Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.

中文翻译：

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儿童高炎症多系统炎症综合征的自身免疫特征

儿童多系统炎症综合征 (MIS-C) 表现为严重且不受控制的炎症反应，累及多器官，发生在 SARS-CoV-2 感染几周后。在这里，我们利用蛋白质组学、RNA 测序、自身抗体阵列和 B 细胞受体 (BCR) 谱分析来表征 MIS-C 免疫发病机制，并确定导致严重表现和入住重症监护室的因素。MIS-C 患者血清中的炎症标志物、体液免疫反应、中性粒细胞激活以及补体和凝血途径高度丰富，重度 MIS-C 病例比轻度 MIS-C 病例具有更多的高炎症特征。我们在 MIS-C 中发现了强烈的自身免疫特征，其自身抗体针对普遍表达的抗原和组织特异性抗原，表明自身抗原释放和过度的抗原驱动可能是由全身组织损伤引起的。我们进一步确定了一组中性粒细胞反应增强以及抗 Spike IgG 和自身抗体滴度较高的患者。对这些患者的 BCR 测序发现了抗原驱动的强烈印记，具有大量 BCR 序列连接性和自身免疫相关免疫球蛋白重链可变区 (IGHV) 基因的使用。该簇与 TRBV11-2 扩展的 T 细胞受体 (TCR) 库相关，与之前表明超抗原驱动的致病过程的研究一致。总体而言，我们确定了最终导致 MIS-C 的致病途径组合，并可能为治疗提供信息。