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

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

doi:10.1038/s41467-021-27544-6

Cited by 59 publications

(59 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the signals from cfRNA are derived from any cell or vascularized tissue type, and there is a plethora of RNA-Seq reference data that can be used to interpret results. Consistent with prior studies, here we observe increased levels of cfRNA from endothelial cells in MIS-C 43 and from neutrophils and thymocytes in MIS-C and COVID-19 9,44,45 as well as increased signaling from disease-specific pathways in MIS-C (IL-6, IL-8, and NF-kB) 12,14 and COVID-19 (olfactory, gustation, sumoylation, coronavirus replication, and HMGB1) 11,13,46–48 . However, the cfRNA data also uncovered several novel features of MIS-C, such as enrichment of neuronal genes associated with synaptogenesis and increased cfRNA burden from Schwann cells.…”

Section: Discussionsupporting

confidence: 93%

WITHDRAWN: Nucleic acid biomarkers of immune response and cell and tissue damage in COVID-19 and MIS-C

Loy

Sotomayor-González

Servellita

et al. 2022

Preprint

View full text Add to dashboard Cite

Differential host responses in coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) remain poorly characterized. Here we use next-generation sequencing to longitudinally analyze blood samples from pediatric patients with acute COVID-19 (n=70) or MIS-C (n=141) across three hospitals. Profiling of plasma cell-free nucleic acids uncovers distinct signatures of cell injury and death between these two disease states, with increased heterogeneity and multi-organ involvement in MIS-C encompassing diverse cell types such as endothelial and neuronal Schwann cells. Whole blood RNA profiling reveals upregulation of similar pro-inflammatory signaling pathways in COVID-19 and MIS-C, but also MIS-C specific downregulation of T cell-associated pathways. Profiling of plasma cell-free RNA and whole blood RNA in paired samples yields different yet complementary signatures for each disease state. Our work provides a systems-level, multi-analyte view of immune responses and tissue damage in COVID-19 and MIS-C and informs the future development of new disease biomarkers.

show abstract

Section: Discussionsupporting

confidence: 93%

WITHDRAWN: Nucleic acid biomarkers of immune response and cell and tissue damage in COVID-19 and MIS-C

Loy

Sotomayor-González

Servellita

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…SARS-CoV-2-specific IFN-γ production was also seen in CD8 + T cells from patients with neurologic involvement (Fig S2 By identifying novel associations with different phenotypes, this study gives insights into potential immunologic mechanisms underlying the clinical heterogeneity of MIS-C. The elevation of serum inflammatory markers -particularly IFN-γ -in patients with severe disease is consistent with findings in other cohorts (2)(3)(4)(5). SARS-CoV-2-specific CD4 + responses in patients with neurological and respiratory involvement suggests that antigen-specific T cell functions may contribute to these symptoms.…”

Section: Research Lettersupporting

confidence: 85%

Deep immune profiling uncovers novel associations with clinical phenotypes of Multisystem Inflammatory Syndrome in Children (MIS-C)

Redmond

Kitakule

Son

et al. 2022

Preprint

View full text Add to dashboard Cite

Multisystem Inflammatory Syndrome in Children (MIS-C) is a systemic inflammatory condition that follows SARS-CoV2 infection or exposure in children. Clinical presentations are highly variable and include fever, gastrointestinal (GI) disease, shock, and Kawasaki Disease-like illness (MIS-C/KD). Compared to patients with acute COVID, patients with MIS-C have a distinct immune signature and expansion of TRVB11 expressing T cells. However, the relationship between immunological and clinical phenotypes of MIS-C is unknown. Here, we measured serum biomarkers, TCR repertoire, and SARS-CoV2-specific T cell responses in a cohort of 76 MIS-C patients. Serum biomarkers associated with macrophage and Th1 activation were elevated in patients with shock, consistent with previous reports. Significantly increased SARS-CoV-2-induced IFN-g; IL-2, and TNF-a; production were seen in CD4+ T cells from patients with neurologic involvement and respiratory failure. Diarrhea was associated with a significant reduction in shock-associated serum biomarkers, suggesting a protective effect. TRVB11 usage was highly associated with MIS-C/KD and coronary aneurysms, suggesting a potential biomarker for these manifestations in MIS-C patients. By identifying novel immunologic associations with the different clinical phenotypes of MIS-C, this study provides insights into the clinical heterogeneity of MIS-C. These unique immunophenotypic associations could provide biomarkers to identify patients at risk for severe complications of MIS-C, including shock and MIS-C/KD.

show abstract

“…On the other hand, IFN-γ was significantly elevated in MIS-C compared to healthy post-COVID children (p = 0.0004) (Fig 1B). This elevation of IFN-γ has been described in MIS-C previously 14,15,22 and may reflect the concurrent T cell activation 15,22 .…”

Section: Resultssupporting

confidence: 64%

“…Other shared features of SLE and MIS-C may involve interferon activation. While increased IFN-γ response has been demonstrated to be a feature shared by MIS-C and SLE [14][15][16] , the activity of type I and type III interferons has only been shown in lupus 17,18 , but not in MIS-C. Interestingly, antibodies against type I interferons have been demonstrated to contribute to COVID-19 mortality and severity 19 .…”

Section: Introductionmentioning

confidence: 99%

B cells, BAFF and interferons in MIS-C

Klocperk

Bloomfield

Paračková

et al. 2022

Preprint

View full text Add to dashboard Cite

Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C) is a late complication of pediatric COVID-19, which follows weeks after original SARS-CoV-2 infection, regardless of its severity. It is characterized by hyperinflammation, neutrophilia, lymphopenia and activation of T cells with elevated IFN-γ. Observing production of autoantibodies and parallels with systemic autoimmune disorders, such as systemic lupus erythematodes (SLE), we explored B cell phenotype and serum levels of type I, II and III interferons, as well as the cytokines BAFF and APRIL in a cohort of MIS-C patients and healthy children after COVID-19.We documented a significant elevation of IFN-γ, but not IFN-α and IFN-λ in MIS-C patients. BAFF was elevated in MIS-C patient sera and accompanied by decreased BAFFR expression on all B cell subtypes. The proportion of plasmablasts was significantly lower in patients compared to healthy post-COVID children. We noted the presence of ENA Ro60 autoantibodies in 4/35 tested MIS-C patients.Our work shows the involvement of humoral immunity in MIS-C and hints at parallels with the pathophysiology of SLE, with autoreactive B cells driven towards autoantibody production by elevated BAFF.Graphical abstractSummary sentenceElevated serum BAFF in children with MIS-C supports the state of polyclonal B cell activation and autoimmune phenomena characterizing this disease.

show abstract

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

Cited by 59 publications

References 55 publications

WITHDRAWN: Nucleic acid biomarkers of immune response and cell and tissue damage in COVID-19 and MIS-C

WITHDRAWN: Nucleic acid biomarkers of immune response and cell and tissue damage in COVID-19 and MIS-C

Deep immune profiling uncovers novel associations with clinical phenotypes of Multisystem Inflammatory Syndrome in Children (MIS-C)

B cells, BAFF and interferons in MIS-C

Contact Info

Product

Resources

About