Browsing by Author "Delmonte, Ottavia M."

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    HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related auto-inflammatory disease
    (2021) Martinez, Caridad; Ebstein, Frédéric; Nicholas, Sarah K.; Guzman, Marietta De; Forbes, Lisa R.; Delmonte, Ottavia M.; Bosticardo, Marita; Castagnoli, Riccardo; Krance, Robert; Notarangelo, Luigi D.; Krüger, Elke; Orange, Jordan S.; Poli, Cecilia
    Inborn errors of immunity that present with concomitant immunodeficiency and auto-inflammation are therapeutically challenging; furthermore, complexity is added when they are caused by mutations in genes that encode for proteins expressed beyond immune cells. The ubiquitin-proteasome system is the main intracellular proteolytic machinery and participates in most cellular processes by degrading ubiquitinated proteins. Mutations in proteasome subunits resulting in proteasome deficiency cause a severe autoinflammatory disease characterized by chronic auto-inflammation neutrophilic dermatosis and fever, collectively referred to as Proteasome Associated Auto-inflammatory Syndromes (PRAAS). POMP is a chaperone for proteasome assembly and AD mutations in POMP cause a form of PRAAS with prominent immunodeficiency referred to as POMP-related auto-inflammation and immune dysregulation (PRAID) manifesting with recurrent, severe and opportunistic infections in addition to inflammatory features that are characteristic for all PRAAS disorders, most importantly early-onset neutrophilic dermatosis. JAK inhibitors partially control the disease in individuals with PRAAS, however life-threatening, recurrent and opportunistic infections in patients with POMP mutations limit immunosuppressive therapies and prompted consideration of hematopoietic stem cell transplant (HSCT). We describe successful HSCT in two patients with POMP deficiency. Despite POMP being ubiquitously expressed, the immunologic and autoinflammatory phenotype were both ameliorated through HSCT which suggests that the clinical and immunological features of PRAID are predominantly derived from a proteasome defect in hematopoietic cells. To our knowledge, these are the first patients with a form of PRAAS cured by HSCT, opening new therapeutic possibilities for these diseases.
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    Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
    (2022) Sacco , Keith; Castagnoli , Riccardo; Vakkilainen, Svetlana; Liu, Can; Delmonte, Ottavia M.; Oguz, Cihan; Kaplan, Ian M.; Alehashemi, Sara; Burbelo, Peter D.; Bhuyan, Farzana; Jesus, Adriana A.; Dobbs , Kerry; Rosen, Lindsey B.; Cheng, Aristine; Shaw, Elana; Vakkilainen, Mikko S.; Pala , Francesca; Lack, Justin; Zhang, Yu; Fink, Danielle L.; Oikonomou, Vasileios; Snow , Andrew L.; Dalgard, Clifton L.; Chen, Jinguo; Sellers, Brian A.; Montealegre Sanchez, Gina A.; Barron, Karyl; Rey-Jurado, Emma; Vial, Cecilia; Poli, Cecilia; Licari, Amelia; Montagna, Daniela; Marseglia, Gian Luigi
    Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n= 110) and MIS-C (n= 76), along with pediatric healthy controls (pHCs; n= 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy

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