine-associated myocarditis with distinct immunologic features.