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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.

SUBMITTER: Ramaswamy A

PROVIDER: S-EPMC8043654 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical illness in children.

2021-04-02 | GSE166489 | GEO

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

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

| PRJNA701047 | ENA

Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-Associated Multisystem Inflammatory Syndrome in Children

Project description:Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C additionally upregulated Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways. Several variants mapped to Notch signaling-related genes including a loss of function mutation in the negative Notch1 regulator NUMB . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation in proxy mouse models. These results establish the Notch1-CD22 axis as an immune dysregulatory mechanism critically involved in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

2021-12-01 | GSE186799 | GEO

SARS-CoV-2 Variants and Multisystem Inflammatory Syndrome in Children.

Project description: Not available

| S-EPMC10052214 | biostudies-literature

Pre-Covid-19, SARS-CoV-2-Negative Multisystem Inflammatory Syndrome in Children.

Project description: Not available

| S-EPMC10755832 | biostudies-literature

An immune correlate of SARS-CoV-2 infection and severity of reinfections.

Project description:BackgroundAn immune correlate of protection from SARS-CoV-2 infection is urgently needed.MethodsWe used an ongoing household cohort with an embedded transmission study that closely monitors participants regardless of symptom status. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity. Sequencing was performed to determine circulating strains of SARS-CoV-2. We investigated the protection associated with seropositivity resulting from prior infection, the anti-spike antibody titers needed for protection, and we compared the severity of first and second infections.ResultsIn March 2021, 62.3% of the cohort was seropositive. After March 2021, gamma and delta variants predominated. Seropositivity was associated with 69.2% protection from any infection (95% CI: 60.7%-75.9%), with higher protection against moderate or severe infection (79.4%, 95% CI: 64.9%-87.9%). Anti-spike titers of 327 and 2,551 were associated with 50% and 80% protection from any infection; titers of 284 and 656 were sufficient for protection against moderate or severe disease. Second infections were less severe than first infections (Relative Risk (RR) of moderated or severe disease: 0.6, 95% CI: 0.38-0.98; RR of subclinical disease:1.9, 95% CI: 1.33-2.73).ConclusionsPrior infection-induced immunity is protective against infection when predominantly gamma and delta SARS-CoV-2 circulated. The protective antibody titers presented may be useful for vaccine policy and control measures. While second infections were somewhat less severe, they were not as mild as ideal. A strategy involving vaccination will be needed to ease the burden of the SARS-CoV-2 pandemic.

| S-EPMC8629202 | biostudies-literature

Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children.

Project description:BackgroundMultisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive.MethodsHerein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C.ResultsWe identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein-Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients.ConclusionsThis study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.

| S-EPMC9742658 | biostudies-literature

The Impact of SARS-CoV-2 Variants on the Clinical Phenotype and Severity of Multisystem Inflammatory Syndrome in Children in South Africa.

Project description:The effects of SARS-CoV-2 variants on disease phenotype and severity of multisystem inflammatory syndrome in children (MIS-C) are unknown. We compared the clinical phenotype of MIS-C in 129 South African children across four distinct (Ancestral type, Beta, Delta, and Omicron) variant-driven waves and found that MIS-C remains a severe disease with a stable clinical presentation, regardless of variant.

| S-EPMC9645446 | biostudies-literature

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

Project description:Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL-6 may be preferable to IL-1 or TNF-α. We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease.

| S-EPMC8487319 | biostudies-literature

Severity and Cardiac Involvement in Multisystem Inflammatory Syndrome in Children.

Project description:Multisystem inflammatory syndrome in children (MIS-C) occurs secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A retrospective study, involving 6 tertiary-care centers in Haryana, was conducted to evaluate the clinical features, severity, laboratory findings, and outcomes of patients with MIS-C. Disease severity was graded (mild/moderate/severe) and presence of cardiac abnormalities noted. Patients with and without cardiac abnormalities and with and without severe disease were compared. Forty-eight children with MIS-C were included (median age - 9.5 y). Fever (100%), gastrointestinal (83.3%) and mucocutaneous (50%) symptoms were common. Only 16.7% patients had previous history of documented SARS-CoV-2 infection/contact. Severe disease and cardiac abnormalities were seen in 47.9% and 54.2% patients, respectively. NT-proBNP > 1286.5 pg/mL and thrombocytopenia (≤ 119500/µL) were significant risk factors for severe MIS-C. Forty-five patients (93.8%) recovered and 3 died. Median hospitalization duration was 7 d (5-9.5). MIS-C must be considered as a possibility in any febrile child, even if a positive epidemiological history is absent. High NT-proBNP and thrombocytopenia are significant risk factors for severe MIS-C. (Trial Registration: The study was registered with the Clinical Trials Registry, India (CTRI/2021/09/036491)).

| S-EPMC9417928 | biostudies-literature

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