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摘要： Il fattore maschile è responsabile di circa il 50% dei casi di infertilità di coppia e l’iter diagnostico di tale condizione inizia con l’analisi del liquido seminale. L’intelligenza artificiale potrebbe aiutare a prevedere l’impatto di diversi parametri sulla fertilità. In questa rassegna analizzeremo le applicazioni della IA per la selezione degli spermatozoi e per il recupero degli spermatozoi da biopsia testicolare, cercando di valutare a che punto siamo arrivati e come tali sistemi, ad oggi, possano essere utili nel campo della riproduzione.

关键词： STING   SAVI   TNF   systemic autoinflammation   vasculopathy  

摘要： Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI). In order to investigate the role of signaling by tumor necrosis factor (TNF) in SAVI, we used genetic inactivation of TNF receptors 1 and 2 in murine SAVI, which is characterized by T cell lymphopenia, inflammatory lung disease, and neurodegeneration. Genetic inactivation of TNFR1 and TNFR2, however, rescued the loss of thymocytes, reduced interstitial lung disease, and neurodegeneration. Furthermore, genetic inactivation of TNFR1 and TNFR2 blunted transcription of cytokines, chemokines, and adhesions proteins, which result from chronic STING activation in SAVI mice. In addition, increased transendothelial migration of neutrophils was ameliorated. Taken together, our results demonstrate a pivotal role of TNFR signaling in the pathogenesis of SAVI in mice and suggest that available TNFR antagonists could ameliorate SAVI in patients.

关键词： influenza A virus   mouse model   human leukocyte antigen (HLA) complex   HLA-restricted T cell epitope  

摘要： Background: Annual influenza epidemics pose a significant burden on the global healthcare system. The currently available vaccines mainly induce the production of neutralizing antibodies against hemagglutinin and neuraminidase, which are prone to antigenic variation, and this can reduce vaccine efficacy. Vaccines designed to target T cell epitopes can be potentially valuable. Considering the difficulties in obtaining clinical samples and the unique advantages of mice in disease-related research, a mouse model that can simulate human immune responses can be a superior alternative to peripheral blood mononuclear cells for epitope screening. Methods: The T cell epitopes of the A/California/07/2009 (H1N1) virus were predicted and utilized to evaluate the cellular immune responses of HLA-A2/DR1 and HLA-A11/DR1 transgenic mice during epitope screening. The selected peptides were used to immunize these two groups of transgenic mice, followed by a viral challenge to assess their protective efficacy. Results: The epitopes that were predicted and screened could stimulate cellular immune responses in HLA-A2/DR1 transgenic mice, HLA-A11/DR1 transgenic mice, and C57BL/6 mice. Moreover, the transgenic mice exhibited stronger ability to produce IFN-gamma than that of the wild-type mice. Upon immunization and subjecting to viral challenge, the selected peptides exhibited protective effects against the influenza virus. Conclusions: The HLA-A2/DR1 and HLA-A11/DR1 transgenic mouse models can be used for the direct screening and validation of influenza virus T cell epitopes, which is crucial for designing T cell epitope vaccines against influenza viruses. Further, this method can be applied in epitope screening and vaccine designing before the spread of other emerging and sudden infectious diseases, thereby supporting epidemic control.

关键词： Very early-onset inflammatory bowel disease   Interleukin-10 receptor-A deficiency   Allogeneic haematopoietic stem cell transplantation   Clinical efficacy   Children  

摘要： Very early onset inflammatory bowel disease (VEO-IBD) with interleukin-10 receptor-A (IL-10RA) defects is characterised by severe and unmanageable intestinal inflammation, perianal lesions, and a high mortality rate, with the onset of the disease occurring at a very early age. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most effective treatments for VEO-IBD patients with IL-10 signaling deficiency. The objective of this study was to evaluate the clinical effectiveness of allo-HSCT in the treatment of children with VEO-IBD and IL-10RA deficiency, and to provide further clinical insights. A retrospective analysis and summary of the clinical data of seven patients with VEO-IBD and IL-10RA deficiency from January 2021 to December 2023 was performed. These patients subsequently underwent allo-HSCT after receiving a reduced-intensity conditioning regimen followed by a cyclosporine-based regimen for the prevention of graft versus host disease (GVHD). Hematopoietic reconstruction was performed on seven children with VEO-IBD combined with IL-10RA deficiency. Four patients developed grade I-II GVHD, while three patients developed grade III-IV GVHD after undergoing allo-HSCT. At a median follow-up of 518 days after allo-HSCT (range: 210-1072 days), six patients were alive, while one patient died 16 months after the procedure because of chronic GVHD and severe infections. The 3-year cumulative overall survival (OS) probability rate was 80.0% (95% CI: 44.7-100.0). All VEO-IBD patients demonstrated weight gain following HSCT, with substantial improvements observed in severe malnutrition and growth retardation associated with IL-10RA deficiency post-transplantation. Allo-HSCT is thus identified as the optimal curative therapy for VEO-IBD patients with IL10-RA deficiency. The importance of early multidisciplinary intervention and co-management of VEO-IBD is paramount in improving HSCT outcomes.

关键词： neutrophils   gamma delta T cells   IL-17A   cell death   physiological condition   innate immunity  

摘要： Background In addition to serving as the primary effector cells against infections, neutrophils have been implicated in the regulation of both innate and adaptive immunity. In this study, we aimed to investigate the role of neutrophils in the regulation of the immune system under physiological *** The in vivo effect of neutrophils on the immune system was examined using neutropenic mice. The interaction between neutrophils and gamma delta T cells was investigated using an in vitro co-culture *** Unexpectedly, we observed an accumulation of gamma delta T cells in the cervical lymph nodes of neutropenic mice. Transcriptomic analysis revealed that these gamma delta T cells exhibited unique expression profiles of cell surface molecules and genes involved in defense responses. Further characterization indicated that the accumulated gamma delta T cells were IL-17 producing CD44+CD62L-CD27- memory cells. Additionally, in vitro experiments demonstrated that neutrophils could inhibit the function of IL-17A producing gamma delta T cells by inducing cell death in a contact-dependent *** This present study demonstrates that neutrophils negatively regulate IL-17 producing gamma delta T cells under physiological conditions. Given that IL-17A is a critical cytokine for the recruitment of neutrophils to peripheral tissues, our study suggests that the crosstalk between neutrophils and IL-17A producing gamma delta T cells is a crucial mechanism for maintaining immune homeostasis under physiological conditions.

摘要： BackgroundCD8+ T-cell activation is initiated by the recognition of epitopes presented on class I major histocompatibility complex (MHC-I) molecules. Identifying such epitopes is useful for molecular understanding of cellular immune responses and can guide the development of personalized vaccines for various diseases including cancer. For a few hundred common human and mouse MHC-I alleles, large datasets of ligands are available and machine learning MHC-I ligand predictors trained on such data reach high prediction accuracy. However, for the vast majority of other MHC-I alleles, no ligand is *** capitalize on an expanded architecture of our MHC-I ligand predictor (MixMHCpred3.0) to systematically assess the extent to which predictions of MHC-I ligands can be applied to MHC-I alleles that currently lack known ligand *** results reveal high prediction accuracy for most MHC-I alleles in human and in laboratory mouse strains, but significantly lower accuracy in other species. Our work further outlines some of the molecular determinants of MHC-I ligand prediction accuracy across alleles and species. Robust benchmarking on external data shows that our MHC-I ligand predictor demonstrates competitive performance relative to other state-of-the-art MHC-I ligand predictors and can be used for CD8+ T-cell epitope *** work provides a valuable tool for predicting antigen presentation across all human and mouse MHC-I alleles. MixMHCpred3.0 tool is available at https://***/GfellerLab/MixMHCpred.

关键词： Sj & ouml   gren's syndrome   MicroRNA let-7f-5p   LGMSC-EVs   Th17/Treg balance   RORC/IL-17A axis  

摘要： Sj & ouml;gren's syndrome (SS) is an autoimmune disease primarily affecting salivary glands, with xerostomia as a distinct clinical manifestation. This disease also poses a significantly increased risk of lymphoma, severely impacting patients' quality of life. The imbalance between Th17 and Treg cells plays a critical role in SS progression, driving severe immune dysregulation, chronic inflammation, and escalating tissue dysfunction. However, current clinical treatments for SS still remain limited, and it continues to be recognized as a refractory disease. Therefore, the development of novel and effective therapeutic strategies is a pressing demand in clinical research. In recent years, extracellular vesicle (EV) therapy has emerged as a promising approach for autoimmune disease treatment, showing encouraging outcomes in modulating immune balance and alleviating symptoms. EVs carry diverse cargo, among which microRNAs (miRNAs) are highly abundant and play critical roles. These small RNAs are essential for EV-mediated functions, particularly in regulating gene expression and modulating the immune microenvironment. Our research team first isolated labial gland mesenchymal stem cells (LGMSCs) and their derived EVs (LGMSC-EVs), which offer potential therapeutic advantages in SS due to their salivary gland origin. Then we screened and identified the highly enriched miRNA let-7f-5p as a key regulator through miRNA profiling analysis. To achieve better therapeutic outcomes, we transfected exogenous miRNA let-7f-5p into LGMSC-EVs to upregulate its expression, thereby constructing let-7f-5p-encapsulated LGMSC-EVs. These modified EVs were subsequently tested in an experimental SS mouse model to evaluate their therapeutic potential. The upregulation of miRNA let-7f-5p in LGMSC-EVs significantly enhanced their therapeutic effects, resulting in clinical improvements such as increased salivary flow and reduced lymphocytic infiltration. Mechanistically, let-7f-5p-encapsulated LGMS

关键词： Autism spectrum disorders   Inflammation   Interleukin   Neuroligin   Neuronal adhesion molecules  

摘要： Autism spectrum disorder (ASD) is characterized by deficits in social interaction, restricted interests, and repetitive behaviors. Several genes, including synaptic proteins and environmental risk factors, play a role in the etiology of autism. We aimed to evaluate the relationship between neuroligin-1 (NLGN-1) and neuroligin-3 (NLGN-3) levels, which are neuronal cell adhesion molecules (CAMs), and inflammatory cytokine (IL-6, IL-8) levels with disease severity and symptom clusters and with each other in children with ASD. Eighty children diagnosed with autism who met the inclusion criteria and sixty-five typically developing children matched for age and sex were included in the study. The children were evaluated psychiatrically through a semi-structured interview, DSM-5 criteria, the Childhood Autism Rating Scale (CARS), and the Social Communication Questionnaire (SCQ). IL-6, IL-8, NLGN-1, and NLGN-3 levels were analyzed in peripheral serum samples using human ELISA kits. IL-8 and NLGN-3 levels were higher in the autism group (p < 0.001, p < 0.001). IL-6 was positively related to CARS and SCQ total scores (p = 0.021, p = 0.040, respectively). IL-8, and NLGN-3 were positively associated with the all subtests of the SCQ and the SCQ total score (all p values <0.001). NLGN-1, NLGN-3, and inflammatory cytokine (IL-6, IL-8) levels were positively correlated (all p values <0.001). Neuroligins play a central role in the brain's ability to process information and maybe a key target in the pathogenesis of ASD. Further research is needed to determine whether, to what extent and how neuronal CAMs and immunity modulate each other and whether this contributes to ASD pathogenesis. Future studies should also be expanded to investigate the influence of variables such as oxidative stress, metalloproteases responsible for ectodomain shedding, or epigenetic regulation.