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关键词： IL-18   immune checkpoint inhibitor   PD-1   NK cells   cDC1  

摘要： The success of cancer immunotherapy depends on the effective coordination of innate and adaptive immunity. We previously reported that IL-18 potentiates the therapeutic effects of immune checkpoint inhibitors in mouse models. Here, we report that IL-18-primed natural killer (NK) cells enhanced the antitumor effects of anti-PD-1 antibodies by mobilizing type 1 conventional dendritic cells (cDC1s) to tumor sites and promoting type 1 immune responses. IL-18-primed NK cells had a premature phenotype, and expressed chemokines involved in cDC1 mobilization. In a combination treatment with IL-18 and anti-PD-1 antibody, NK cell depletion inhibited cDC1 mobilization and abrogated the therapeutic effects. Additionally, adoptive transfer of IL-18-primed NK cells induced cDC1 mobilization and enhanced the therapeutic effects of anti-PD-1 antibodies. IL-18 also increased IL-12 mRNA expression in DCs and IL-12 blood levels, and IL-12 upregulated XCL1 expression in NK cells. These results suggest that IL-18 primes NK cells and enhances the therapeutic effects of immune checkpoint inhibitors by promoting a feed-forward loop involving DCs.

摘要： Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat C. albicans infections, the underlying mechanisms remain unclear. Using global and conditional Il1r1 knockouts in mice, here we show that IL-1R signaling in non-hematopoietic cells in the kidney and brain is crucial for a protective response. In the kidney, endothelial IL-1R contributes to fungal clearance independent of neutrophil recruitment, while IL-1R in hematopoietic cells is dispensable. IL-1R signaling indirectly recruits neutrophils and monocytes in the brain by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing data implicates excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of Il1r1-deficient mice within a few hours upon infection, with associated, localized hypoxia at infection foci. Lastly, we find that hypoxia promotes fungal growth and pathogenicity. In summary, our results show that IL-1R-signaling in non-hematopoietic cells is required to prevent fatal candidiasis by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia.

关键词： HLA class I   TAP2   Biomarkers   CD8 T-cell   CD11b   IL-4R alpha   Immunotherapy   Epigenetics  

摘要： BackgroundResistance to both naturally occurring anti-cancer immunity and to immunotherapy is common in patients with aggressive non-small cell lung cancer (NSCLC). Recent studies indicate a role of loss of the HLA class-I antigen presentation machinery (APM) protein beta-2-microglobulin in acquired resistance to immune checkpoint blockers. However, the mechanisms, functional consequences and therapeutic potential of APM defects in NSCLC remain poorly *** multiplexed immunofluorescence, we spatially mapped CD8+ effector Tumor-Infiltrating Lymphocytes (TILs) and the APM components TAP1 and TAP2 in 819 baseline/pre-treatment NSCLCs from patients treated with and without PD-1 axis blockers in 4 independent cohorts. The impact of TAP1/2 silencing in lung cancer cells using siRNAs and CRISPR/Cas9 was studied using transcriptomic analysis, phosphoprotein arrays, ATAC-sequencing, measurement of surface HLA-peptide complexes and in vitro tumor-antigen specific T-cell killing. We established autologous co-cultures of tumor and immune cells from primary human NSCLCs to study the functional impact of IL4R alpha and/or PD-1 blockade using monoclonal antibodies. A high-throughput drug screen supported the identification of compounds able to increase TAP2 expression in NSCLC *** identified cancer cell selective TAP2 protein downregulation in 42.4% of treatment na & iuml;ve NSCLCs associated with reduced sensitivity to immune checkpoint blockers. TAP1 downregulation occurred in 24.4% of lung tumors without survival impact. Silencing of TAP2 in lung cancer cells altered key intracellular immunomodulatory pathways, limited sensitivity to proinflammatory cytokines, reduced the levels of surface peptide-HLA complexes and protected malignant cells from tumor antigen-specific T-cell killing via SOCS1 upregulation. TAP2 loss in human NSCLCs was associated with reduced TAP2 promoter chromatin accessibility and elevated IL-4 IL-4 expression. Treatment with I

摘要： The peripheral nervous system (PNS) plays a critical role in pathological conditions, including chronic pain disorders, that manifest differently in men and women. To investigate this sexual dimorphism at the molecular level, we integrated quantitative proteomic profiling of human dorsal root ganglia (hDRG) and peripheral nerve tissue into the expanding omics framework of the PNS. Using data-independent acquisition (DIA) mass spectrometry, we characterized a comprehensive proteomic profile, validating tissue-specific differences between the hDRG and peripheral nerve. Through multi-omic analyses and functional assays, we identified sex-specific molecular differences, with TNFα signalling emerging as a key sexually dimorphic pathway with higher prominence in males. Genetic evidence from genome-wide association studies (GWAS) further supports the functional relevance of TNFα signalling in the periphery, while clinical trial data and meta-analyses indicate a sex-dependent response to TNFα inhibitors. Collectively, these findings underscore a functionally sexual dimorphism in the PNS, with direct implications for sensory and pain-related clinical translation.

关键词： HDFlu   Influenza vaccine   MF59Flu   antibody   chemokines   cytokines   older adults  

摘要： BACKGROUND:Antibody responses to MF59-adjuvanted (MF59Flu) and high-dose (HDFlu) influenza vaccines have been well-characterized in older adults, yet corresponding cellular immune response data remain limited. METHODS:Blood samples were collected from 106 MF59Flu recipients and 112 HDFlu recipients at four time points: before vaccination (Day 0), and on Days 1, 8, and 28 post-vaccination. Antibody responses were assessed in serum samples using a hemagglutination inhibition assay. Eight pro-inflammatory cytokines and chemokines, including IFN-α2a, IFN-γ, IP-10, MCP-1, MIP-1α, IL-1β, IL-6, and IL-8, were quantified from PBMCs using a multiplex assay. Associations between cytokine/chemokine secretion levels and antibody responses were examined, along with the effect of sex, age, body mass index (BMI), and cytomegalovirus infection status. RESULTS:Age was positively correlated with IL-8 levels on Day 1 (r = 0.24, p < 0.001) and the change in IL-8 levels from Day 0 to Day 1 (r = 0.16, p = 0.021). Notably, the change in IL-8 levels was negatively associated with Day 28 HAI titers (r = -0.15, p = 0.026). Causal mediation analysis demonstrated that IL-8 exerted significant causal mediation effects on antibody responses at both Day 8 (p = 0.046) and Day 28 (p = 0.0045). No significant effects of other cytokines and chemokines, vaccine type, sex, or BMI on antibody responses were observed. CONCLUSION:Our findings underscore IL-8 as a potential mediator of antibody responses to influenza vaccination in older adults, suggesting that IL-8 inhibition could serve as a molecular intervention to improve antibody responses in this high-risk population.

摘要： Tumor necrosis factor-α （TNF-α） is a key player in the pathogenesis of rheumatoid arthritis （RA） and considered a promising target for therapeutic drug development. Activation of the nuclear factor-kappa B （NF-κB） pathway upon TNF-α binding to its receptor is crucial for progression of RA. Stephanine （SA）， an isoquinoline aporphine-type alkaloid recently identified in Stephania plants， exhibits anti-inflammatory properties， but its underlying mechanisms of action are unknown at present. In this study， we explored whether SA could ameliorate RA through inhibition of the NF-κB signaling pathway in association with TNF-α activity. Our experiments revealed a binding affinity (KD) of SA for TNF-α of 2.934×10-6M. Additionally， SA at a concentration of 10 μmol/L effectively hindered the binding of TNF-α to its receptors TNFR1 and TNFR2. In vitro， SA prevented TNF-α-induced death of L929 cells and blocked NF-κB activation triggered by TNF-α in 293-TNF-α responsive， as well as HFLS and MH7A cell lines. Furthermore， in a collagen-induced arthritis （CIA） mouse model， SA alleviated the symptoms of RA through suppression of NF-κB signaling. Our collective findings support the therapeutic efficacy of SA， a natural compound targeting TNF-α， in the management of RA.

关键词： Plaque psoriasis   HLA   Systemic treatment   Immunology  

摘要： Plaque psoriasis is a common, chronic, papulosquamous skin disorder. TNF, IL-17 and IL-23 have been identified as key cytokines in the pathogenesis of psoriasis. Certain human leukocyte antigen (HLA) variants, such as HLA-Cw6 and HLA-B27, were proposed to affect the clinical course of the disease and the response to standard and biological treatment. In individuals positive for HLA-B27, psoriatic arthritis tends to progress more rapidly, with a higher prevalence of dactylitis and nail changes, suggesting HLA-B27 being a genetic biomarker for early-onset psoriatic arthritis. HLA-Cw6 is associated with the early onset of cutaneous manifestations in psoriasis. In these cases, cutaneous lesions are commonly localised on the chest and limbs, with less pronounced scalp and nail involvement. Psoriatic arthritis tends to develop later in HLA-Cw6-positive patients. The presence of HLA-Cw6 is associated with a more favourable therapeutic response to methotrexate and p40IL-12/23 inhibitors than to TNF inhibitors. Therefore, HLA-Cw6 testing may be a valuable tool for identifying patients who are likely to benefit from treatment with specific monoclonal antibodies, especially p40IL-12/23 inhibitors.

关键词： MHC-I epitope   Pioneer Translation Products   bi-directional transcripts   bi-directional translation   reverse strand antigenic peptides  

摘要： Antisense transcripts play an important role in generating regulatory non-coding RNAs but whether these transcripts are also translated to generate functional peptides remains poorly understood. In this study, RNA sequencing and six-frame database generation were combined with mass spectrometry analysis of peptides isolated from polysomes to identify Nascent Pioneer Translation Products (Na-PTPs) originating from alternative reading frames of bi-directional transcripts. Two Na-PTP originating peptides derived from antisense strands stimulated CD8+ T cell proliferation when presented to peripheral blood mononuclear cells (PBMCs) from nine healthy donors. Importantly, an antigenic peptide derived from the reverse strand of two cDNA constructs was presented on MHC-I molecules and induced CD8+ T cell activation. The results demonstrate that three-frame translation of bi-directional transcripts generates antigenic peptide substrates for the immune system. This discovery holds significance for understanding the origin of self-discriminating peptide substrates for the major histocompatibility class I (MHC-I) pathway and for enhancing immune-based therapies against infected or transformed cells.

摘要： This study aimed to determine the prevalence of oral and maxillofacial anomalies among newborns in the Ha'il Region, Saudi Arabia, and to explore associations with parental health, socioeconomic status, and environmental factors. Given the scarcity of regional data on congenital anomalies, this research furthers the understanding of localised health risks and could inform targeted interventions. A cross-sectional hospital-based study was conducted involving 40,000 newborns born between December 2019 and June 2024. Data were collected from medical records and parental interviews at one of the main hospitals in the Ha'il Region. Anomalies were categorised and analysed using the Statistical Package for Social Sciences software, with statistical significance set at p < 0.05. Forty-seven cases (0.146%) of oral and maxillofacial anomalies were identified, with a higher prevalence seen in female newborns. Relationship were found between these anomalies and parental smoking, socioeconomic status, and parental health history. Anomalies, such as cleft lips and palates, were more frequent in females, while other conditions, like the eruption of chlorodontia, were exclusive to males. This study underscores the importance of addressing environmental and socioeconomic factors to prevent congenital anomalies. These findings provide crucial data for healthcare planning in the Ha'il Region, aligning with Saudi's Vision 2030 objectives related to improving neonatal and maternal care.