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

• Published in: Science immunology 2023-05, Vol.8 (83), p.eadh3455-eadh3455
• Main Authors: Barmada, Anis, Klein, Jon, Ramaswamy, Anjali, Brodsky, Nina N., Jaycox, Jillian R., Sheikha, Hassan, Jones, Kate M., Habet, Victoria, Campbell, Melissa, Sumida, Tomokazu S., Kontorovich, Amy, Bogunovic, Dusan, Oliveira, Carlos R., Steele, Jeremy, Hall, E. Kevin, Pena-Hernandez, Mario, Monteiro, Valter, Lucas, Carolina, Ring, Aaron M., Omer, Saad B., Iwasaki, Akiko, Yildirim, Inci, Lucas, Carrie L.
• Format: Article
• Language: English
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.adh3455

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, IL-15), chemokines (CCL4, CXCL1, CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, 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 lymphocyte populations phenotypically resembled cytokine-driven killer cells. Additionally, patients displayed signatures of inflammatory and profibrotic CCR2 + CD163 + monocytes, coupled with elevated serum soluble CD163. These findings may be linked to the late gadolinium enhancement seen on cardiac MRI, which can persist for months after vaccination. Taken together, our results demonstrate upregulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by macrophage-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. Cytokine-driven killer lymphocytes and inflammatory monocytes characterize myopericarditis after SARS-CoV-2 mRNA vaccination.