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TGFβ links EBV to multisystem inflammatory syndrome in children
(Springer Science and Business Media LLC, 2025-03-12)
Carl Christoph Goetzke
;
Mona Massoud
;
Stefan Frischbutter
;
Gabriela Maria Guerra
;
Marta Ferreira-Gomes
<jats:title>Abstract</jats:title> <jats:p>In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock<jats:sup>1</jats:sup> termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion<jats:sup>2</jats:sup> and systemic hyperinflammation<jats:sup>3</jats:sup>. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. <jats:sup>4,5</jats:sup>). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein–Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.</jats:p>
Scopus© Citations 4 2
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Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
(American Association for the Advancement of Science (AAAS), 2025-01-10)
Marita Bosticardo
;
Kerry Dobbs
;
Ottavia M. Delmonte
;
Andrew J. Martins
;
Francesca Pala
<jats:p> Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of <jats:italic>RAG</jats:italic> -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic <jats:italic>RAG</jats:italic> variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T <jats:sub>H</jats:sub> 2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease. </jats:p>
Scopus© Citations 2 1
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Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children
(2023)
Danyel Lee
;
Jérémie Le Pen
;
Ahmad Yatim
;
Beihua Dong
;
Yann Aquino
<jats:p> Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of <jats:italic>OAS1</jats:italic> , <jats:italic>OAS2</jats:italic> , or <jats:italic>RNASEL</jats:italic> in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)–sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the single-stranded RNA–degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L–deficient cells. Cytokine production in RNase L–deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C. </jats:p>
11Scopus© Citations 137
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Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
(2022)
Keith Sacco
;
Riccardo Castagnoli
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Svetlana Vakkilainen
;
Can Liu
;
Ottavia M. Delmonte
Scopus© Citations 204 11
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Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C
(2022)
Peter D. Burbelo
;
Riccardo Castagnoli
;
Chisato Shimizu
;
Ottavia M. Delmonte
;
Kerry Dobbs
<jats:p>The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring <jats:italic>in vivo</jats:italic> decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring &gt;100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.</jats:p>
Scopus© Citations 25 1
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Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19
(2022)
Carmelo Carmona-Rivera
;
Yu Zhang
;
Kerry Dobbs
;
Tovah E. Markowitz
;
Clifton L. Dalgard
13Scopus© Citations 30

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