Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Science immunology - 8(2023), 83 vom: 12. Mai, Seite eadh3455 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Klein, Jon [VerfasserIn] |
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| Links: |
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| Themen: |
AU0V1LM3JT |
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| Anmerkungen: |
Date Completed 08.05.2023 Date Revised 10.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/sciimmunol.adh3455 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM356493059 |
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| 245 | 1 | 0 | |a Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis |
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| 500 | |a Date Revised 10.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Klein, Jon |e verfasserin |4 aut | |
| 700 | 1 | |a Ramaswamy, Anjali |e verfasserin |4 aut | |
| 700 | 1 | |a Brodsky, Nina N |e verfasserin |4 aut | |
| 700 | 1 | |a Jaycox, Jillian R |e verfasserin |4 aut | |
| 700 | 1 | |a Sheikha, Hassan |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Kate M |e verfasserin |4 aut | |
| 700 | 1 | |a Habet, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Sumida, Tomokazu S |e verfasserin |4 aut | |
| 700 | 1 | |a Kontorovich, Amy |e verfasserin |4 aut | |
| 700 | 1 | |a Bogunovic, Dusan |e verfasserin |4 aut | |
| 700 | 1 | |a Oliveira, Carlos R |e verfasserin |4 aut | |
| 700 | 1 | |a Steele, Jeremy |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, E Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Pena-Hernandez, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Monteiro, Valter |e verfasserin |4 aut | |
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| 700 | 1 | |a Ring, Aaron M |e verfasserin |4 aut | |
| 700 | 1 | |a Omer, Saad B |e verfasserin |4 aut | |
| 700 | 1 | |a Iwasaki, Akiko |e verfasserin |4 aut | |
| 700 | 1 | |a Yildirim, Inci |e verfasserin |4 aut | |
| 700 | 1 | |a Lucas, Carrie L |e verfasserin |4 aut | |
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