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关键词： Metabolomics   Serum   FTIR   Rheumatoid arthritis   TNFi  

摘要： Introduction Rheumatoid arthritis (RA) is an auto-immune disease which causes irreversible damage to tissue and cartilage within synovial joints. Rapid diagnosis and treatment with disease-modifying therapies is essential to reduce inflammation and prevent joint destruction. RA is a heterogeneous disease, and many patients do not respond to front-line therapies, requiring escalation of treatment onto biologics, of which TNF inhibitors (TNF-i) are the most common. Objectives/methods In this study we determined whether serum metabolomics, using nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy, could discriminate RA blood sera from healthy human controls and whether the technologies could be used to predict response or non-response to TNF inhibitor (TNF-i) therapy. Results NMR spectroscopy identified 35 metabolites in RA sera, with acetic acid being significantly lower in RA sera compared to healthy controls (HC, FDR < 0.05). PLS-DA modelling identified 2-hydroxyisovalericacetic acid, acetoacetic acid, mobile lipids, alanine and leucine as important metabolites for discrimination of RA and HC sera by H-1 NMR spectroscopy (averaged 83.1% balanced accuracy, VIP score > 1). FTIR spectroscopy identified a significant difference between RA and HC sera in the 1000-1200 cm(- 1) spectral area, representing the mixed region of carbohydrates and nucleic acids (FDR < 0.05). Sera from RA patients who responded to TNF-i were significantly different from TNF-i non-responder sera in the 1600-1700 cm(- 1) region (FDR < 0.05). Conclusion We propose that NMR and FTIR serum metabolomics could be used as a diagnostic tool alongside current clinical parameters to diagnose RA and to predict whether someone with severe RA will respond to TNF-i.

摘要： While lymphoid progenitors have demonstrated unexpected plasticity in vivo, their differentiation into myeloid cells under in vitro conditions has been largely dismissed as an artifact or biologically irrelevant. Consequently, the functional properties of these cells remain poorly characterized. In this study, we show that cultured common lymphoid progenitors (cCLPs) differentiate into CD11b(+)CD115(+) monocytic cells (cCLP-Ms) via IL-6-C/EBP beta signaling. Molecular and phenotypic analyses revealed that cCLP-Ms acquire essential features of myeloid cells, including innate immune sensor expression and phagocytic capacity, while retaining unique characteristics distinct from bone marrow-derived macrophages (BMDMs), such as reduced MHC class II expression and TNF-alpha production. Functionally, cCLP-Ms exhibit immunoregulatory properties, effectively suppressing IgE-mediated cutaneous allergic inflammation upon adoptive transfer. These findings highlight the plasticity of lymphoid progenitors and establish a robust platform for investigating the mechanisms underlying myeloid differentiation. This system deepens our understanding of hematopoietic cell lineage flexibility and offers a foundation for exploring therapeutic applications in immune regulation and inflammation.

摘要： Increases in retroelement-derived double-stranded RNAs (dsRNAs) in various types of cancer cells facilitate the activation of antitumor immune responses. The long noncoding RNA EPIC1 interacts with the histone methyltransferase EZH2 and contributes to tumor immune evasion. Here, we found that EPIC1 in tumor cells suppressed cytoplasmic dsRNA accumulation, type I interferon (IFN) responses, and antitumor immunity. In various cancer cell lines, knockdown of EPIC1 stimulated the production of dsRNA from retroelements and an antiviral-like type I IFN response that activated immune cells. EPIC1 inhibited the expression of LINE, SINE, and LTR retroelements that were also repressed by EZH2, suggesting a potential role for the EPIC1-EZH2 interaction in regulating dsRNA production. In a humanized mouse model, in vivo delivery of EPIC1-targeting oligonucleotides enhanced dsRNA accumulation in breast cancer xenografts, reduced tumor growth, and increased the infiltration of T cells and inflammatory macrophages into tumors. Furthermore, EPIC1 knockdown improved the therapeutic efficacy of the immunotherapy drug pembrolizumab, a PD-1 inhibitor, in the humanized mouse model. Together, our findings establish EPIC1 as a key regulator of dsRNA-mediated type I IFN responses and highlight its potential as a therapeutic target to improve the efficacy of immunotherapy.

关键词： cytokines   cytokines and cardiovascular diseases   interleukin-40   pericardial fluid and cytokines  

摘要： Background and Objectives: The aim of this study was to investigate IL-40 levels in preoperative blood and intraoperative pericardial fluid samples obtained from healthy individuals and patients with diagnosed heart disease who were scheduled for open heart surgery to determine whether it is a biomarker for cardiovascular diseases. Material and Methods: A total of 90 individuals were included in the study and divided into three groups. Group 1 (Healthy Group, n = 45): Blood was collected from a total of 45 healthy men and women over 18 years of age without any diagnosis of cardiovascular disease. Group 2 (Patient Group 1, n = 45): In this group, blood samples from a total of 45 male and female patients over 18 years of age with a diagnosis of heart disease and scheduled for open heart surgery were studied. Group 3 (Patient Group 2, n = 45): Pericardial fluids were obtained from patients in Group 3 immediately after pericardial incision during surgery. IL-40, TAS, TOS and OSI levels in blood plasma and pericardial fluid were determined by the ELISA kit method. Results: In the statistical analysis between the groups, IL-40, TOS and OSI levels were found to be higher in the patient group and in the pericardial fluid (p < 0.001), while TAS was higher in the control group. It was considered statistically significant (p < 0.001). Conclusions: IL-40, TOS and OSI levels were elevated in patient serum and pericardial fluid. Therefore, we suggest that IL-40 may be a new biomarker for the detection of cardiovascular diseases.

关键词： MHC-II alleles   tuberculosis   CD4 T-cell populations   immune activation/exhaustion   IFN-gamma  

摘要： Previously we have shown that H2-congenic recombinant mice of the B6.I-9.3 (H2-Ab1 j) strain are significantly more susceptible to tuberculosis (TB) infection compared to their C57BL/6 (B6, H2-A b) ancestors. Impaired TB control was characterized by decreased selection and maintenance of CD4+ T-cells, their profoundly narrower TCR repertoires, and a disproportionally enlarged neutrophil population. All phenotypes were expressed before TB infection, thus reflecting the steady state of the immune system and providing the basis of true genetic TB susceptibility. We anticipated that the differences in parameters of pre-infection immune homeostasis would seriously influence development of specific immune responses shortly after mycobacterial invasion and affect TB defense thereafter. In this study, we report on the dynamic phenotypes of CD4+ T-cells responding to infection which differ profoundly between mice bearing different MHC-II alleles. First, during post-challenge week 3, despite identical lung mycobacterial load, mice carrying the "resistant" H2-A b allele recruited significantly more mycobacteria-specific, IFN-gamma-producing CD4+ T-cells to their lungs compared to H2-Ab1 j allele carriers. Second, during a few months post challenge, B6 mice were able to control both the size of the IFN-gamma-producing CD4+ T-cell population and the total proportion of activated CD4+ T-cells at levels significantly lower than those in B6.I-9.3 mice. Finally, in TB-susceptible mice, a higher proportion of CD4+ T-cells expressed both activation-associated and immune inhibition (checkpoint) markers, accompanied by functional CD4+ T-cell exhaustion at late stages of infection. Together, these observations suggest that suboptimal pre-infection MHC-II-dependent shifts in immune homeostasis affect both early and late immune reactions against TB.

关键词： Assymptomatics   ELISA   feline   IFN-gamma   IL-12   leishmaniasis   parasite load  

摘要： Visceral leishmaniasis is a potentially fatal zoonosis with an increasing incidence. Most infected felines present the disease in its subclinical form and demonstrate greater resistance to parasitemia than dogs. However, the role of cellular immunity in felines is still poorly understood. This study measured serum levels of interleukin (IL)-12 and interferon-gamma (IFN-gamma) in asymptomatic cats naturally infected with antibodies against Leishmania spp. and in uninfected cats. IL-12 and IFN-gamma were measured in serum samples by ELISA. Parasite load quantification was performed on DNA from bone marrow samples using qPCR. Cats naturally infected by Leishmania spp. showed significantly higher serum levels of IL-12 and IFN-gamma compared to control animals. IL-12 showed a positive correlation with IFN-gamma suggesting a regulatory role of IL-12 in activating the Th1 immune response, which enhances macrophage function and promotes intracellular parasite elimination. Additionally, IL-12 showed a moderate negative correlation with parasite load, indicating a protective effect of IL-12 in feline leishmaniasis. These findings suggest that IL-12 and IFN-gamma play critical roles in modulating the feline immune response against parasitic infection, possibly contributing to the control of parasite replication and in the prevention of clinical signs. The immune response observed in felines could be explored for future immunotherapeutic approaches, helping to mitigate the progression of leishmaniasis in cats and reducing the risk of transmission in endemic regions.

关键词： B7-H6   bispecific antibodies   NK cells   IL-15R alpha sushi   solid tumor  

摘要： Introduction: B7-H6, a tumor-specific immune checkpoint molecule within the B7 family, represents a promising therapeutic target due to its selective overexpression in malignancies and negligible expression in normal tissues. Method: Here, we developed bispecific antibodies (BsAbs) targeting B7-H6 to redirect T and NK cells against solid tumors. Through phage display, 15 high-affinity B7-H6 monoclonal antibodies were generated. Results: Two optimized BsAbs, B7-H6M4-OKT3 (T cell-engaging) and B7-H6M4-LC21 (NK cell-engaging), were constructed in and scFv-hFc-scFv format. Both demonstrated nanomolar affinity (EC50: 0.04-1.22 nM) and selective cytotoxicity against B7-H6+ cells (H446, Huh-7, HepG2), while showing minimal cytotoxicity against B7-H6-negative cells (A431). B7-H6M4LC21 exhibited enhanced tumor-killing efficacy (IC50: 5 ng/mL) compared to B7H6M4-OKT3(IC50: 1 ng/mL) when combined with an IL-15/IL-15Ra sushi fusion protein, which augmented NK cell proliferation and cytotoxicity. In H446 xenograft models, both BsAbs suppressed tumor growth in a dose-dependent manner (0.1-20 mg/kg) without significant toxicity. Combination therapy with B7-H6M4-LC21 (10 mg/kg) and B7-H6M18/IL-15/IL-15Ra sushi (0.03 mg/kg) achieved synergistic tumor inhibition (p<0.05), surpassing the efficacy of T cell-based combinations. Discussion: These findings establish B7-H6-targeted BsAbs combined with cytokine engineering as a viable strategy for treating refractory solid tumors.

摘要： Enteroviruses are major causes of neonatal morbidity and mortality, with echovirus infections commonly associated with severe disease, including acute liver failure. The human neonatal Fc receptor (hFcRn) is the primary receptor for echoviruses, and its expression is required for infection of the liver in mouse models. While type I interferons (IFNs) are known to protect against echovirus-induced disease, the specific innate immune cells responsible for initiating this antiviral signaling in the liver remain undefined. To dissect the relative contributions of type I and type III IFNs in protecting the liver during echovirus infection, we combined mouse models (expressing hFcRn and deficient in Ifnar1, Ifnlr1, or both) with single cell RNA sequencing (scRNA-seq). This approach enabled us to pinpoint the hepatic cell types targeted by echoviruses and to identify the specific cells producing IFNs in response. We found that hepatocytes and Kupffer cells were the most heavily infected cell types. In contrast, early and robust type I IFN responses were primarily driven by Kupffer cells and a subset of dendritic cells. To determine whether type I IFNs act directly on hepatocytes to mediate protection, we generated conditional knockout mice lacking Ifnar1 specifically in hepatocytes. These mice showed similar morbidity, mortality, and hepatic viral titers as whole-body Ifnar1 animals, indicating that hepatocytes depend on protective IFN signals produced by immune cells during echovirus infection. These findings uncover cell-type-specific mechanisms by which echoviruses subvert host immunity and show how dysregulated IFN responses drive liver pathology and neonatal mortality.

关键词： Colorectal neoplasms   Gut microbiota   Streptococcus Gallolyticus   Macrophages   IL-17  

摘要： BackgroundColorectal cancer (CRC) is a prevalent global malignancy where gut microbiota plays a key role. Streptococcus gallolyticus (Sg), a gut commensal and opportunistic pathogen, is associated with CRC. This study investigates the impact of the supernatant derived from Sg cultures (hereafter referred to as Sgsup) on CRC progression and examines the underlying mechanisms. MethodsQuantitative PCR (qPCR) was employed to assess Sg colonization in paired tumors and adjacent normal tissues from 46 CRC patients. CRC cell lines (HCT116, HT29) were treated with Sgsup, and cell proliferation was measured using the CCK-8 assay. Non-targeted metabolomic profiling of Sgsup was performed via liquid chromatography-mass spectrometry (LC-MS). An azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model of CRC was used to evaluate in vivo tumor burden, inflammation, and macrophage polarization (flow cytometry). Transcriptomic analysis via RNA-seq was conducted to identify enriched signaling pathways. ResultsThe detection rate of Sg was significantly higher in tumor tissues compared to adjacent tissues (47.8% vs. 30.4%, P < 0.01). Sgsup significantly increased CRC cell proliferation (P < 0.05). Non-targeted metabolomic analysis revealed an enrichment of metabolites, including inosine monophosphate (IMP), methionine, uridine, and creatine in Sgsup. In vivo, Sgsup increased tumor number/burden (P < 0.05), elevated inflammation scores (P < 0.05), and shortened colon length. Flow cytometry indicated that Sgsup promoted M2 macrophage polarization (as evidenced by increased CD206+ cells and reduced M1/M2 ratio). RNA-seq demonstrated significant enrichment of the IL-17 signaling pathway, with upregulated expression of IL-17 F and IL-22 (P < 0.05). ConclusionSgsup is associated with CRC progression by promoting cell proliferation and inflammation, facilitating M2 macrophage polarization, and elevating IL-17 F and IL-22 expression. Metabolites such as creatine, along with IL-17 F/I