Combined Adaptive Immune Mechanisms Mediate Cardiac Injury After COVID-19 Vaccination
Abstract
BACKGROUND: The COVID-19 pandemic, caused by SARS-CoV-2, has led to the first approval of mRNA vaccines in humans. By producing the full-length SARS-CoV-2 Spike protein, they induce protective antiviral immunity. Acute myopericarditis (AMP) development after vaccination has repeatedly been reported; however, the pathogenesis of this complication remains elusive. METHODS: In-depth phenotyping of peripheral blood T cells was undertaken in cohorts of patients who developed AMP after mRNA vaccination, patients hospitalized for severe COVID-19, and healthy subjects with no cardiac side effects after mRNA vaccine. Validation studies were carried out using an experimental model of cardiac inflammation, in which a shared epitope elicits functional responses in patients and mice and induces AMP. RESULTS: We show that T cells from patients with AMP recognize vaccine-encoded Spike epitopes homologous to those of cardiac self-proteins. One of these epitopes, mimicking an amino acid sequence from a cardiomyocyte-expressed K + channel, induced AMP in mice. When functional responses to the Kv2 were analyzed, patients with AMP after mRNA vaccination, but not patients with COVID-19, displayed an expanded pattern of cytokine production similar to that observed in AMP mice and in autoimmune myocarditis. Crucially, T-cell autoimmunity segregates to cardiotropic cMet (c-mesenchymal epithelial transition factor)–expressing T cells and is prevented by cMet inhibition, suggesting that heart homing imprinting, permitted by the unique mRNA vaccine biodistribution, is required for AMP development. CONCLUSIONS: AMP development after mRNA vaccines is mediated by distinct immune components, including molecular mimicry, T-cell receptor affinity, and, importantly, homing imprinting.
Article Details
Authors (23)
Silvia Fanti
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, United Kingdom (S.F., F.M.-B.).
Carlene Dyer
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Inga Jóna Ingimarsdóttir
Departments of Cardiology (I.J.I.), Landspitali – The National University Hospital of Iceland, Reykjavik, Iceland.
Daniel Harding
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Guosu Wang
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Antonio D’Amati
Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy (A.D.).
Eriomina Shahaj
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Adalbjorg Ýr Sigurbergsdóttir
Department of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (I.J.I., A.Ý.S., H.T., O.B.G., S.F.B., B.R.L.).
Helga Thórsdóttir
Department of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (I.J.I., A.Ý.S., H.T., O.B.G., S.F.B., B.R.L.).
Oddný Brattberg Gunnarsdóttir
Department of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (I.J.I., A.Ý.S., H.T., O.B.G., S.F.B., B.R.L.).
Stavroula Kanoni
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Paul Wright
Barts Heart Centre, Barts Health NHS Trust, St Bartholomew’s Hospital, West Smithfield, London, UK (D.H., P.W., S.A.M.).
John Martin
Jamie Chorlton
The Salt Hill Charity, London, UK (J.M., J.C., Z.H.).
Zoe Hollowood
The Salt Hill Charity, London, UK (J.M., J.C., Z.H.).
Siggeir Fannar Brynjólfsson
Immunology (S.F.B., B.R.L.), Landspitali – The National University Hospital of Iceland, Reykjavik, Iceland.
Bjorn Rúnar Lúdvíksson
Immunology (S.F.B., B.R.L.), Landspitali – The National University Hospital of Iceland, Reykjavik, Iceland.
Egle Solito
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Serena Bert
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Jack M. Keane
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Saidi A. Mohiddin
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
M. Paula Longhi
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).
Federica M. Marelli-Berg
William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, UK (S.F., C.D., D.H., G.W., E.S., S.K., E.S., S.B., J.M.K., S.A.M., M.P.L., F.M.M.-B.).