Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.
Anis BarmadaJonathan KleinAnjali RamaswamyNina N BrodskyJillian R JaycoxHassan SheikhaKate M JonesVictoria HabetMelissa CampbellTomokazu S SumidaAmy R KontorovichRoosheel S PatelCarlos R OliveiraJeremy M SteeleE Kevin HallMario Pena-HernandezValter Vinícius Silva MonteiroCarolina LucasAaron M RingSaad B OmerAkiko IwasakInci B YildirimCarrie L LucasPublished in: Science immunology (2023)
Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2-specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1β, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3 + cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2 + CD163 + monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell-associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine--associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.
Keyphrases
- sars cov
- single cell
- left ventricular
- respiratory syndrome coronavirus
- rna seq
- dendritic cells
- end stage renal disease
- nk cells
- ejection fraction
- newly diagnosed
- healthcare
- high throughput
- cell migration
- bone marrow
- immune response
- rheumatoid arthritis
- peripheral blood
- prognostic factors
- oxidative stress
- acute myeloid leukemia
- heart failure
- palliative care
- genome wide
- photodynamic therapy
- induced apoptosis
- atrial fibrillation
- cell death
- zika virus
- dna methylation
- stem cells
- chronic pain
- liver injury
- regulatory t cells