The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery

Syrimi, Eleni; Fennell, Éanna; Richter, Alex; Vrljicak, Pavle; Stark, Richard; Ott, Sascha; Murray, Paul G.; Al‐Abadi, Eslam; Chikermane, Ashish; Dawson, Pamela; Hackett, Scott; Jyothish, Deepthi; Kanthimathinathan, Hari Krishnan; Monaghan, Sean; Nagakumar, Prasad; Scholefield, Barnaby R.; Welch, S; Khan, Naeem; Faustini, Sian; Davies, Kate; Zelek, Wioleta M.; Kearns, Pamela; Taylor, Graham S.

doi:10.1016/j.isci.2021.103215

Cited by 38 publications

(45 citation statements)

References 78 publications

(118 reference statements)

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“…Analysis suggests a positive correlation between disease severity and white blood cell (WBC) and neutrophil count and degree of lymphopenia and eosinopenia. As reported by Syrimi et al (2021) , higher CRP was found in MIS-C patients with compromised heart function, quantified as reduced left ventricular fractional shortening. Although only minimally increased liver enzymes (aspartate transaminase [AST]/alanine transaminase [ALT]/γ-glutamyltransferase [GGT]) were noted, GGT levels correlated with disease severity.…”

Section: Resultssupporting

confidence: 72%

“…Increased concentrations of an array of proinflammatory (e.g., IL-1β, IL-2, IL-6, IL-8, IL-17A, IL-18, IFNγ, TNFα) and regulatory (e.g., IL-1RA, IL-10, sTNFR1, and sTNFR2) cytokines have been documented in MIS-C, but the relative contributions of these are debated ( Consiglio et al, 2020 ; Diorio et al, 2020 ; Gruber et al, 2020 ; Syrimi et al, 2021 ; Vella et al, 2021 ). The immune cells implicated in MIS-C pathogenesis are also controversial as critical roles have been ascribed to granulocytes and monocytes ( Gruber et al, 2020 ; de Cevins et al, 2021 Preprint ; Syrimi et al, 2021 ), natural killer (NK) cells ( Beckmann et al, 2020 Preprint ; Gruber et al, 2020 ; Ramaswamy et al, 2021 ), γδ T cells ( Carter et al, 2020 ), classical cluster of differentiation (CD) 4 T cells ( Carter et al, 2020 ; Vella et al, 2021 ), and cytotoxic T cells ( Beckmann et al, 2020 Preprint ; Ramaswamy et al, 2021 ; Vella et al, 2021 ). In addition, several groups suggested a role for autoantibodies (e.g., anti-Jo and anti-La antibodies) inducing tissue damage in MIS-C ( Consiglio et al, 2020 ; Gruber et al, 2020 ; Ramaswamy et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C

Hoste

Roels

Naesens

et al. 2021

Journal of Experimental Medicine

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In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRβ repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.

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Section: Resultssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C

Hoste

Roels

Naesens

et al. 2021

Journal of Experimental Medicine

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“…However, as noted in the previous section, endothelial release of NO via eNOS is attenuated in COVID-19 patients, resulting in vasoconstriction and arterial and venous thrombosis. In addition, ARG1 is upregulated in whole blood, plasma, and peripheral blood mononuclear cells of patients with COVID-19 and may be a valuable diagnostic marker of the disease [ 132 , 133 , 134 ]. The expansion of MDSCs seen in COVID-19 directly correlates to elevated ARG activity and lymphopenia [ 135 ].…”

Section: Role Of Nos and Arg In Covid-19mentioning

confidence: 99%

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

Durante

2022

Metabolites

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Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19.

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“…While MIS-C bears similarities to Kawasaki Disease (KD), a vasculitis that presents in children, its immunologic profile is distinct, indicating likely differing pathobiology ( 7 – 10 ). Recent studies have shown an association between development of MIS-C and expansion of Vbeta 21.3+ CD4+ and CD8+ T cells, activation of vascular patrolling CX3CR1+ CD8+ T cells, putative autoantibody expression, and decreased numbers of tolerogenic dendritic cells, though its cause remains undefined ( 7 , 11 – 14 ). Following the identification of MIS-C, multisystem inflammatory syndrome in adults (MIS-A) was also described as a likely post-infectious inflammatory sequela in adults, though it appears to be rarer than MIS-C and its overlap with severe COVID-19 and pediatric MIS-C is not yet well-understood ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection

et al. 2022

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BackgroundDespite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. We hypothesized that these differences in presentation are related to differences in the magnitude and/or antigen specificity of SARS-CoV-2-specific T cell (CST) responses between adults and children. We therefore set out to measure the CST response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection.MethodsCSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay.FindingsTwenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses in MIS-C patients were significantly higher than children with uncomplicated SARS-CoV-2 infection, but weaker than CST responses in convalescent adults.InterpretationAge-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults post uncomplicated infection. Children with MIS-C have CST responses that are stronger than children with uncomplicated SARS-CoV-2 infection and weaker than convalescent adults, despite near uniform seropositivity.

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The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery

Cited by 38 publications

References 78 publications

TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C

TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection

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