The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children
Rebecca A. Porritt, … , Mascha Binder, Moshe Arditi
Rebecca A. Porritt, … , Mascha Binder, Moshe Arditi
Published August 26, 2021
Citation Information: J Clin Invest. 2021;131(20):e151520. https://doi.org/10.1172/JCI151520.
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The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children

Abstract

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.

Authors

Rebecca A. Porritt, Aleksandra Binek, Lisa Paschold, Magali Noval Rivas, Angela McArdle, Lael M. Yonker, Galit Alter, Harsha K. Chandnani, Merrick Lopez, Alessio Fasano, Jennifer E. Van Eyk, Mascha Binder, Moshe Arditi

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Figure 5

Autoantibody analysis of MIS-C.

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Autoantibody analysis of MIS-C. (A) Autoantibody analysis was performed ...
(A) Autoantibody analysis was performed on serum from febrile controls (n = 5) and MIS-C patients (n = 11) using HuProt array. MIS-C samples correspond to RNA cluster 1 (n = 6) and RNA cluster 2 (n = 5) identified in Figure 4. (B) Venn diagram of candidate IgG autoantibody targets in MIS-C and RNA clusters (P < 0.05, FC > 2). (C) Venn diagram of candidate IgA autoantibody targets in MIS-C and RNA clusters (P < 0.05, FC > 2). (D) IgG autoantibody targets identified in MIS-C (n = 11) compared with febrile controls (n = 5). The bar represents log2(FC). Each symbol represents 1 MIS-C patient presented as log2(FC) above the mean of febrile controls. (E) IgA autoantibody targets identified in MIS-C (n = 11) compared with febrile controls (n = 5). The bar represents log2(FC). Each symbol represents 1 MIS-C patient presented as log2(FC) above the mean of febrile controls. (F) IgG autoantibody targets separated based on RNA cluster 1 (n = 6) and RNA cluster 2 (n = 5). Data are presented as log2(FC) above the mean of febrile controls. (G) IgA autoantibody targets separated based on RNA cluster 1 (n = 6) and RNA cluster 2 (n = 5). Data are presented as log2(FC) above the mean of febrile controls. For box-and-whisker plots, the bounds of the boxes represent the interquartile range (IQR, Q1 to Q3) and the whiskers represent the minimum and maximum values. The median values are marked with a horizontal line within the box. *FDR < 0.05 compared with febrile controls.