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Immunity
05 11, 2021;54 (5): 1083-1095.e7.

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

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
Author Information
  1. Anjali Ramaswamy: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA.
  2. Nina N Brodsky: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA; Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA.
  3. Tomokazu S Sumida: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA.
  4. Michela Comi: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA.
  5. Hiromitsu Asashima: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA.
  6. Kenneth B Hoehn: Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA.
  7. Ningshan Li: Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06520, USA.
  8. Yunqing Liu: Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06520, USA.
  9. Aagam Shah: Department of Internal Medicine (Cardiology), Yale University School of Medicine, New Haven, CT, 06510, USA; Department of Computer Science, Yale University, New Haven, CT, 06520, USA.
  10. Neal G Ravindra: Department of Internal Medicine (Cardiology), Yale University School of Medicine, New Haven, CT, 06510, USA; Department of Computer Science, Yale University, New Haven, CT, 06520, USA.
  11. Jason Bishai: Department of Internal Medicine (Cardiology), Yale University School of Medicine, New Haven, CT, 06510, USA; Department of Computer Science, Yale University, New Haven, CT, 06520, USA.
  12. Alamzeb Khan: Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA.
  13. William Lau: NIH Center for Human Immunology (CHI), NIAID, NIH, Bethesda, MD, 20892, USA; Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, 20892, USA.
  14. Brian Sellers: NIH Center for Human Immunology (CHI), NIAID, NIH, Bethesda, MD, 20892, USA.
  15. Neha Bansal: NIH Center for Human Immunology (CHI), NIAID, NIH, Bethesda, MD, 20892, USA; Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, 20892, USA.
  16. Pamela Guerrerio: Food Allergy Research Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, 20892, USA.
  17. Avraham Unterman: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New, Haven, CT, 06520, USA.
  18. Victoria Habet: Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA.
  19. Andrew J Rice: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA.
  20. Jason Catanzaro: Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA.
  21. Harsha Chandnani: Department of Pediatrics, Loma Linda School of Medicine, Loma Linda, CA, 92354, USA.
  22. Merrick Lopez: Department of Pediatrics, Loma Linda School of Medicine, Loma Linda, CA, 92354, USA.
  23. Naftali Kaminski: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New, Haven, CT, 06520, USA.
  24. Charles S Dela Cruz: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New, Haven, CT, 06520, USA.
  25. John S Tsang: NIH Center for Human Immunology (CHI), NIAID, NIH, Bethesda, MD, 20892, USA; Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, 20892, USA.
  26. Zuoheng Wang: Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06520, USA.
  27. Xiting Yan: Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06520, USA; Department of Computer Science, Yale University, New Haven, CT, 06520, USA.
  28. Steven H Kleinstein: Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA; Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, 06511, USA.
  29. David van Dijk: Department of Internal Medicine (Cardiology), Yale University School of Medicine, New Haven, CT, 06510, USA; Department of Computer Science, Yale University, New Haven, CT, 06520, USA.
  30. Richard W Pierce: Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA.
  31. David A Hafler: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA.
  32. Carrie L Lucas: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA. Electronic address: carrie.lucas@yale.edu.
PMID: 33891889 DOI: 10.1016/j.immuni.2021.04.003

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.

Keywords

MIS-C SARS-CoV-2 TRBV11-2 alarmins cytotoxicity inflammation pediatric plasmablasts

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Grants

  1. UL1 TR001863/NCATS NIH HHS
  2. R21 AI144315/NIAID NIH HHS
  3. R01 AI104739/NIAID NIH HHS
  4. K08 HL136898/NHLBI NIH HHS
  5. T32 AI007019/NIAID NIH HHS
  6. R21 LM012884/NLM NIH HHS

MeSH Term

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

Chemicals

Alarmins
Autoantibodies
Receptors, Antigen, T-Cell
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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