Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency ...characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.
Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65495-503 peptide to specific CTLs. In addition, we show that the ...rs17481334 G variant, naturally occurring in the ERAP1 3′ UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 3′ UTR of ERAP1 A variant, but not the 3′ UTR of ERAP1 G variant, and, accordingly, ERAP1 expression is reduced both at RNA and protein levels only in human fibroblasts homozygous for the A variant. Consistently, HCMV-infected GG fibroblasts were more efficient in trimming viral antigens and being lysed by HCMV-peptide-specific CTLs. Notably, a significantly decreased HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV is negatively associated with adult-onset disorder. Overall, our results identify a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy with potential implications for individual susceptibility to infection and other diseases.
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•HCMV miR-112-5p targets ERAP1, preventing the presentation of viral epitopes to CTLs•The rs17481334 variant G preserves ERAP1 from miR-UL112-5p-mediated degradation•HCMV-infected GG cells are more efficiently lysed by HCMV-peptide-specific CTLs•Decreased HCMV seropositivity is detected among multiple sclerosis GG patients
Romania et al. identify a single-nucleotide polymorphism in ERAP1 gene, which represents a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy, with potential implications for individual susceptibility to viral infection and other diseases.
Major histocompatibility complex (MHC) class I molecules present antigenic peptides on the cell surface to alert natural killer (NK) cells and CD8+ T cells for the presence of abnormal intracellular ...events, such as virus infection or malignant transformation. The generation of antigenic peptides is a multistep process that ends with the trimming of N‐terminal extensions in the endoplasmic reticulum (ER) by aminopeptidases ERAP1 and ERAP2. Recent studies have highlighted the potential role of ERAP1 in reprogramming the immunogenicity of tumor cells in order to elicit innate and adaptive antitumor immune responses, and in conferring susceptibility to autoimmune diseases in predisposed individuals. In this review, we will provide an overview of the current knowledge about the role of ERAP1 in MHC class I antigen processing and how its manipulation may constitute a promising tool for cancer immunotherapy and treatment of MHC class I‐associated autoimmune diseases.
Nowadays geomatic techniques can guarantee not only a precise and accurate survey for the documentation of our historical heritage but also a solution to monitor its behaviour over time after, for ...example, a catastrophic event (earthquakes, landslides, ecc). Europe is trying to move towards harmonized actions to store information on cultural heritage (MIBAC with the ICCS forms, English heritage with the MIDAS scheme, etc) but it would be important to provide standardized methods in order to perform measuring operations to collect certified metric data. The final result could be a database to support the entire management of the cultural heritage and also a checklist of “what to do” and “when to do it”. The wide range of geomatic techniques provides many solutions to acquire, to organize and to manage data at a multiscale level: high resolution satellite images can provide information in a short time during the “early emergency” while UAV photogrammetry and laser scanning can provide digital high resolution 3D models of buildings, ortophotos of roofs and facades and so on. This paper presents some multiscale survey case studies using UAV photogrammetry: from a minor historical village (Aielli) to the centre of L’Aquila (Santa Maria di Collemaggio Church) from the post-emergency to now. This choice has been taken not only to present how geomatics is an effective science for modelling but also to present a complete and reliable way to perform conservation and/or restoration through precise monitoring techniques, as shown in the third case study.
Industrial mathematics is evolving into an important branch of mathematics. Mathematicians, in particular in Italy, are becoming increasingly aware of this new trend and are engaged in bridging the ...gap between highly specialized mathematical research and the emerging demand for innovation from industry. The contributions in this volume provide both R&D workers in industry with a general view of existing skills, and academics with state-of-the-art applications of mathematics to real-world problems, which may also be incorporated in advanced courses.
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