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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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Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
(2023)
Tom Le Voyer
;
Audrey V. Parent
;
Xian Liu
;
Axel Cederholm
;
Adrian Gervais
<jats:title>Abstract</jats:title><jats:p>Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)<jats:sup>1,2</jats:sup>, conferring a predisposition to life-threatening COVID-19 pneumonia<jats:sup>3</jats:sup>. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52<jats:sup>LOF</jats:sup>/IκBδ<jats:sup>GOF</jats:sup>). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for <jats:italic>NFKB2</jats:italic> variants causing haploinsufficiency of p100 and p52 (hereafter, p52<jats:sup>LOF</jats:sup>/IκBδ<jats:sup>LOF</jats:sup>) or gain-of-function of p52 (hereafter, p52<jats:sup>GOF</jats:sup>/IκBδ<jats:sup>LOF</jats:sup>). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.</jats:p>
3Scopus© Citations 90
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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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