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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Research Article Inflammation

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 6

B cell repertoire metrics, connectivity characteristics, and skewing of IGHV-J usage of MIS-C patients in RNA clusters 1 and 2.

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B cell repertoire metrics, connectivity characteristics, and skewing of ...
(A) Richness and somatic hypermutation of productive IGH repertoires of MIS-C patients of RNA cluster 1 (n = 5) and RNA cluster 2 (n = 6) compared with age-matched febrile control patients (n = 15). Bars indicate mean ± SD. Statistical analysis: ordinary 1-way ANOVA for global analysis and unpaired Student’s t test for paired comparison. (B) Petri dish plots of IGH repertoire networks of MIS-C patients of RNA cluster 1 and 2. A sample of 1000 unique CDR3 amino acid clones per repertoire were subjected to imNet network analysis (75). Petri dish plots are shown for Levenshtein distance 1. Percentages of connected sequences of MIS-C patients of RNA cluster 1 and 2 obtained from networks with Levenshtein distance 1 and 3 are shown as bar plots. Bars indicate mean ± SD. Statistical analysis: unpaired Student’s t test. (C) PCA of differential IGHV-J gene usage in MIS-C patients of RNA cluster 1 (n = 5) versus cluster 2 (n = 6) versus age-matched febrile controls (n = 15). Statistical analysis: Pillai-Bartlett test of MANOVA of all principal components. Frequencies per repertoire of the 10 most skewed IGHV genes in MIS-C and febrile control patients are shown as box-and-whisker plots. The boxes extend from the 25th to 75th percentiles, whiskers from minimum to maximum, and the line within the box indicates the median. (D) BAFF expression in MIS-C cluster 1 and cluster 2, using the RNA-seq data in Figure 5. Data are presented as mean ± SEM. (E) IL-6 and IL-10 levels in serum of MIS-C cluster 1 and cluster 2 patients, using cytokine data from Supplemental Figure 1. Data are presented as mean ± SEM. Statistical analysis: Mann-Whitney test (D and E). **P < 0.01.