{"doi":"10.1126/sciimmunol.adh3455","title":"Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis","abstract":"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.","journal":"Science Immunology","year":2023,"id":317495,"datarank":0.6554171778700533,"base_score":4.3694478524670215,"endowment":4.3694478524670215,"self_citation_contribution":0.6554171778700533,"citation_network_contribution":0.0,"self_endowment_contribution":0.6554171778700533,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":78,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":105755,"name":"Jon Klein","orcid":"0000-0002-3552-7684","position":1,"is_corresponding":false},{"id":620702,"name":"Anjali Ramaswamy","orcid":"0000-0003-1717-6582","position":2,"is_corresponding":false},{"id":620703,"name":"Nina N. 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Oliveira","orcid":"0000-0003-1897-6581","position":12,"is_corresponding":false},{"id":578498,"name":"Jeremy Steele","orcid":"0000-0003-3121-3036","position":13,"is_corresponding":false},{"id":630499,"name":"E. Kevin Hall","orcid":"0000-0001-7865-5208","position":14,"is_corresponding":false},{"id":808383,"name":"Mario A. Peña-Hernández","orcid":null,"position":15,"is_corresponding":false},{"id":933951,"name":"Valter Silva Monteiro","orcid":"0000-0003-1785-6713","position":16,"is_corresponding":false},{"id":105754,"name":"Carolina Lucas","orcid":"0000-0003-4590-2756","position":17,"is_corresponding":false},{"id":17340,"name":"Aaron M. Ring","orcid":"0000-0003-3699-2446","position":19,"is_corresponding":false},{"id":23206,"name":"Saad B. 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