Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.

• Authors: Anjali Ramaswamy, Nina N Brodsky, Tomokazu S Sumida, Michela Comi, Hiromitsu Asashima, Kenneth B Hoehn, Ningshan Li, Yunqing Liu, Aagam Shah, Neal G Ravindra, Jason Bishai, Alamzeb Khan, William Lau, Brian Sellers, Neha Bansal, Pamela Guerrerio, Avraham Unterman, Victoria Habet, Andrew J Rice, Jason Catanzaro, Harsha Chandnani, Merrick Lopez, Naftali Kaminski, Charles S Dela Cruz, John S Tsang, Zuoheng Wang, Xiting Yan, Steven H Kleinstein, David van Dijk, Richard W Pierce, David A Hafler, Carrie L Lucas
• Journal: Immunity (Immunity) Vol. 54 Issue 5 Pg. 1083-1095.e7 (05 11 2021) ISSN: 1097-4180 [Electronic] United States
• PMID: 33891889 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Alarmins
• Autoantibodies
• Receptors, Antigen, T-Cell

Topics

• Adolescent
• Alarmins (immunology)
• Autoantibodies (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• COVID-19 (immunology, pathology)
• Child
• Child, Preschool
• Cytotoxicity, Immunologic (genetics)
• Endothelium (immunology, pathology)
• Humans
• Killer Cells, Natural (immunology)
• Myeloid Cells (immunology)
• Plasma Cells (immunology)
• Receptors, Antigen, T-Cell (genetics, immunology)
• SARS-CoV-2 (immunology)
• Severity of Illness Index
• Systemic Inflammatory Response Syndrome (immunology, pathology)