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

• Published in: Science immunology Vol. 8; no. 83; p. 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: Journal Article
• Language: English
• Published: United States 12-05-2023
• Subjects: Antineoplastic Agents; Contrast Media; COVID-19 - prevention & control; COVID-19 Vaccines - adverse effects; Cytokines; Gadolinium; Humans; Killer Cells, Natural; Leukocytes, Mononuclear; Myocarditis - etiology; SARS-CoV-2
• 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, 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.