Poli, CeciliaCarrión Arriagada, FlavioJarur Chamy, Valentina Lucía2022-01-182022-01-182022-01http://hdl.handle.net/11447/5479Thesis presented to the Faculty of Medicine Clínica Alemana-Universidad del Desarrollo to apply for Doctoral degree in Science and Innovation in MedicineMonogenic Immune Dysregulatory Syndromes are rare life-threatening diseases in which a single genetic defect causes global immune dysregulation manifested by either immunodeficiency, autoinflammation or autoimmunity in a nonexclusive way. Particularly, Proteasome-associated autoinflammatory Syndromes (PRAAS) are a group of Immune Dysregulatory Syndromes in which loss of function variants in proteasome subunits cause Type I IFN-mediated autoinflammation, ulcerative skin lesions and lipodystrophy through still unknown mechanisms. Proteasome-related Autoinflammation and Immunodeficiency Disease (PRAID) is a novel PRAAS caused by pathogenic variants in POMP, a proteasome assembly chaperone. PRAID patients present PRAAS-like clinical manifestations but also, they have an increased susceptibility to pneumocystis and mycobacterial infections, delineating a combined immunodeficiency that paradoxically co-exist with the autoinflammatory features in this Immune Dysregulatory Syndrome. PRAID patients present low expression of proinflammatory cytokines in T cells in vitro and NFkB deficiency is a known cause of immunodeficiency. In this regard, the proteasome plays a critical role in the activation of NFkB pathway that could be underlying the immunodeficiency in PRAID patients. Conversely, here we identified a sustained up-regulation of NFkB signaling in PRAID patients, suggesting the contribution of NFkB to the Type I IFN-mediated autoinflammatory phenotype in PRAID patients. Additionally, we identified that Type I IFN and NFkB dysregulation in PRAID patients are mediated by the Protein Kinase R (PKR), a cytosolic RNA sensor that triggers Type I IFN and NF-kB signaling upon activation. The mechanisms by which PKR is up-regulated in PRAID still remains elusive and a constitutive activation of PKR does not explain the immunodeficiency in these patients. In this regard, we demonstrated that pathogenic variants in POMP causing PRAID impair the interaction of the chaperone POMP with the immune-proteasome catalytic subunits suggesting a potential role of impaired immune proteasome assembly in the combined immunodeficiency of PRAID patients. PRAID supports the notion of Immune Dysregulatory Syndromes as complex immune-related phenotypes with more than one compromised pathway, reinforcing the relevance of a complete characterization of the pro-inflammatory environment in each genetically-determined disease. In this regard, we used the Type I IFN Signature previously standardized in PRAID patient-derived cells as a translational application for the diagnosis of Immune Dysregulatory patients with clinical features compatible with Type I IFN dysregulation. Here, we empirically demonstrated the relevance of Type I IFN evaluation through the Type I IFN signature for the genetic interpretation and functional validation of novel genetic candidates in patients with type I IFN dysregulation with and without proteasome dysfunction.145 p.enPrimary immunodeficienciesMonogenic Immune Dysregulatory Syndromes090036SThesis