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关键词： CD4 lymphopaenia   Cryptococcal meningitis   Cryptococcosis   IL-17/ interleukin-17   IgM+ memory B-cells   Immunodeficiency  

摘要： INTRODUCTION:We describe the immunophenotyping and genetic analysis of HIV-uninfected apparently immunocompetent adults presenting with disseminated cryptococcosis. Cryptococci are environmentally ubiquitous fungi that may cause disseminated infection including meningitis. Cryptococcosis occurs predominantly in immunocompromised hosts and most commonly in the context of human immunodeficiency virus (HIV) infection. In apparently immunocompetent patients, cryptococcal disease is rare, often diagnosed later and associated with higher mortality. The immunologic work-up and management of this patient group is challenging and poorly studied. METHODS:Between 2015-2021, eight apparently immunocompetent adults at the time of diagnosis with cryptococcosis underwent extensive diagnostic immunological work-up including T-/B-cell subsets, immunoglobulins, T-cell proliferation and phenotyping, serum-specific antibody responses, mannose binding lectin, measurement of selected cytokines, anti-cytokine autoantibodies and targeted genetic next-generation sequencing. RESULTS:The production of interleukin (IL)-17 following phytohaemagglutinin (PHA) stimulation was significantly reduced in all eight patients with cryptococcosis compared to healthy controls (median IL-17 concentration in whole blood stimulation assay 88.1pg/mL in patients; 452.1pg/mL in controls, p=0.0047). In 5/5 patients tested, the percentage of CD4+ T-cells positive for IL-17, including memory CD4+CD45RO+ IL-17+ T-cells, after stimulation with staphylococcal enterotoxin B (SEB) was significantly reduced (<=0.4% cells). Reduced IgM+ memory B-cells were noted in 4/5 tested. 4/8 patients were found to have CD4 lymphopaenia. One patient with Cryptococcus gattii infection had autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). No underlying genetic causes were identified. CONCLUSION:Patients had several immunological risk factors, but reduced IL-17 production was a striking feature across th

关键词： Acute coronary syndrome   Cytokines   Interleukins   Meta-analysis   Polymorphism  

摘要： Inflammatory cytokines are pivotal in the pathophysiology of acute coronary syndrome (ACS) and have been associated with major adverse cardiovascular events. In this study, we aimed to assess the association of eight polymorphisms in IL-10, IL-6, and TNF-α with the risk of ACS through a systematic review, meta-analysis, and trial sequential analysis. A comprehensive literature review was conducted across multiple databases, including PubMed/Medline, Web of Science, Scopus, and Cochrane Library, up until August 8, 2024. The Review Manager 5.3 software was utilized to compute the effect sizes such as the odds ratio accompanied by a 95% confidence interval. Out of 1499 records identified from databases, sources, or electronic searches, 51 articles were included in qualitative and quantitative syntheses (meta-analysis). For IL-6 -174G > C, the allelic and homozygous models showed significant associations with ACS risk. IL-6 -572G > C showed no significant association across all genetic models. IL-10 polymorphisms (-592C > A, -819C > T, and -1082A > G) generally showed no significant associations. TNF-α -308G > A polymorphism showed significant associations in all models. TNF-α -1031T > C and -238G > A showed no significant associations, with varying degrees of heterogeneity. Results suggest that certain cytokine polymorphisms, notably IL-6 -174G > C and TNF-α -308G > A, may play a crucial role in increasing susceptibility to ACS. These associations are especially pronounced in certain ethnic groups, such as Asians and Arabs, highlighting the importance of considering genetic diversity in clinical assessments.

关键词： Bone remodelling   Corticotomy   Gingival crevicular fluid   IL-1β   Orthodontic acceleration   Piezocision  

摘要： BACKGROUND:Accelerating orthodontic treatment is crucial in reducing complications such as root resorption, caries, and oral hygiene compromise, especially in adults. Piezocision and corticotomy are surgical techniques that accelerate tooth movement by causing bone remodelling. This study compares and evaluates changes in Interleukin-1β (IL-1β) levels in gingival crevicular fluid (GCF) following piezocision and corticotomy-facilitated orthodontics in adults. AIM:To assess and compare IL-1β fluctuations in GCF of adult patients undergoing corticotomy and piezocision-assisted orthodontic treatment. MATERIALS & METHODS:This split-mouth study consisted of 16 adult patients (18-25 years) who needed premolar extractions. One half of the maxilla was randomly assigned for piezocision and the other half for corticotomy. GCF samples were taken from maxillary canines at varying time intervals: pre-treatment (T0), before surgery (T1), and 24 h (T2), 7 days (T3), and 21 days (T4) following surgery. IL-1β concentrations were quantified using an ELISA kit, and statistical analysis was done. RESULTS:IL-1β concentrations were highest at 24 h after surgery (T2) in both groups and decreased steadily by day 21 (T4), but were still elevated above pre-treatment levels. IL-1β concentrations were significantly greater in the piezocision group at all time points after surgery than in the corticotomy group (p < 0.001), reflecting a more intense inflammatory reaction and greater bone cell metabolism. CONCLUSION:This study suggests that piezocision elicits a more intense biological response than corticotomy, as reflected by higher IL-1β levels in gingival crevicular fluid. While this may indicate a potential for enhanced bone remodelling and accelerated tooth movement, further research is needed to directly correlate cytokine expression with the rate of orthodontic tooth movement.

摘要： During the resolution of inflammation, Ly6CF4/80 monocytes differentiate to Ly6CF4/80 macrophages that exert apoptotic cell engulfment (efferocytosis) properties and consequently convert to interferon (IFN)-β-producing macrophages. Here, we report that exposure to IFN-β, or transforming growth factor (TGF)-β, or a deficiency in the pro-apoptotic protein ARTS, results in the conversion of mature macrophages to an Ly6CF4/80CCR2 phenotype in vivo and ex vivo. Deficiency in ARTS or caspase inhibition results in enhanced conversion of macrophages to the Ly6C phenotype. Moreover, IFN-β-triggered Ly6C macrophages are hyper-efferocytic and express higher levels of the efferocytic receptor CD36. Inhibition of CD36 ligation results in complete abrogation of efferocytosis ex vivo in both Ly6C and Ly6C macrophages. Notably, IFN-β also promotes the emergence of Ly6C macrophages during the resolution of liver fibrosis, while transcriptomic analysis further links this rejuvenated phenotype to macrophage subsets found in human inflammatory liver disease. Altogether, our findings indicate IFN-β promotes macrophage conversion to a distinct hyper-efferocytic phenotype that is limited by ARTS and apoptosis during the resolution of inflammation.

关键词： Anti-TNF-alpha   Antisynthetase syndrome   Autoimmunity   Interstitial lung disease   Myositis  

关键词： TNF-alpha   pregnancy   inflammation   uterine artery   endothelial dysfunction   hypertension   preeclampsia  

摘要： While pregnancy is known to be an inflammatory condition, preeclampsia (PE) is a more extreme state associated with higher cytokines and/or altered growth factors. It is generally assumed these PE-elevated factors come from stimulation of immune cells and/or hypoxic uterine tissue, but several studies have shown that endothelial cells may also be a source. The goal of this study was to determine to what extent TNF, a factor overproduced by uteroplacental tissue in PE pregnancy, may influence uterine artery endothelial cells to contribute to these other PE-specific factors in the maternal circulation. Herein, we use multiple analytical methods to show that uterine artery endothelial cells from pregnant sheep (P-UAEC) on exposure to cytokines can secrete multiple cytokines and chemokines seen in PE women, which may contribute to production of Th17 cells and attraction of these and other cells to the vessel surface. Furthermore, the factors not significantly increased by TNF include those known to be specifically secreted by proinflammatory T cells. This begs the question if endothelium itself is the initial primary orchestrator of chemokine and cytokine imbalance, acting directly and indirectly to promote the symptoms of impaired vasodilation and reduced uteroplacental blood flow. If so, future preventive therapies for PE should be targeted at endothelium as well as immune cells.

关键词： EAT   epicardial adipose tissue   HFpEF   heart failure with preserved ejection fraction   FAC   fatty acid composition   SFA   saturated fatty acid   NLRP3   NOD-, LRR- and pyrin domain-containing protein 3   MUFA   monounsaturated fatty acid   PUFA   polyunsaturated fatty acid   SGLT2i   sodium-glucose cotransporter-2 inhibitor   SAT   subcutaneous adipose tissue   UFA   unsaturated fatty acid   HOSVD   higher-order singular value decomposition   ECG   electrocardiogram   SNR   signal-to-noise ratio   NUFFT   nonuniform fast Fourier Transform   PDFF   proton density fat fraction   Gd   gadolinium   MAE   mean absolute error   SSIM   structural similarity   HFHSD   high-fat high-sucrose diet   EMPA   empagliflozin   HFD   high-fat diet   GM-CSF   granulocyte-macrophage colony-stimulating factor   IL   interleukin   LIF   leukemia inhibitor factor   MIP-1α   macrophage inflammatory protein-1 alpha   Epicardial adipose tissue   Fatty acid composition   T1 mapping   Preclinical imaging  

摘要： Background Epicardial adipose tissue (EAT) plays a central role in metabolic heart disease through local inflammatory signaling. In obesity, EAT undergoes pathological remodeling marked by increased adipocyte size, saturated fatty acids (SFAs), macrophage infiltration, and inflammatory cytokine secretion. Proton density fat fraction (PDFF), T 1 , and the fatty acid composition (FAC) (the amount of SFAs, monounsaturated fatty acids [MUFAs], and polyunsaturated fatty acids [PUFAs]) are promising metrics of EAT quality, yet their role as biomarkers of proinflammatory EAT has not been established. This study presents an accelerated CMR method for simultaneous EAT FAC and T 1 mapping and evaluates their relationships with histological and cytokine markers of inflammation. Methods An ECG-gated inversion recovery multi-echo gradient-echo sequence with radial golden-angle sampling was developed for simultaneous FAC and T 1 mapping. A high-dimensionality patch-based low-rank reconstruction was applied to undersampled images. Phantom validation was performed using oil mixture and gadolinium phantoms, followed by in vivo imaging of mice (n=16–20/group) fed a high-fat high-sucrose diet (HFHSD), HFHSD plus the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin (HFHSD+EMPA), or a high-fat diet (HFD). PDFF, SFA fraction, MUFA fraction, PUFA fraction, R 2 *, and T 1 measurements were made in EAT and subcutaneous adipose tissue (SAT). EAT FAC values were indexed to those of SAT. Ex vivo histology and cytokine assays were used to assess EAT and myocardial inflammation. Results Phantom validation demonstrated strong agreement between MRI-derived and reference FAC and T 1 values (r > 0.94, p < 0.05). Diet-induced changes in adipose tissue FAC were detected by MRI. HFHSD+EMPA mice had lower EAT SFA index than both HFHSD (p < 0.01) and HFD (p < 0.05) mice, and higher MUFA index (p < 0.01), PUFA index (p < 0.05), and T 1 (p < 0.05) compared HFHSD mice. EAT SFA index positivel

关键词： Cancer immunotherapy   Immunology   Oncology  

摘要： We assessed the therapeutic efficacy of a semiallogeneic dendritic cell (DC) vaccine in comparison to a syngeneic one for suppression of B16-F10 and TC-1 tumors. Syngeneic bone marrow-derived DCs (BMDCs) were generated from C57BL/6J mice and semiallogeneic BMDCs with a mutation in either MHC class I or II were generated from B6.C-H2-Kbm1/ByJ or B6(C)-H2-Ab1bm12/KhEgJ mice, respectively. We demonstrated in vivo and in vitro that the MHC class II semiallogeneic BMDC vaccine had superior efficacy over the syngeneic and the MHC class I semiallogeneic BMDC vaccine, providing allogeneic CD4+ T cell help to enhance the antitumor CD8+ T cell response through allogeneic stimulation by the mutant MHC class II molecules. We discovered that this help was induced only at an early stage of tumor growth and at a later stage of tumor growth; combining our BMDC vaccine with Treg depletion enhanced tumor suppression. We demonstrated the improved efficacy of a semiallogeneic BMDC vaccine that kept tumor-peptide presentation intact on syngeneic MHC class I molecules so that mutant MHC class II could provide allogeneic help. This strategy should enable promising new DC-based cancer immunotherapies, offering an alternative to autologous DC vaccines by incorporating allogenicity as an adjuvant.

关键词： TLR2   TNF   Association study   Immune   Inflammation   Schizophrenia  

摘要： BACKGROUND:Clinical and genetic studies have suggested that immune dysregulation and neuroinflammation are involved in the pathogenesis of schizophrenia. Peripheral laboratory markers are accessible indicators linked to systemic inflammation and immune function. Genetic studies have demonstrated that blood parameters are highly heritable. Therefore, the aim of this study was to analyze the association between blood parameters and IL10, TNF, TLR2, and TLR6 gene polymorphisms in Mexican patients with schizophrenia. METHODS:We included 236 Mexican patients with schizophrenia. Peripheral blood samples were obtained in the early morning, prior the breakfast, from each participant. Complete blood count was analyzed. Genomic DNA was extracted, and genotyping was performed using TaqMan Discrimination assay of IL10 (rs1554286), TNF (rs1800629), TLR2 (rs7656411), and TLR6 (rs5743827). Association analyses between blood parameters and genotypes of the four genetic variants were performed using chi-square tests and ANOVA with Tukey's post-hoc multiple comparisons. RESULTS:We observed higher monocyte levels (F = 5.57; p = 0.004) and monocyte-lymphocyte ratio (F = 5.49; p = 0.004) in patients carrying the GG genotype of rs7656411/TLR2 compared with TT or TG genotype carriers. Additionally, we observed a high frequency of the G allele of rs1800629/TNF, showing a low platelet count compared with carriers of the A allele (χ = 8.6, p = 0.003; OR = 3.82; CI, 1.46-9.96). Furthermore, we were unable to detect any gene-gene interaction in the analysis of MPV and platelet count after 1000-fold permutation testing. CONCLUSIONS:Our findings indicate that blood parameter levels may be affected by genetic variants of TNF and TLR2 genes, indicating a potential role for innate immune response activation in schizophrenia in the Mexican population. Further studies with larger cohorts and comprehensive genetic analyses are essential to validate these findings and clarify the role of innate immune