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关键词： HLA-E   Estonia   Allele frequency   Population diversity   Sequencing  

摘要： Estonia is a small country in the Baltic region of Northern Europe with 1.3 million inhabitants. As a coastal area, the population of Estonia was subjected to migration influences. Due to this admixture of populations, HLA gene diversity in Estonia is interesting to study with regard to allele frequencies, haplotypes, and polymorphism. In this study, we focused on HLA-E polymorphism within the Estonian population and compared these with the polymorphism identified in other populations. Full-length HLA-E sequencing of 143 individuals originating from Estonia show dimorphism frequencies at amino acid position 107 (0.55 R vs 0.45 G) comparable to other populations. Within the study population, 16 different HLA-E alleles were identified, including four novel alleles. These 16 alleles encode four different protein variants. Despite a strong differentiation between the South-East and the rest of the Estonian country, no allele frequency differences for HLA-E between these regions were identified. Comparing the allele and SNP frequencies to frequencies found in the different neighboring countries revealed no major differences, except for the SNP encoding for HLA-E*01:06. Association analysis between classical HLA class I genes and polymorphism at amino acid position 107 of HLA-E revealed higher frequencies of HLA-A*01 with R107 and HLA-A*03 and HLA-C*04 with G107. In summary, our study provides new insights into HLA-E variation within the Estonian population and demonstrates that its level of polymorphism is comparable to those observed in other global populations.

关键词： clinical high risk   IL-6   psychosis   schizophrenia   TNF-alpha  

摘要： Background Cognitive deficits and immune system dysregulation are core features of psychotic disorders. Among inflammatory markers, interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been linked to both psychosis pathophysiology and related cognitive *** We investigated associations among IL-6, TNF-alpha, and neurocognitive performance in 107 participants: individuals at clinical high risk for psychosis (CHR-P, n = 35), first-episode psychosis (FEP, n = 39), and healthy controls (HC, n = 33). Assessments included memory, processing speed, executive function, and social cognition. Cytokines were measured from fasting serum samples. Analyses included ANOVA, correlations, and multivariate regressions controlling for age, sex, IQ, group, and symptom *** TNF-alpha levels were significantly elevated in FEP compared to CHR-P (p = 0.0251);IL-6 differences were non-significant. FEP showed poorer performance in multiple cognitive domains, especially social cognition. CHR-P individuals exhibited intermediate profiles between FEP and HC in cognition. In adjusted regression models, IL-6 was significantly associated with undermentalization on the MASC task (beta = 0.28, p = 0.0337) and showed a trend-level association with slower processing speed (beta = 0.98, p = 0.075). TNF-alpha levels predicted poorer facial emotion recognition (beta = -1.37, p = 0.0022). IQ and group were significant covariates in most *** Our findings suggest that peripheral inflammation, particularly IL-6 and TNF-alpha, may selectively impact social cognitive functioning in early psychosis. Though modest, these associations highlight potential inflammatory contributions to functional impairment and support further investigation of immunological targets in early intervention.

关键词： M1 macrophage   pancreatic cancer   ferroptosis   ACSL4   MAPK pathway  

摘要： Introduction Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most malignant gastrointestinal tumors. M1 macrophage, a subtype within the Tumor Microenvironment (TME), plays a vital role in the development of cancer. Despite its anti-tumoral functions, the specific mechanisms of its action remain incompletely *** The effect of M1 macrophages on the proliferation ability and cell viability of PDAC cells was evaluated by Cell Counting Kit-8 (CCK-8) cell proliferation assay, cell clone formation assay, and flow cytometry. Western blot, qRT-PCR, confocal microscope, RNA-sequencing, and transmission electron microscope were performed to assess lipid peroxidation and ferroptosis level of PDAC cells in the context of M1 macrophage or *** M1 macrophages inhibited cell proliferation and promoted cell death of PDAC cells, in which ferroptosis played a vital role. Mechanistically, Tumor Necrosis Factor-alpha (TNF-alpha) released by M1 macrophages binds to the TNFR1 receptor on pancreatic cancer cells, activating the p38 MAPK signaling, which upregulates Acyl-CoA Synthetase Long-chain family member 4 (ACSL4) expression, a critical lipid metabolism enzyme linked to ferroptosis, thereby promoting ferroptosis. Knockdown of ACSL4 or TNFR1 significantly reduced TNF-alpha-induced *** TNF-alpha is a major inflammatory cytokine and is mainly generated by macrophages and T lymphocytes. It is involved in many pathological processes, such as inflammatory diseases, autoimmune diseases, and cancer. Studies have shown that the administration of recombinant TNF-alpha can induce tumor regression in mice with sarcomas. In our study, systemic injection of TNF-alpha slowed the tumor growth in nude mice, but with no significant difference compared with the control group, which may partially be attributed to its angiogenic activity. TNF-alpha signals via two distinct membrane-binding receptors, TNFR1 and TNFR2, which regulate various diseases. In

关键词： Copyrights  

摘要： Lupus nephritis is recognized as a common and severe complication of systemic lupus erythematosus, without an optimal therapeutic strategy currently available. While mesenchymal stem cells (MSCs) hold therapeutic promise, their efficacy varies substantially, likely due to their plasticity and capacity to adopt pro-inflammatory (MSC1) or anti-inflammatory (MSC2) functional states in response to different microenvironments. Here, we report for the first time that IL-27, via JAK1-STAT1 signaling, up-regulates indoleamine 2,3-dioxygenase (IDO) in MSCs, driving MSC differentiation toward an IDO-positive MSC2 phenotype with low immunogenicity. These IDO-positive MSC2 cells produce kynurenine and kynurenic acid, the metabolites of tryptophan, which bind to the intracellular aryl hydrocarbon receptor. This interaction stimulates an increase in the anti-inflammatory factor TSG-6 and induces the differentiation of regulatory T cells. Notably, IL-27-conditioned MSC2 demonstrated superior therapeutic efficacy compared to conventional MSCs in a murine lupus nephritis model. In conclusion, this study revealed that IL-27 is a critical modulator of MSC immune plasticity and presented a novel therapeutic strategy utilizing IL-27-enhanced MSC2 for autoimmune diseases.

关键词： calcium oxalate   interleukin-10   macrophage transplantation   nephrocalcinosis  

摘要： Nephrocalcinosis provides a nidus for stone formation and is strongly linked to renal injury and chronic kidney disease. Although the crucial role of macrophages in the formation and progression of calcium oxalate (CaOx) crystals has long been widely recognized, finding effective immunotherapies for nephrocalcinosis remains a challenge. In this study, we described an innovative macrophage-based method that delivers interleukin-10 (IL-10) into the kidney, reduces the deposition of CaOx crystals, and alleviates renal injury in a mouse model of glyoxylate-induced CaOx. Compared with recombinant IL-10 direct injection, the macrophage-based method has the advantages of biocompatibility and sustaining action. We found that the transplantation of engineered macrophages via the tail vein significantly reduced the volume of crystals in the kidney, thereby alleviating the kidney injury caused by crystal. In mechanistic studies, IL-10-secreting macrophages inhibited crystal formation and promoted crystal clearance by promoting macrophage M2 polarization, exerting a protective effect on renal tissue. Our data suggest that macrophage-based delivery of IL-10 to the kidney can be a potential treatment method for nephrocalcinosis.

关键词： breast cancer   IL-21   IL-22   tumour microenvironment  

摘要： Breast cancer is one of the most commonly diagnosed malignant tumours in women worldwide. Although modern medicine has led to advanced diagnostic methods and therapies that allow for increasingly effective treatment, the mechanisms underlying breast cancer development and progression remain the subject of intensive research. In the pathogenesis of this cancer, significant importance is attributed to interactions between tumour cells and the tumour microenvironment, in which soluble immune system mediators-cytokines-play a key role, including IL-21 and IL-22. These interleukins, by modulating the immune response, can both promote and inhibit tumour progression, and analysing their concentrations may prove helpful in diagnosis, disease progression prognosis, and the development of new therapies, including immunotherapy. The aim of this study was to determine the concentrations of IL-21 and IL-22 in a group of patients with invasive cancer, depending on the biological type of the tumour and its malignancy grade. The study involved 60 women with breast cancer and 20 women with benign breast lesions, and the analysis of IL-21 and IL-22 protein concentrations was performed using the enzyme-linked immunosorbent assay (ELISA) method. The analysis shows that the concentrations of IL-21 and IL-22 do not differ significantly depending on the malignancy grade of the tumour. However, a statistically significant negative correlation between the concentrations of IL-21 and IL-22 was observed exclusively in the group of patients with benign breast lesions. Due to the high heterogeneity of breast cancers, further research with a larger study group is necessary to better understand these parameters and possibly apply them clinically in patients with breast cancer.

关键词： PTX3   Glioma   Poor-prognosis predictor   Clinical stage   Immune cell infiltration  

摘要： Background. Glioma, a highly aggressive brain tumor, presents significant challenges in prognosis and treatment. This study investigates the role of PTX3 expression in glioma and its correlation with patient outcomes, addressing a gap in current research regarding its molecular mechanisms. Materials and Methods. RNA sequencing data and clinical information for glioma patients were obtained from The Cancer Genome Atlas (TCGA). A multigene prognostic signature based on IL-18 signaling-related genes (ISRGs) was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression method. The functional roles of PTX3 were analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Single-sample GSEA (ssGSEA) was used to assess the association between PTX3 expression and immune cell infiltration. The relationship between PTX3 expression and clinicopathological features was also examined. Prognostic relevance was evaluated using univariate and multivariate Cox regression models, and Kaplan-Meier survival analysis was performed. PTX3 protein expression was validated via immunohistochemistry in 56 glioma specimens. Results. The LASSO Cox regression model identified a nine-gene prognostic signature, including BMP2, NCF1, HSPB1, PIGT, PTX3, CCNA2, CCNB2, CCN4, and DES. Functional enrichment analysis revealed that PTX3-associated differentially expressed genes were significantly enriched in pathways such as cytokine-cytokine receptor interaction and PI3K-Akt signaling, which are critical for immune response and cell proliferation in glioma. PTX3 expression showed a strong correlation with immune cell infiltration, particularly macrophages, neutrophils, T cells, and natural killer cells, suggesting a role in modulating the tumor microenvironment. Pan-cancer analysis indicated that PTX3 is markedly upregulated in various cancers, especially gliomas, highlighting its potential as a biomarker.

关键词： Infectious disease and host defense   Lymphocyte biology  

摘要： Plasmodium falciparum malaria remains a significant global health challenge. Current vaccines elicit antibody responses against circumsporozoite protein (PfCSP) that prevent the infection of hepatocytes but offer only moderate protection. Cellular immunity has emerged as a critical component of preerythrocytic protection that might be leveraged to develop improved PfCSP vaccines. Here, we characterized the clonality, molecular features, epitope specificity, and HLA restrictions of the human PfCSP-specific CD4+ and CD8+ T cell response to vaccination with an adjuvanted PfCSP vaccine, FMP013/ALFQ. Using TCR expression cloning, we identified novel conserved CD4+ T cell epitopes in the PfCSP N terminus and showed that the C-terminal CS.T3 epitope was targeted by CD4+ and rare CD8+ T cells, which recognized this epitope co-receptor independently presented on a class II HLA. Our findings provide insights into the utility of these epitopes as targets for strain-transcending immunity compared with the immunodominant but highly polymorphic epitopes in the PfCSP C terminus, offering guidance for the design of improved malaria vaccines.

关键词： 中性粒细胞淋巴细胞比值   凝血指标   脓毒症伴DIC患者   血浆治疗  

摘要： 探索NLR与凝血参数动态监测指导血浆输注对脓毒症合并DIC患者的治疗效应。方法 将62例确诊患者随机分配至干预组(n=31)与对照组(n=31),对照组接受常规血浆输注,干预组依据NLR及凝血指标(PT、FDP、D-二聚体)实时调整输注方案。主要观察指标包括炎症反应变化(NLR)、凝血功能恢复情况(PT、APTT、D-二聚体、FIB)、DIC及SOFA评分改善程度,以及28天病死率和ICU住院时间等预后指标。结果 干预组治疗后24h及72hNLR值较对照组降低(P<0.05),凝血功能指标PT、APTT及D-二聚体水平改善更明显(P<0.05)。DIC评分改善率干预组(80.6%)高于对照组(54.8%)(P=0.027),SOFA评分降幅更大(P<0.001)。预后方面,干预组28天病死率(25.8%)低于对照组(45.2%)(P=0.042),ICU住院时间缩短(7.8±2.6天vs10.5±3.2天,P<0.001)。结论 在脓毒症伴DIC患者中,基于NLR联合凝血指标动态调整的血浆输注方案较常规方案能更有效控制炎症反应,改善凝血功能,降低病死率并缩短ICU住院时间,具有临床推广价值。