Browsing by Author "Astudillo, Camila"
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Publication Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency(2023) Le Voyer, Tom; Parent, Audrey V.; Liu, Xian; Cederholm, Axel; Gervais, Adrian; Rosain, Jérémie; Nguyen, Tina; Perez Lorenzo, Malena; Elze Rackaityte, Elze; Rinchai, Darawan; Zhang, Peng; Bizien, Lucy; Hancioglu, Gonca; Ghillani-Dalbin, Pascale; Charuel, Jean-Luc; Philippot, Quentin; Sokhna Gueye, Mame; Raj Luxman, Majistor; Maglorius Renkilaraj; Ogishi, Masato; Soudée, Camille; Migaud, Mélanie; Rozenberg, Flore; Momenilandi, Mana; Riller, Quentin; Imberti, Luisa; Delmonte, Otavia M.; Müller, Gabriele; Keller, Baerbel; Orrego, Julio; Franco Gallego, William Alexander; Rubin, Tamar; Emiroglu, Melike; Parvaneh, Nima; Eriksson, Daniel; Aranda-Guillen, Maribel; Berrios, David I.; Vong, Linda; Katelaris, Constance H.; Mustillo, Peter; Johannes Raedler, Jonathan; Bohlen, Jonathan; Celik, Jale Bengi; Astudillo, CamilaPatients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. 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, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). 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.Publication Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile(2024) Poli Harlowe, María Cecilia; Rebolledo Jaramillo, Boris; Lagos, Catalina; Orellana, Joan; Moreno, Gabriela; Martín, Luz M.; Encina, Gonzalo; Böhme, Daniela; Faundes, Víctor; Zavala, M. Jesús; Hasbún, María Trinidad; Fischer, Sara; Brito, Florencia; Araya, Diego; Lira, Manuel; Cruz, Javiera de la; Astudillo, Camila; Lay-Son, Guillermo; Cares, Carolina; Aracena, Mariana; San Martín, Esteban; Coban-Akdemir, Zeynep; Posey, Jennifer E.; Lupski, James R.; Repetto, GabrielaRare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.Publication Deep immunophenotyping reveals biomarkers of multisystemic inflammatory syndrome in children in a Latin American cohort(2022) Rey, Emma; Espinosa, Yazmin; Astudillo, Camila; Jimena, Lina; Hormazábal, Juan; Noguera, Loreani; Cofré, Fernanda; Piñera, Cecilia; González, Ricardo; Bataszew, Alexander; Muñoz, Paula; Benadof, Dona; Álvarez, Patricia; Acevedo, Valeria; Vial, Pablo; Vial, Cecilia; Poli, CeciliaBackground: Multisystemic inflammatory syndrome in children (MIS-C) is a life-threatening disease that occurs 2-5 weeks after severe acute respiratory syndrome coronavirus 2 exposure and is characterized by severe multisystemic inflammation. Early recognition of MIS-C is key to prognosis; therefore, establishing clinical and laboratory biomarkers that predict complications is urgently needed. Objective: We characterized the immune response and clinical features of patients with acute MIS-C and determined biomarkers of disease in a cohort of 42 Latin American patients. Methods: Immune characterization was performed using flow cytometry from peripheral mononuclear cells and severe acute respiratory syndrome coronavirus 2-specific humoral and cellular response was performed using flow cytometry, enzyme-linked immunospot, enzyme-linked immunosorbent assay, and neutralizing antibody assays. Results: MIS-C is characterized by robust T-cell activation and cytokine storm. We uncovered that while C-X-C motif chemokine ligand (CXCL) 9, IL-10, CXCL8, CXCL10, IL-6, and IL-18 are significantly elevated in patients with shock, while CCL5 was increased in milder disease. Monocyte dysregulation was specifically associated with KD-like MIS-C. Interestingly, MIS-C patients show a natural killer cell degranulation defect that is persistent after 6 months of disease presentation, suggesting it could underlie disease susceptibility. Most MIS-C had gastrointestinal involvement, and higher levels of neopterin were identified in their stools, potentially representing a biomarker of intestinal inflammation in MIS-C. Severe acute respiratory syndrome coronavirus 2-specific cellular response and neutralizing antibodies were identifiable in convalescent MIS-C patients, suggesting sustained immunity. Conclusion: Clinical characterization and comprehensive immunophenotyping of Chilean MIS-C cohort provide valuable insights in understanding immune dysregulation in MIS-C and identify relevant biomarkers of disease that could be used to predict severity and organ involvement.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.