Browsing by Author "Discepolo, Valentina"
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Publication Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C(2022) Burbelo, Peter; Castagnoli, Riccardo; Shimizu, Chisato; Delmonte, Ottavia; Dobbs, Kerry; Discepolo, Valentina; Lo Vecchio, Andrea; Guarino, Alfredo; Licciardi, Francesco; Ramenghi, Ugo; Rey, Emma; Vial, Cecilia; Marseglia, Gian; Licari, Amelia; Montagna, Daniela; Rossi, Camillo; Montealegre, Gina; Barron, Karyl; Warner, Blake; Chiorini, John; Espinosa, Yazmin; Noguera, Loreani; Dropulic, Lesia; Truong, Meng; Gerstbacher, Dana; Mató, Sayonara; Kanegaye, John; Tremoulet, Adriana; Pediatric Emergency Medicine Kawasaki Group; Eisenstein, Eli; Su, Helen; Imberti, Luisa; Poli, Cecilia; Burns, Jane; Notarangelo, Luigi; Cohen, JeffreyThe 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 in vivo 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 >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.Publication Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19(2022) Carmona, Carmelo; Zhang, Yu; Dobbs, Kerry; Markowitz, Tovah; Dalgard, Clifton; Oler, Andrew; Claybaugh, Dillon; Draper, Deborah; Truong, Meng; Delmonte, Ottavia; Licciardi, Francesco; Ramenghi, Ugo; Crescenzio, Nicoletta; Imberti, Luisa; Sottini, Alessandra; Quaresima, Virginia; Fiorini, Chiara; Discepolo, Valentina; Lo Vecchio, Andrea; Guarino, Alfredo; Pierri, Luca; Catzola, Andrea; Biondi, Andrea; Bonfanti, Paolo; Poli, Cecilia; Espinosa, Yasmin; Astudillo, Camila; Rey, Emma; Vial, Cecilia; De la Cruz, Javiera; González, Ricardo; Pinera, Cecilia; Mays, Jacqueline; Ng, Ashley; Platt, Andrew; NIH COVID Autopsy Consortium; COVID STORM Clinicians; Drolet, Beth; Moon, John; Cowen, Edward; Kenney, Heather; Weber, Sarah; Castagnoli, Riccardo; Magliocco, Mary; Stack, Michael; Montealegre, Gina; Barron, Karyl; Fink, Danielle; Kuhns, Douglas; Hewitt, Stephen; Arkin, Lisa; Chertow, Daniel; Su, Helen; Notarangelo, Luigi; Kaplan, MarianaDysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes," remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.Publication TGFβ links EBV to multisystem inflammatory syndrome in children(2025) Goetzke, Carl; Massou, Mona; Frischbutt, Stefan; Guerra, Gabriela; Ferreira, Marta; Heinrich, Frederik; Von Stuckra, Anne; Wisniewsk, Sebastian; Lich, Jan; Bondarev, Marina; Ehler, Lisa; Khaldi, Samira; Javouhe, Etienne; Pons, Sylvie; Trouillet, Sophie; Ozsurek, Yasemin; Zhang, Yu; Poli Harlowe, María Cecilia; Discepolo, Valentina; Lo Vecchio, Andrea; Sahin, Bengü; Verboom, Murielle; Hallenslebe, Michael; Heuhse, Anja; Astudillo, Camila; Espinosa, Yazmin; Vial, Maria Cecilia; Dobbs, Kerry; Delmont, Ottavia; Montealegre, Gina; Magliocco, Mary; Barron, Karyl; Danielson, Jeffrey; Petrov, Lev; Unterwalder, Nadine; Sawitzk,i Birgit; Matz, Mareen; Lehmann, Katrin; Gratop, Alexander; Von Bernuth, Horst; Burkhardt, Lisa; Wiese, Niklas; Peter, Lena; Schmueck, Michael; Amini, Leila; Maurer, Marcus; Roehmel, Jobst; Gewur, Benjamin; Yonker, Lael; Witkowsk, Mario; Kruglov, Andrey; Mall, Marcus; Su, Helen; Ozen, Seza; Radbruch, Andreas; Belot, Alexandre; Durek, Pawel; Kallinich, Tilmann; Mashregh, Mir-FarzinIn a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock1 termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion2 and systemic hyperinflammation3. 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. 4,5). 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.