Unique cellular immune signatures of multisystem inflammatory syndrome in children

Ray, Anuradha; Nathella, Pavan Kumar; Venkataraman, Aishwarya; Varadarjan, Poovazhagi; Kannan, Srinithi; Pandiarajan, Arul Nancy; Renji, Rachel Mariam; Elavarasan, Elayarani; Thimmaiah, Akshith; Kandasamy, Sasidaran; Nedunchelian, K; Natarajan, Suresh; Ganesh, Ramaswamy; Sundaram, Balasubramanian; Putlibai, Sulochana; Hissar, Syed; Selladurai, Elilarasi; Devi, K R Uma; Nutman, Thomas B.; Babu, Subash

doi:10.1371/journal.ppat.1010915

Cited by 8 publications

(8 citation statements)

References 37 publications

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“…In addition, IL‐6, IL‐1β, and IL‐12 have been consistently implicated in severe disease 13 . We have previously demonstrated that children with COVID‐19 also show a distinct cytokine/chemokine upregulation as well as alterations in acute phase proteins, complement components and MMPs 14–18 . However, in this study, we show that although most of the pro‐inflammatory cytokines, chemokines, growth factors, and acute phase proteins were elevated in children, they were significantly decreased in children compared to the elderly population.…”

Section: Discussioncontrasting

confidence: 58%

“…13 We have previously demonstrated that children with COVID-19 also show a distinct cytokine/ chemokine upregulation as well as alterations in acute phase proteins, complement components and MMPs. [14][15][16][17][18] However, in this study, we show that although most of the pro-inflammatory cytokines, chemokines, growth factors, and acute phase proteins were elevated in children, they were significantly decreased in children compared to the elderly population. Our results are similar to the finding by Pierce et al, 13 where they showed decreased levels of IL-6, TNFα, and IP-10 compared to adults.…”

Section: Discussionmentioning

confidence: 76%

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Elucidating systemic immune responses to acute and convalescent SARS‐CoV‐2 infection in children and elderly individuals

Rajamanickam,

Nathella,

Venkataraman

et al. 2024

Immunity Inflam & Disease

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BackgroundSevere Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2), a causative pathogen of the COVID‐19 pandemic, affects all age groups. However, various studies have shown that COVID‐19 presentation and severity vary considerably with age. We, therefore, wanted to examine the differences between the immune responses of children with COVID‐19 and elderly COVID‐19 individuals.MethodsWe analyzed cytokines, chemokines, growth factors, and acute phase proteins in acute and convalescent COVID‐19 children and the elderly with acute and convalescent COVID‐19.ResultsWe show that most of the pro‐inflammatory cytokines (interferon [IFN]γ, interleukin [IL]‐2, tumor necrosis factor‐α [TNFα], IL‐1α, IFNα, IFNβ, IL‐6, IL‐12, IL‐3, IL‐7, IL‐1Ra, IL‐13, and IL‐10), chemokines (CCL4, CCL11, CCL19, CXCL1, CXCL2, CXCL8, and CXL10), growth factors (vascular endothelial growth factor and CD40L) and acute phase proteins (C‐reactive protein, serum amyloid P, and haptoglobin) were decreased in children with acute COVID 19 as compared with elderly individuals. In contrast, children with acute COVID‐19 exhibited elevated levels of cytokines‐ IL‐1β, IL‐33, IL‐4, IL‐5, and IL‐25, growth factors—fibroblast growth factor‐2, platelet‐ derived growth factors‐BB, and transforming growth factorα as compared with elderly individuals. Similar, differences were manifest in children and elderly with convalescent COVID‐19.ConclusionThus, COVID‐19 children are characterized by distinct cytokine/chemokine/growth factor/acute phase protein markers that are markedly different from elderly COVID‐19 individuals.

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Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 76%

Elucidating systemic immune responses to acute and convalescent SARS‐CoV‐2 infection in children and elderly individuals

Rajamanickam,

Nathella,

Venkataraman

et al. 2024

Immunity Inflam & Disease

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“…1). Given that immunothrombosis is common in COVID-19 and the complement system likely contributes to these responses (22)(23)(24), we heated and inactivated plasma from PASC donors at 55˚C and repeated the experiments. We observed that platelets were persistently activated if spiked with room temperature plasma or heat-inactivated plasma prior to agonist stimulation from PASC patients suggesting that complement activation is unlikely to be a driver in the augmented platelet response observed (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Dysregulated Platelet Function in Patients with Post-Acute Sequelae of COVID-19

Aggarwal

Singh

Pham

et al. 2023

Preprint

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Objective: Post-acute sequelae of COVID-19 (PASC, also referred as Long-COVID) sometimes follows COVID-19, a disease caused by SARS-CoV-2. While SARS-CoV-2 is well-known to promote a prothrombotic state, and especially to activate platelets acutely, less is known about the thrombosis risk in PASC. Approach and Results: PASC patients and age-matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by Light Transmission Aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under venous shear stress conditions. While only a mild increase in platelet aggregation in PASC patients through the thromboxane receptor was observed platelet activation through the glycoprotein VI (GPVI) receptor was markedly decreased in PASC patients compared to age- and sex-matched healthy controls. Thrombosis under venous shear conditions as well as Factor Xa activity were reduced in PASC patients. Plasma from PASC patients was an extremely potent activator of washed, healthy platelets - a phenomenon not observed using age- and sex-matched platelets from healthy individuals. Conclusions: PASC patients demonstrate dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating plasma-derived molecule that promotes thrombosis. A hitherto undescribed protective response appears to exists in PASC patients to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.

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“…Previous studies have shown that children with MIS have presented with lymphopenia, which would thereby lead to a weakened immune system in the host ( 2 ). A cellular study on MIS-C immune signatures showcases reduced CD4 + and CD8 + T-cell memory subsets in children with MIS ( 14 ). Similarly, the downregulation of host-protecting T-cell responses was suggested as evidence of MIS-C and COVID-19 infection ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of components of the innate immune response in MIS-C showed marked neutrophil activation, degranulation signatures, and neutrophil extracellular traps ( 13 ). Rajamanickam et al explored cellular biomarkers for MIS-C, inclusive of B cells, dendritic cells, monocytes, and T cells, which significantly distinguish MIS-C from other diseases that have overlapping clinical symptoms ( 14 ). Moreover, HLA-genotype alterations in the T cells of children with MIS were reported as MIS-C biomarkers ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Multisystem inflammatory syndrome in children characterized by enhanced antigen-specific T-cell expression of cytokines and its reversal following recovery

Pavan Kumar,

Abbas,

Renji

et al. 2023

Front. Pediatr.

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BackgroundMultisystem inflammatory syndrome (MIS) in children is considered to be a post-infectious complication of COVID-19. T-cell responses in children with this condition have not been well-studied.MethodsWe aimed to study the immune responses in children with MIS in comparison to children with acute COVID-19 and children with other infections. Whole blood was stimulated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)–specific antigens and flow cytometry was performed to examine CD4+ and CD8+ T-cell responses.ResultsChildren with MIS had higher frequencies of CD4+ and CD8+ T cells expressing cytokines at baseline and upon SARS-CoV-2 antigen–specific stimulation in comparison to children with COVID-19 and/or other infections. Children with COVID-19 also exhibited higher frequencies of CD4+ and CD8+ T cells expressing cytokines at baseline and upon SARS-CoV-2 antigen–specific stimulation in comparison to children with other infections. At 6–9 months following treatment and recovery, this enhanced response against SARS-CoV-2 antigens was down modulated in children with MIS.ConclusionOur study, therefore, provides evidence of enhanced activation of CD4+ and CD8+ T-cell responses in children with MIS and reversal following recovery.

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Unique cellular immune signatures of multisystem inflammatory syndrome in children

Cited by 8 publications

References 37 publications

Elucidating systemic immune responses to acute and convalescent SARS‐CoV‐2 infection in children and elderly individuals

Elucidating systemic immune responses to acute and convalescent SARS‐CoV‐2 infection in children and elderly individuals

Dysregulated Platelet Function in Patients with Post-Acute Sequelae of COVID-19

Multisystem inflammatory syndrome in children characterized by enhanced antigen-specific T-cell expression of cytokines and its reversal following recovery

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