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Diorio C, Shraim R, Vella LA, et al. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat Commun. 2021;12(1):7222doi: 10.1038/s41467-021-27544-6.
Diorio, C., Shraim, R., Vella, L. A., Giles, J. R., Baxter, A. E., Oldridge, D. A., Canna, S. W., Henrickson, S. E., McNerney, K. O., Balamuth, F., Burudpakdee, C., Lee, J., Leng, T., Farrel, A., Lambert, M. P., Sullivan, K. E., Wherry, E. J., Teachey, D. T., Bassiri, H., & Behrens, E. M. (2021). Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nature communications, 12(1), 7222. https://doi.org/10.1038/s41467-021-27544-6
Diorio, Caroline, et al. "Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction." Nature communications vol. 12,1 (2021): 7222. doi: https://doi.org/10.1038/s41467-021-27544-6
Diorio C, Shraim R, Vella LA, Giles JR, Baxter AE, Oldridge DA, Canna SW, Henrickson SE, McNerney KO, Balamuth F, Burudpakdee C, Lee J, Leng T, Farrel A, Lambert MP, Sullivan KE, Wherry EJ, Teachey DT, Bassiri H, Behrens EM. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat Commun. 2021 Dec 10;12(1):7222. doi: 10.1038/s41467-021-27544-6. PMID: 34893640.
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Nat Commun. 2021 Dec 10;12(1):7222. doi: 10.1038/s41467-021-27544-6.

Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction.

Nature communications

Caroline Diorio, Rawan Shraim, Laura A Vella, Josephine R Giles, Amy E Baxter, Derek A Oldridge, Scott W Canna, Sarah E Henrickson, Kevin O McNerney, Frances Balamuth, Chakkapong Burudpakdee, Jessica Lee, Tomas Leng, Alvin Farrel, Michele P Lambert, Kathleen E Sullivan, E John Wherry, David T Teachey, Hamid Bassiri, Edward M Behrens

Affiliations

  1. Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  2. Immune Dysregulation Frontier Program, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  3. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  4. Division of Infectious Diseases, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  5. Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  6. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
  7. Division of Pathology and Laboratory Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  8. Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  9. Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  10. Division of Emergency Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  11. Division of Hematology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  12. Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].
  13. Immune Dysregulation Frontier Program, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].

PMID: 34893640 DOI: 10.1038/s41467-021-27544-6

Abstract

Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. Here we perform a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesize that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. We show that protein signatures demonstrate overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is an important marker of MIS-C that associates with TMA. We find that IFNγ responses are dysregulated in MIS-C patients, and that IFNγ levels delineate clinical heterogeneity.

© 2021. The Author(s).

References

  1. Verdoni L, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;(Published online May 13, 2020 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31103-X/fulltext) . - PubMed
  2. Riphagen S, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;(published online May 7, 2020 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31094-1/fulltext) . - PubMed
  3. Viner RM, Whittaker E. Kawasaki-like disease: emerging complication during the COVID-19 pandemic. Lancet. 2020;(Published online May 13, 2020 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31129-6/fulltext) . - PubMed
  4. Feldstein, L. R. et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N. Engl. J. Med. 383, 334–346 (2020). - PubMed
  5. Consiglio, C. R. et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 183, 968–981.e967 (2020). - PubMed
  6. Rowley, A. H. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat. Rev. Immunol. 20, 453–454 (2020). - PubMed
  7. Esteve-Sole, A. et al. Similarities and differences between the immunopathogenesis of COVID-19-related pediatric multisystem inflammatory syndrome and Kawasaki disease. J. Clin. Investig. 131, e144554 (2021). - PubMed
  8. Ouldali, N. et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA 325, 855–864 (2021). - PubMed
  9. Elias, M. D. et al. Management of multisystem inflammatory syndrome in children associated with COVID-19: a survey from the international Kawasaki disease registry. CJC Open. 2, 632–640 (2020). - PubMed
  10. McMurray, J. C. et al. Multisystem Inflammatory Syndrome in Children (MIS-C), a post-viral myocarditis and systemic vasculitis-A critical review of its pathogenesis and treatment. Front. Pediatr. 8, e626182 (2020). - PubMed
  11. Brodsky, N. N. et al. The mystery of MIS-C post-SARS-CoV-2 infection. Trends Microbiol. 28, 956–958 (2020). - PubMed
  12. Gruber, C. N. et al. Mapping systemic inflammation and antibody responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell 183, 982–995.e914 (2020). - PubMed
  13. Lee PY, et al. Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children. J. Clin. Investig. 130, 5942–5950 (2020). - PubMed
  14. Fajgenbaum, D. C. & June, C. H. Cytokine storm. N. Engl. J. Med. 383, 2255–2273 (2020). - PubMed
  15. Carter, M. J. et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat. Med. 26, 1701–1707 (2020). - PubMed
  16. Klok, F. A. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb. Res. 191, 148–150 (2020). - PubMed
  17. Diorio, C. et al. Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. Blood Adv. 4, 6051–6063 (2020). - PubMed
  18. George, J. N. & Nester, C. M. Syndromes of thrombotic microangiopathy. N. Engl. J. Med. 371, 654–666 (2014). - PubMed
  19. Dvorak, C. C. et al. Transplant-associated thrombotic microangiopathy in pediatric hematopoietic cell transplant recipients: a practical approach to diagnosis and management. Front. Pediatr. 7, e133 (2019). - PubMed
  20. Vella, L. et al. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. Sci. Immunol. 6, eabf7570 (2020). - PubMed
  21. Diorio, C. et al. Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2. J. Clin. Investig. 130, 5967–5975 (2020). - PubMed
  22. Anderson, E. M. et al. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) antibody responses in children with Multisystem Inflammatory Syndrome in Children (MIS-C) and mild and severe Coronavirus Disease 2019 (COVID-19). J. Pediatr. Infect. Dis. Soc. 10, 669–673 (2021). - PubMed
  23. Diorio, C. et al. Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome. Pediatr. Blood Cancer 67, e28693 (2020). - PubMed
  24. Hall, C. Essential biochemistry and physiology of (NT-pro)BNP. Eur. J. Heart Fail 6, 257–260 (2004). - PubMed
  25. Ulgen, E. et al. pathfindR: an R package for comprehensive identification of enriched pathways in omics data through active subnetworks. Front. Genet. 10, e858 (2019). - PubMed
  26. Aste-Amezaga, M. et al. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J. Immunol. 160, 5936–5944 (1998). - PubMed
  27. Mizuta, M. et al. Clinical significance of serum CXCL9 levels as a biomarker for systemic juvenile idiopathic arthritis associated macrophage activation syndrome. Cytokine 119, 182–187 (2019). - PubMed
  28. Crayne, C. B. et al. The immunology of macrophage activation syndrome. Front. Immunol. 10, e119 (2019). - PubMed
  29. Bracaglia, C. et al. Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann. Rheum. Dis. 76, 166–172 (2017). - PubMed
  30. Grom, A. A. et al. Macrophage activation syndrome in the era of biologic therapy. Nat. Rev. Rheumatol. 12, 259–268 (2016). - PubMed
  31. Yuan, S. et al. Serum soluble VSIG4 as a surrogate marker for the diagnosis of lymphoma-associated hemophagocytic lymphohistiocytosis. Br. J. Haematol. 189, 72–83 (2020). - PubMed
  32. Ravelli, A. et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann. Rheum. Dis. 75, 481–489 (2016). - PubMed
  33. Schulert, G. S. et al. Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome. Ann. Rheum. Dis. 80, 617–625 (2021). - PubMed
  34. Higgs, R. et al. Self protection from anti-viral responses–Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS ONE 5, e11776 (2010). - PubMed
  35. Yoshimi, R. et al. Gene disruption study reveals a nonredundant role for TRIM21/Ro52 in NF-kappaB-dependent cytokine expression in fibroblasts. J. Immunol. 182, 7527–7538 (2009). - PubMed
  36. Ma, L. et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci. Immunol. 6, eabh2259 (2021). - PubMed
  37. McGeachy, M. J. et al. The IL-17 family of cytokines in health and disease. Immunity 50, 892–906 (2019). - PubMed
  38. Imai, T. et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91, 521–530 (1997). - PubMed
  39. Umehara, H. et al. Fractalkine in vascular biology. Arterioscler. Thromb. Vasc. Biol. 24, 34–40 (2004). - PubMed
  40. Boudreau, L. H. et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 124, 2173–2183 (2014). - PubMed
  41. Kitano, N. et al. Patient age and the seasonal pattern of onset of Kawasaki’s disease. N. Engl. J. Med. 378, 2048–2049 (2018). - PubMed
  42. Lindbom, J. et al. Interferon gamma-induced gene expression of the novel secretory phospholipase A2 type IID in human monocyte-derived macrophages is inhibited by lipopolysaccharide. Inflammation 29, 108–117 (2005). - PubMed
  43. Ponzoni, M. et al. Stimulation of receptor-coupled phospholipase A2 by interferon-gamma. FEBS Lett. 310, 17–21 (1992). - PubMed
  44. Wu, T. et al. Interferon-gamma induces the synthesis and activation of cytosolic phospholipase A2. J. Clin. Investig. 93, 571–577 (1994). - PubMed
  45. Jodele, S. et al. Interferon-complement loop in transplant-associated thrombotic microangiopathy. Blood Adv. 4, 1166–1177 (2020). - PubMed
  46. Gloude, N. J. et al. Thinking beyond HLH: clinical features of patients with concurrent presentation of hemophagocytic lymphohistiocytosis and thrombotic microangiopathy. J. Clin. Immunol. 40, 699–707 (2020). - PubMed
  47. Berry, E. et al. Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever. J. Am. Heart Assoc. 4, e001868 (2015). - PubMed
  48. Abers, M. S. et al. An immune-based biomarker signature is associated with mortality in COVID-19 patients. JCI Insight 6, e11 (2021). - PubMed
  49. Sjöstrand, M. et al. Expression of the immune regulator tripartite-motif 21 is controlled by IFN regulatory factors. J. Immunol. 191, 3753–3763 (2013). - PubMed
  50. Lacinel Gurlevik, S. et al. Hemophagocytosis in bone marrow aspirates in multisystem inflammatory syndrome in children. Pediatr. Blood Cancer 68, e28931 (2021). - PubMed
  51. Behrens, E. M. et al. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J. Rheumatol. 34, 1133–1138 (2007). - PubMed
  52. Bleesing, J. et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 56, 965–971 (2007). - PubMed
  53. Mehta, P. et al. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol. 2, e358–e367 (2020). - PubMed
  54. Henderson, L. A. et al. American College of Rheumatology Clinical Guidance for multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: version 2. Arthritis Rheumatol. 73, e13–e29 (2021). - PubMed
  55. Harris, P. A. et al. The REDCap consortium: building an international community of software platform partners. J. Biomed. Inf. 95, e103208 (2019). - PubMed
  56. CDC. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19); 2020. https://emergency.cdc.gov/han/2020/han00432.asp . - PubMed
  57. Kaddourah, A. et al. Epidemiology of acute kidney injury in critically ill children and young adults. N. Engl. J. Med. 376, 11–20 (2016). - PubMed
  58. R Studio Team. RStudio: Integrated Development for R. Boston, MA: PBC; 2020. - PubMed
  59. Van der Maaten, L. & Hinton, G. Visualizing data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008). - PubMed

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