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关键词： TNF inhibitors   rheumatic diseases   ex vivo cell-based assay   gene expression   response prediction  

摘要： Objective There are five TNF inhibitors (TNFis), whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of patients with rheumatic diseases may respond inadequately to TNFis. The downstream signalling of the various TNFis may determine their clinical efficacy. Several reports have shown that the different TNFis exhibited differential effects on Th17 cells. We analysed the effects of the various TNFis on IL-17A expression in peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases, in order to evaluate the possibility of predicting responses in an ex vivo *** PBMCs were co-cultured with the various TNFis or medium (control), and IL-17A mRNA levels were analysed by quantitative PCR. IL-17A expression levels in response to four TNFis (not including certolizumab pegol) were compared with that of the control. The IL-17A expression level as determined by the assay was correlated with the clinical response. The assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) *** The results of the assay for a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the various TNFis with 89.5% accuracy. Our results indicated that the assay predicted the responses of a prospective cohort (n = 54) to specific TNFis with 79% *** This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi.

关键词： Blood brain barrier   IL   Japanese encephalitis   TNF-α   cytokine   neuroinflammation  

摘要： Background & objectives We aimed to conduct a comprehensive analysis of the cytokine profile in Japanese encephalitis (JE) patients and healthy individuals. Additionally, the correlation between the cytokines and the disease outcome in terms of survival or non-survival was also studied. Methods The study included 72 laboratory-confirmed JE cases and 50 healthy controls. Plasma levels of cytokines viz., GM-CSF, IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, and TNF-α were analysed using Bio-plex200 (Bio-Rad) following manufacturer's guidelines and compared between JE patients and healthy control group. Additionally, quantitative real-time PCR (qRT-PCR) was done for the quantification of expression of the above-mentioned cytokine genes. Results Except IL-4 and IL-13, the levels of GM-CSF, IFN-γ, IL-2, IL-5, IL-10, IL-12, and TNF-α were significantly higher in JE patients in comparison to healthy controls. Significantly upregulated expression of IL-12, IL-10, and TNF-α was observed in the JE group as compared to that in healthy controls. Additionally, significantly downregulated expression of IL-4and IL-13 was observed in the JE group compared to the control group. Interpretation & conclusions A higher level of several pro-inflammatory cytokines and downregulation of a few anti-inflammatory cytokines were observed in JE patients compared to the healthy controls indicating co-association of inflammation with disease severity. Hence, a regulator of these pro and anti-inflammatory cytokines may stand out as a potential candidate for therapy in JE.

关键词： BDNF   IL-1 beta   Neuroinflammation  

摘要： Background: The detrimental and protective effects of interleukin 1(3 (IL-1(3) have been reported. We have previously shown that the periods of IL-1(3 elevation is related to its dual effects. However, the effects of different IL- 1(3 concentrations on neuropathological processes are unclear. Studies have demonstrated that mature brain- derived neurotrophic factor (mBDNF) and its precursor (proBDNF) have opposing functions in neuronal survival. We previously showed that mBDNF is involved in IL-1(3-mediated neuropathology. Here, we investigated whether different IL-1(3 concentrations differentially affect mBDNF and proBDNF, determining their beneficial or harmful effects. Methods: HT22 cells were cultured and exposed to various IL-1(3 concentrations for different durations. HT22 cell viability and the expression of mBDNF, proBDNF and their receptors were evaluated by a Cell Counting Kit-8 (CCK-8) assay and western blot. Results: Compared with untreated cells, a significant reduction in cell viability was observed after exposure to high IL-1(3 concentrations for more than 24 h. Increased expression of proBDNF and its receptor p75NTR and decreased expression of mBDNF and its receptor TrkB, as well as decreased furin and PC1/3 (which promote the cleavage of proBDNF to mBDNF) expression, were detected. In contrast, low IL-1(3 concentrations increased cell viability, but a significant effect was observed only at an optimal concentration;in contrast to our predictions, low IL-1(3 concentrations did not induce significant alterations in mBDNF and proBDNF expression levels, but rather, low concentrations significantly increased the mBDNF/proBDNF ratio. Conclusions: These results demonstrated that changes induced by low (neuroprotection) and high (neurodegeneration) IL-1(3 concentrations were oriented in different directions. These dual effects occur partly through the modulation of mBDNF signaling.

关键词： natural killer (NK) cell   human leukocyte antigen (HLA)   killer cell immunoglobulin-like receptor (KIR) & immunopeptidome  

摘要： Natural killer (NK) cell activation is regulated by killer cell immunoglobulin-like receptors (KIRs) that recognize human leukocyte antigen (HLA) class I molecules. While polymorphism in HLA can directly impact these interactions, the extent to which the HLA-associated peptide repertoire modulates NK cell function is less well understood. Therefore, the peptide requirements for the recognition of 2 ligands, HLA-B*57:01 and HLA-A*24:02, that share similar KIR3DL1 binding residues but differ in their capacity to inhibit human NK cells were assessed. Immunopeptidome and functional analyses of endogenous peptides associated with each allotype showed that both repertoires contained peptides capable of facilitating or impairing KIR3DL1-dependent recognition of target cells. While distinct sequence features at positions 7 and 8 of the bound peptide similarly impacted recognition of both HLA class I allotypes, HLA-B*57:01 remained a more potent ligand overall. In silico analyses suggested that most peptides presented by HLA-B*57:01 would facilitate KIR3DL1 engagement, whereas the peptide repertoire of HLA-A*24:02 possessed fewer peptides predicted to support strong KIR3DL1 recognition. Nevertheless, the exogenous addition of highly permissive peptides to cells expressing HLA-A*24:02 could bolster KIR3DL1-mediated NK cell inhibition of peptide-competent cells to levels seen with HLA-B*57:01. Together, these data indicate that allotypic differences in peptide repertoire impact KIR recognition of HLA class I and suggest that NK cells have the potential to sense infection- or transformation-induced repertoire perturbations, particularly when the intrinsic KIR/HLA interactions are of modest avidity.

关键词： Platelets   Secretome   Acute myocardial infarction   Vascular biology   Cytokines   Inflammation  

摘要： Background and aims: Platelets and inflammation play crucial roles in the atherothrombotic process of acute myocardial infarction (AMI), particularly in ischemia/reperfusion injury. This study aims to characterize the pro-inflammatory content of the platelet secretome in AMI patients, assess its effect on nitric oxide (NO) production, and correlate these findings with clinical parameters. Methods: Blood samples from 20 AMI patients and 20 controls were analyzed. Platelets were isolated and stimulated with thrombin, and their secretomes were collected. Endothelial cells were exposed to these secretomes, and NO production was measured. Our results demonstrate a significant reduction in NO production in endothelial cells exposed to the AMI platelet secretome (p < 0.05), suggesting acute endothelial dysfunction. Results: Elevated levels of interleukin-6 (IL-6) (p = 0.0323) and interleukin-8 (IL-8) (p = 0.0197) were identified in the secretome of AMI patients, correlating with clinical markers of myocardial injury. Specifically, IL-6 positively correlated with CK-MB levels (p = 0.04, Pearson r = 0.53), while IL-8 levels inversely correlated with NO production (p = 0.0141, Pearson r = -0.5652). Conclusions: These findings underscore the critical role of platelet-derived IL-6 and IL-8 in endothelial dysfunction and myocardial injury in AMI patients. Future studies should explore the interactions between these cytokines in endothelial cells to further elucidate their roles in AMI pathology.

关键词： Sulforaphane   STAT1   PD-L1   Antitumor immunity  

摘要： Sulforaphane (SFN), a natural compound found in cruciferous vegetables, possesses well-documented antitumor properties. However, the precise functions and mechanisms of SFN in cancer suppression remain poorly understood. Here we provide evidence to demonstrate that SFN exerts more pronounced antitumor effects in immunocompetent mice compared to immunodeficient mice, suggesting the involvement of the host immune system in SFN-mediated tumor suppression. Furthermore, we reveal that SFN primarily acts through CD8+ cytotoxic T lymphocytes (CTLs) to enhance antitumor immunity by blocking the IFN-gamma-mediated induction of PDL1, a critical immune checkpoint receptor expressed in cancer cells. Importantly, our findings indicate that the suppression of PD-L1 expression by SFN is independent of the NRF2 protein stabilization pathway. Instead, SFN inhibits IFN-gamma-mediated activation of STAT1, a key transcription factor involved in PD-L1 induction. Mechanistically, SFN covalently modifies specific cysteine residues (C155 and C174) on STAT1, resulting in the inhibition of its transcriptional activity. Notably, SFN-mediated downregulation of PD-L1 contributes to its antitumor immune effects, as demonstrated by enhanced anti-CTLA-4-mediated cytotoxicity. These findings indicate that SFN's antitumor effect extends beyond its direct cytotoxic properties, as it also actively engages the host immune system. This underscores SFN's immense potential as an immune-modulating agent in cancer therapy.

关键词： anti-PD1 immunotherapy   IFN-gamma response genes   LASSO   pan-cancer   prognosis   tumour microenvironment  

摘要： Background The IFN-gamma cytokine plays a dual role in anti-tumor immunity, enhancing immune defense against cancer cells while promoting tumor survival and progression. Its influence on prognosis and therapeutic responses across cancer types remains unclear. Objective This study aimed to perform a pan-cancer analysis of IFN-gamma response genes to determine their prognostic significance and evaluate their impact on clinical outcomes and anti-PD1 immunotherapy responses. Methods Using multiple datasets, 46 IFN-gamma response genes were identified as prognostic for disease-specific survival, and their expression was used to construct the IFN-gamma Response Gene Network Signature (IFGRNS) score. The prognostic and therapeutic relevance of the IFGRNS score was assessed across cancer types, considering tumor pathology, genomic alterations, tumor mutation burden, and microenvironment. Single-cell transcriptomic analysis identified cellular contributors, and a murine pancreatic cancer (PAN02) model was used to validate findings with anti-PD1 therapy. Results The IFGRNS score emerged as a robust prognostic indicator of survival, with higher scores correlating with worse outcomes in most cancer types. The prognostic significance of the score was influenced by factors such as cancer type, tumor pathology, and the tumor microenvironment. Single-cell analysis revealed that myeloid cells, particularly the M2 macrophage subtype, demonstrated high levels of IFGRNS expression, which was associated with tumor progression. A negative correlation was observed between the IFGRNS score and outcomes to anti-PD1 immunotherapy in urologic cancers, where patients with higher scores showed worse prognosis and lower response rates to therapy. Experimental validation in the PAN02 murine model confirmed that anti-PD1 therapy significantly reduced tumor size and IFGRNS expression in M2 macrophages, supporting the clinical findings. Conclusions The IFGRNS score is a novel prognostic indicator fo

关键词： allergy   delayed-type hypersensitivity   extracellular vesicles   IL-17A   microRNA   rodent   T cells  

摘要： Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by transporting functional molecules between donor cells and recipient cells, thereby regulating biological processes, such as immune responses. miR-451a, an immune regulatory microRNA, is highly abundant in circulating EVs;however, its precise physiological significance remains to be fully elucidated. Here, we demonstrate that miR-451a deficiency exacerbates delayed-type hypersensitivity (DTH) in mice. Notably, miR-451a knockout resulted in a significant increase in the number of interleukin (IL)-17A-expressing T helper 17 and gamma delta T cells infiltrating DTH-induced ear lesions. miR-451a deficiency also increased the number of gamma delta T cells in the secondary lymphoid tissues. Comprehensive analyses revealed that miR-451 deficiency promoted the expression of Rorc and gamma delta T cell-related genes following sensitization with allergens. Moreover, intravenous administration of wild-type EVs to miR-451a knockout mice increased cellular miR-451a levels in tissues and significantly attenuated the severity of DTH. Furthermore, synthetic lipid nanoparticles encapsulating miR-451a effectively mitigated DTH. Our findings indicate the importance of circulating miR-451a in the proliferation of gamma delta T cells and highlight the therapeutic potential of lipid nanoparticle-based microRNA delivery platforms for interventions in immune-related diseases.

摘要： Background: Surgical nerve injuries lead to persistent neuropathic pain (NP) in up to 30% of patients. Among many other factors, polymorphisms in the human leukocyte antigen (HLA) genes have been suggested to contribute to the development of neuropathic pain. Methods: We performed a genetic association analysis of HLA class I and class II alleles in women who had been operated on for breast cancer. Patients had a surgeon-confirmed perioperative nerve injury and were examined 4-9 years after their surgery. Patients with painful (cases, n = 27) and painless (controls, n = 30) intercostobrachial nerve resection were studied. Cases included patients with definite NP with worst pain intensity in the past week >= 4/10 on a numerical rating scale (NRS) and controls had the same nerve injury with no NP or other pains. Whole-genome single nucleotide polymorphism data were produced, and HLA class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQA1, -DQB1 and -DPB1) alleles were determined by imputation. Results: HLA-DRB1*03:01, DQA1*05:01 and DQB1*02:01 alleles appeared to be associated with painful nerve injury after breast cancer surgery (nominal p = 0.007 for all, carriership OR = 12.0, 95% CI 1.38-104;FDR corrected p > 0.07). These alleles comprise the DR3-DQ2 haplotype, which is part of the ancestral haplotype AH8.1. Conclusions: Our results provide further support for the role of HLA genetic variation in the development of persistent post-surgical neuropathic pain, which indirectly implies a mechanism involving immunological memory in this process.