Cytokinopathy with aberrant cytotoxic lymphocytes and pro-fibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis

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. Description Cytokine-driven killer lymphocytes and inflammatory monocytes characterize myopericarditis after SARS-CoV-2 mRNA vaccination. Immunopathology signatures in myocarditis Myocarditis and/or pericarditis are rare adverse cardiac events observed after SARS-CoV-2 mRNA vaccination with a predilection for adolescent and young adult males. To investigate the pathogenesis of myopericarditis in this setting, Barmada and Klein et al. used unbiased immune profiling techniques to search for immune signatures that distinguished patients who developed myopericarditis from healthy vaccinated controls. Immune events associated with myopericarditis included elevated systemic levels of cytokines, an increased frequency of activated T and NK cells, and induction of inflammatory monocytes with profibrotic features. Neither immune targeting of cardiac autoantigens nor enhanced clonal expansion of B and T lymphocytes was detected. These findings provide deeper insights into the chain of events that can rarely lead to myopericarditis in the mRNA vaccine setting. —IRW