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关键词： Alloimmunization   HLA   Antigen-specific immunotherapy   Fc fusion protein  

摘要： Diverse human leukocyte antigens (HLA) play a crucial role in adaptive immune responses via peptide presentation. Unrelated to this role, alloimmunization to mismatched HLA represents a significant barrier to allogeneic transplantation. Despite the complexity of HLA structures and the diversity of alleles, advancements in recombinant HLA protein production have enabled their use in diagnostics and are paving the way for therapeutic applications. HLA-Fc fusion proteins, combining the extracellular domains of HLA molecules with the Fc region of immunoglobulins, offer a promising approach for antigen-specific immunotherapy. This review examines the engineering challenges and therapeutic potential of HLA-Fc fusion proteins in mitigating unwanted HLA alloimmunization and antibody-mediated rejection (AMR) following transplantation. HLA-Fc fusion proteins provide enhanced stability and effector functions, enabling the selective targeting and depletion of anti-HLA antibody-producing cells. Preclinical studies demonstrate their efficacy in neutralizing anti-HLA antibodies and depleting cognate antibody-producing cells, highlighting their potential to improve transplant outcomes and reduce AMR. Future research may focus on optimizing these fusion proteins, understanding their effects on primary B cells and long-lived plasma cells, and exploring combination therapies to enhance their clinical efficacy.

关键词： CDKN1A   IL‐17 signaling pathway   autism spectrum disorder   oxidative stress  

摘要： Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social interaction, communication deficits, and repetitive behaviors. However, the underlying molecular mechanisms remain elusive. This study aims to investigate the role of cyclin-dependent kinase inhibitor 1 A (CDKN1A) in ASD. This study integrated multi-omics bioinformatics analysis to identify differentially expressed genes (DEGs) related to oxidative stress in ASD. Hub genes were screened using machine learning models. In vivo, an ASD rat model was established by maternal lipopolysaccharide (LPS) injection. Behavioral tests (open field, three-chamber social, morris water maze) were performed. Histopathology change was observed by hematoxylin-eosin staining. In vitro, LPS-stimulated BV2 microglia were treated with IL-17A for feedback experiments. Enzyme-linked immunosorbent assay was carried out to measure inflammatory factors and oxidative stress indicators. Western blot was used to detect protein expression. Bioinformatics analysis revealed 30 DEGs, with CDKN1A emerging as a prominent hub gene associated with oxidative stress. ASD model rats exhibited behavioral deficits, neuroinflammation, and hippocampal neurodegeneration. CDKN1A knockdown significantly attenuated these phenotypes, improving social interaction, reducing anxiety-like behaviors, and enhancing spatial learning and memory. Moreover, IL-17 pathway was screened as downstream pathway of CDKN1A. CDKN1A silencing suppressed LPS-induced apoptosis, inflammation, and oxidative stress in BV2 microglial cells, which was weakened by IL-17A. CDKN1A drives ASD pathogenesis via IL-17 pathway activation. Its suppression mitigates neuroinflammation, oxidative stress, and behavioral impairments, establishing CDKN1A as a novel therapeutic target for ASD. Trial Registration: Clinical trial number: Not applicable.

关键词： AM   alveolar macrophage   APC   antigen-presenting cell   ARG1   arginase 1   BCG   bacille Calmette-Guérin   CCL2   C-C motif chemokine ligand 2   CD   cluster of differentiation   CTB   beta subunit of cholera toxin   CTC   circulating tumor cell   CTLA-4   cytotoxic T-lymphocyte-associated antigen-4   CXCL12   C-X-C motif chemokine ligand 12   DC   dendritic cell   ECM   extracellular matrix   EMT   epithelial-to-mesenchymal transition   GM-CSF   granulocyte-monocyte CSF   H3K4me3   histone H3 trimethylation at Lys4   HDL   high-density lipoprotein   HIF-1α   hypoxia-inducible factor 1-alpha   HSPC   hematopoietic stem and progenitor cell   IAV   influenza A virus   ICI   immune checkpoint inhibitor   IDO   indoleamine 2,3-dioxygenase   IFN   Interferon   IL   interleukin   IL-1RA   IL-1 receptor antagonist   IM   interstitial macrophage   iNOS   inducible nitric oxide synthase   LOX1   low-density lipoprotein receptor 1   LPS   lipopolysaccharide   M-CSF   monocyte colony stimulating factor   M-MDSC   monocytic MDSCs   MDSC   myeloid-derived suppressor cell   MHC   major histocompatibility complex   MMP   matrix metalloproteinase   MoDC   monocyte-derived DCs   mTOR   mechanistic target of rapamycin   NET   neutrophil extracellular trap   NF-κB   nuclear factor kappa-B   NK   natural killer   NMIBC   non-muscle-invasive bladder cancer   NOD2   nucleotide-binding and oligomerization domain-containing protein 2 receptor   OMV   outer membrane vesicle   PI3K   phosphoinositide 3-kinase   pDC   plasmacytoid DC   PD-1   programmed cell death-1   PD-L1   programmed cell death-ligand 1   PGE2   prostaglandin E2   PMN   polymorphonuclear   ROS   reactive oxygen species   SCFA   short-chain fatty acid   SQLE   squalene epoxidase   STING   stimulator of interferon gene   TAM   tumor-associated macrophage   TAN   tumor-associated neutrophils   TGF   transforming growth factor   TLR4   Toll-like receptor 4   TME   tumor microenvironment   TNF   tumor necrosis factor   TRAIL   TNF-related apoptosis-inducing ligand   Tregs   regulatory T cells   TRM   tissue-resident macrophage   VEGF   vascular endothelial growth factor   VISTA   V-domain immunoglobulin suppressor of T-cell activation   WGP   whole glucan particle  

摘要： Myeloid innate immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells, and dendritic cells, represent major components of the tumor microenvironment (TME), exhibiting remarkable plasticity and dual roles in cancer progression and immune regulation. In recent years, microbial-induced innate immune memory, also termed "trained immunity" (TRIM), has emerged as a novel strategy to reprogram myeloid cells into an immunostimulatory, antitumor state. In this review, we explore the intricate landscape of myeloid cells in cancer and examine how microbial ligands, such as the Bacillus Calmette-Guerin vaccine and beta-glucan, reprogram both bone marrow progenitors and tissue-resident myeloid cells to enhance inflammatory and antitumor responses. Notable findings include the hematopoietic stem and progenitor cell reprogramming by Bacillus Calmette-Guerin for sustained anticancer immunity, and the enhanced granulopoiesis and neutrophil-mediated tumor killing mediated by beta-glucan-induced TRIM. These mechanisms synergize with immunotherapies, such as immune checkpoint inhibitors, by reshaping the immunosuppressive TME and enhancing adaptive immunity. However, challenges remain, including the structural complexity of microbial products, the lack of predictive biomarkers, and the need for optimized dosing and delivery strategies. Addressing these gaps by introducing precise characterization of microbial-derived ligands, biomarker-driven patient selection through large-scale clinical trials, as well as the development of novel approaches for targeted therapy will be essential to harness the full potential of microbial-induced TRIM, ultimately paving the way for more effective and durable cancer immunotherapies. Significance Statement: Tumor-promoting myeloid cells within the tumor microenvironment remain a major barrier to effective cancer immunotherapy. Microbial-induced trained immunity offers a novel strategy to reprogram myeloid cells into an antitu

关键词： acitretin   biologic therapy   brodalumab   case series   Darier disease   IL-17  

关键词： IL-23   IL-17   bioinformatics   cytokine   gene   inflammation   receptor  

摘要： Introduction/Objective Bioinformatic analysis is a valuable tool that allows us to collect, archive, analyze, and disseminate biological data for further interpretation. Analysis of the IL-23/IL-17A axis and its receptors will provide us with essential information about their functions, interactions, and relationships with various diseases. This review aims to identify the central genes co-expressed in the IL-23/IL-17A axis and their receptors and to understand their ontology and modifying *** We used several databases, including COXPRESdb to obtain the co-expressed genes, ShinyGO and ToppGene platforms to explore gene functional enrichment, and the NetworkAnalyst 3.0 platform for gene expression *** We found that genes encoding IL-23/IL-17A axis proteins and their receptors mainly respond to microbial components, participate in the inflammatory response, and are primarily associated with inflammatory and autoimmune diseases. In addition, we observed an association of the IL-23/IL-17 axis with Behcet's disease, Graft-versus-host disease, and Hodgkin's disease, although there is no direct evidence of their *** The IL-23/IL-17A axis is associated with several inflammatory and autoimmune pathologies. Therefore, we suggest further research to confirm its role in these pathologies and, if possible, use it as a therapeutic target.

关键词： Sec6   BEFV   MAVS   Viral replication   IFN-I signaling response  

摘要： Sec6 is one of the eight subunits of the exocyst complex, playing a specific role in cell-cell adhesion and vesicle trafficking. However, its role in the replication of bovine ephemeral fever virus (BEFV) and the antiviral innate immune response has remains unclear. In this study, we demonstrate that Sec6 inhibits the BEFV-triggered type I IFN (IFN-I) signaling response and promotes viral replication. Further research revealed that Sec6 degrades mitochondrial antiviral signaling protein (MAVS) through the autophagy pathway. Mechanistically, Sec6 promotes the association between autophagy receptor P62 and MAVS, enhancing autophagy degradation of MAVS. Silencing Sec6 inhibits the interaction between MAVS and P62. In addition, Sec6 failed to degrade MAVS in P62knockdown cells, resulting in the loss of its ability to suppress IFN-I signaling and enhance viral replication. This study reveals a previously unrecognized role of Sec6 in modulating the antiviral innate immunity and its impact on BEFV replication.

关键词： IL-18   T cells   NK cells   Immunotherapy   cancer   Immune-oncology   Syngeneic tumor models  

摘要： Recombinant interleukin-18 (IL-18) holds promise as a therapeutic for oncology, as a robust activator of adaptive and innate immune cells and a potent producer of IFN-gamma. However, clinical success has been limited due to rapid upregulation of the natural IL-18 inhibitor, IL-18 binding protein (IL-18BP), and fast systemic clearance of active IL-18, unbound to IL-18BP. To overcome these limitations, human IL-18 and mouse orthologs were engineered with resistance to IL-18BP and extended half-life by fusion to an Fc scaffold, with the goal of creating an improved IL-18-based therapeutic. IL-18 variants with a range of potencies showed no detectable binding to IL-18BP and retained full biological activity in the presence of super-physiological levels of IL-18BP. Pharmacokinetic studies comparing the mouse orthologs with a "naked" IL-18BP resistant tool IL-18 variant confirmed the importance of half-life extension. Importantly, the mouse Fc orthologs exhibited stronger and more durable TH1 cytokine production and expansion of cytotoxic NK cells and effector CD8+ T cells when compared to the naked IL-18 variant. Remarkably, mouse engineered IL-18 variants administered once a week demonstrated strong tumor growth inhibition and improved survival compared to vehicle treated mice in multiple syngeneic tumor models. Human IL-18 variants dosed in humanized mice mirrored in vivo findings from mouse orthologs, displaying extended pharmacokinetics and durable upregulation of serum TH1 cytokines. These promising pre-clinical results highlight engineered IL-18 solutions that resist IL-18BP binding and extend half-life, unlocking its full potential for sustained anti-cancer immune responses.

关键词： Influenza A virus (IAV)   Non-structural protein 1 (NS1)   Interleukin-10 (IL-10)   Phosphoinositide 3-kinase (PI3K)   Exosome  

摘要： Influenza A virus (IAV) has a potential pandemic threat and is a major challenge to human health. Interleukin-10 (IL-10) is a pleiotropic factor that can be induced by influenza infection and is closely associated with the development of pneumonia. However, the specific viral protein responsible for regulating IL-10 production during IAV infection, as well as its detailed mechanisms involved, remains incompletely understood. In this study, we screened the IAV genes and found that IAV Non-structural protein 1 (NS1) upregulates the production of IL-10 through the PI3K-AKT pathway. Moreover, we found that NS1 interacted with PI3K p85(3 subunit, leading to the activation of PI3K-AKT. This subsequently inhibits GSK3(3, thereby promoting the phosphorylation and nuclear translocation of CREB, and ultimately inducing the expression of IL-10. Furthermore, IAV-infected A549-derived exosomes carrying NS1 promoted IL-10 by the same pathway. Together, these results suggest that IAV increased IL-10 expression through multiple pathways, including direct action of NS1 or through exosomes. Our findings provide novel insights into additional functionalities of IAV NS1 during infection.

关键词： Influenza   Interleukin-6 (IL-6)   Mendelian randomization   COVID-19   JAK-STAT