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.

中文翻译：

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SARS-CoV-2 mRNA 疫苗相关心肌炎中细胞因子异常细胞毒性淋巴细胞和促纤维化骨髓反应

疫苗接种后（包括 SARS-CoV-2 mRNA 疫苗接种后）可能会发生罕见的免疫介导的心脏组织炎症。然而，驱动这种病理学的潜在免疫细胞和分子机制仍然知之甚少。在这里，我们调查了一组在 SARS-CoV-2 mRNA 疫苗接种后不久出现心肌炎和/或心包炎、肌钙蛋白、B 型钠尿肽和 C 反应蛋白水平升高以及心脏影像异常的患者。与早期的假设相反，患者没有表现出过敏性心肌炎的特征，也没有夸大与超免疫体液机制一致的 SARS-CoV-2 特异性或中和抗体反应。我们还没有发现针对心脏的自身抗体的证据。相反，公正的系统免疫血清分析显示循环白细胞介素（IL-1β、IL-1RA 和 IL-15）、趋化因子（CCL4、CXCL1 和 CXCL10）和基质金属蛋白酶（MMP1、MMP8、MMP9 和 TIMP1）升高。 。随后在急性疾病期间使用单细胞 RNA 和外周血单核细胞的库测序进行的深度免疫分析揭示了激活的 CXCR3 的扩展+细胞毒性 T 细胞和 NK 细胞，两者的表型都类似于细胞因子驱动的杀伤细胞。此外，患者表现出炎症和促纤维化 CCR2 的特征+CD163+单核细胞，加上血清可溶性 CD163 升高，可能与心脏 MRI 的晚期钆增强有关，这种增强在疫苗接种后可持续数月。总之，我们的结果表明炎症细胞因子和具有组织损伤能力的相应淋巴细胞上调，表明细胞因子依赖性病理学，这可能进一步伴有骨髓细胞相关的心脏纤维化。这些发现可能排除了之前提出的一些与 mRNA 疫苗相关的心肌心包炎机制，并指出了与疫苗开发和临床护理相关的新机制。