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关键词： IL-2R beta   Inborn errors of immunity   Immunodeficiency   Autoimmunity   Hematopoietic stem cell transplantation   Conditioning  

关键词： Chikungunya virus   Chikungunya fever   Cytokine storm   Signatures   Proinflammatory response  

摘要： Introduction The present study aimed at evaluating the systemic profile and network connectivity of immune mediators during acute chikungunya fever (CHIKF) according to days of symptoms onset and ageing. Methods A total of 161 volunteers (76 CHIKF patients and 85 non-infected healthy controls) were enrolled. Results and discussion Data demonstrated that a massive and polyfunctional storm of serum immune mediators was observed in CHIKF. Distinct patterns of mediators were observed according to days of symptoms onset. Most chemokines and proinflammatory cytokines were increased early at D0-1, with some increased throughout the kinetics timeline, while others presented a waning profile towards D4-12. Rhythmic signatures further underscored these findings. Increased levels IL-17 appeared as a hallmark of intense arthralgia, while CCL5&IL-5 and TNF-alpha&IL-10 duets are age-tunning features in CHIKF. Differential connectivity of networks was observed with ageing, with a progressive increase in the overall connectivity from < 8 yo towards 51-89 yo. Of note, subsets of immune mediators (IL-17, IL-2 and IL-5) displayed hotspots of hyperconnectivity in elderly as compared to younger patients. Conclusion Together, the overall scenario reveals unique patterns of soluble immune mediators during acute CHIKF infection with an oscillating symphony according to days of symptoms and ageing, which brings insight to future tailor-made therapeutic interventions.

关键词： Allergic rhinitis   Follicular regulatory T cells   Type 2 follicular helper T   Interleukin-35  

摘要： BackgroundAllergic rhinitis (AR) represents a persistent inflammatory condition affecting the upper respiratory tract, characterized by abnormal initiation of the immunoglobulin E (IgE)-mediated cascade. Follicular helper T (Tfh) cells and regulatory T (Tfr) cells are pivotal in orchestrating the development of IgE production in AR patients. IL-35, an anti-inflammatory cytokine, secreted by various cellular *** investigate the interplay and underlying mechanisms between interleukin-35 (IL-35) and Tfr/Tfh2 cells in the context of *** animal models employing BALB/c mice and IL-35-deficient mice underwent sensitization and challenge procedures utilizing ovalbumin (OVA) as the antigen in vivo. IL-35 was administered intranasally prior to OVA challenges. Nasal histopathological examination, PBMC isolation, Tfr/Tfh2 cell staining, Tfr/Tfh2 sorting and culture, and qPCR analysis as well as enzyme-linked immunosorbent assay (ELISA) were conducted for exploring the effect of IL-35 on Tfr/Tfh2 *** of IL-35 suppressed OVA-elicited allergic inflammation in murine models. IL-35 treatment led to an elevation in the proportion of peripheral blood Tfr cells and a decrease in Tfh2 cells. IL-35 also downregulated IL-4 and IL-21 protein expression by Tfh2 cells and upregulated IL-10 and transforming growth factor-beta (TGF-beta) production by Tfr cells. The anti-ICOS treatment abrogated the effect of IL-35 on Tfh2 and Tfr *** study provided novel insights into the mechanisms of IL-35 action and its promoting effects on Tfh2 and inhibiting effects on Tfr cells by targeting key transcription factors, contributing to the understanding of the pathogenesis and treatment of AR.

关键词： Type 1 diabetes   Islet antigen-specific T cells   T cell epitopes   Islet-specific autoantibodies  

摘要： A proportion of patients with new-onset diabetes share similar symptoms with type 1 diabetes (T1D) patients but they are negative for islet antigen-specific autoantibodies. This study was to develop an islet antigen-specific CD8(+) T-cell assay to provide autoimmune evidence regarding these "suspected" T1D patients. HLA-A*0201 individuals with autoAbs(+) T1D, autoAbs(-) suspected T1D, and type 2 diabetes, along with HLA-A*0201 healthy controls were recruited. Using interferon-gamma enzyme-linked immunospot assays, the percentages of participants in each group with various islet antigen-specific CD8(+) T cells were determined. Sixteen out of the 28 islet antigen-specific epitopes tested were T1D specific, meaning that there was a significantly (P < 0.05) greater epitope positivity rate in the autoAbs(+) T1D cohort than in the healthy controls. Using a cutoff value of two positive epitopes, the 16-epitope panel led to a sensitivity of 75.0% and a specificity of 94.4% regarding the autoAbs(+) T1D patients. Even when using an optimized five-epitope panel, the results were highly accurate. Notably, in the application phase of the study, 77.8% of a new cohort of autoAbs(-) suspected T1D patients exhibited positivity when using the five-epitope optimized panel. This highly accurate method, especially for pediatric patients, will improve clinical diagnosis and etiological classification of autoimmune T1D.

关键词： Diabetic kidney disease   Neutrophil extracellular traps   Inflammation   Subtype   IL-33  

摘要： BackgroundChronic inflammation is well recognized as a key factor related to renal function deterioration in patients with diabetic kidney disease (DKD). Neutrophil extracellular traps (NETs) play an important role in amplifying inflammation. With respect to NET-related genes, the aim of this study was to explore the mechanism of DKD progression and therefore identify potential intervention *** NET-related DEGs were screened via differential expression analysis and three machine learning methods, namely, LASSO, SVM-RFE and random forest. Consensus clustering was performed to analyze NET-related subtypes in DKD patients. KEGG enrichment analysis, GSEA, GSVA, ssGSEA and ESTIMATE were conducted to explore the molecular features of DKD patient subtypes. Leveraging single-nucleus RNA-seq datasets, the "scissor" and "bisqueRNA" algorithms were applied to identify the composition of renal cell types in DKD patient subtypes. Soft clustering analysis was performed to obtain gene groups with similar expression patterns during the development and progression of DKD. The correlations between hub NET-related DEGs and clinical parameters were mined from the Nephroseq V5 database. The core gene among the hub NET-related DEGs was selected by calculating semantic similarity. "Cellchat" algorithm, immunostaining, ELISA and flow cytometry were performed to explore the expression and function of the core gene. The Drug-Gene Interaction Database (DGIdb) was searched to identify candidate *** hub NET-related DEGs, namely, ACTN1, ITGB2, IL33, HRG, NFIL3 and CLEC4E, were identified. On the basis of these 6 genes, DKD patients were classified into 2 clusters. Cluster 1 patients, with higher NET scores, were evidently more immune-activating than those of cluster 2. Markedly increased numbers of immune cells, fibroblasts and proinflammatory proximal tubular cells were observed in cluster 1 but not in cluster 2. Cluster 1 also represented a more clinically advanced

关键词： Cancer immunotherapy   Epitope prediction   HLA   Machine learning   MHC  

摘要： Cancer immunotherapy hinges on accurate epitope prediction for advancing vaccine development. VaxOptiML (available at https://***/) is an integrated pipeline designed to enhance epitope prediction and prioritization. This study aims to develop and deploy a robust tool for accurate prediction and prioritization of highly immunogenic and optimized MHC-I and MHC-II T-cell epitopes for cancer vaccine development and immunotherapy. Utilizing a curated dataset of experimentally validated epitopes and employing sophisticated machine learning techniques, VaxOptiML features three models: epitope prediction from target sequences, personalized HLA typing, and prioritization the predicted epitopes based on immunogenicity scores. Our rigorous data extraction, cleaning, and feature extraction processes, coupled with model building, yield exceptional accuracy, sensitivity, specificity, and F1 score, surpassing existing prediction methods. Comprehensive visual representations underscore VaxOptiML's robustness and efficacy in accelerating epitope discovery and vaccine design for cancer immunotherapy. Deployed via Streamlit for public use, VaxOptiML enhances accessibility and usability for researchers and clinicians, demonstrating significant potential in cancer immunotherapy.

关键词： Pyroptosis   Glucocorticoid resistance   IL-8   Epithelial cells  

摘要： ObjectiveThis study seeks to elucidate the role and molecular mechanisms of IL-8 in nasal epithelial cell pyroptosis and its impact on glucocorticoid (GC) *** assessed the expression of pyroptosis-related biomarkers and IL-8 in tissues and human nasal epithelial cells (hNECs) from both control and nasal polyp patients using western blot. Their localization was determined through immunohistochemistry and immunofluorescence. Cell death and cytotoxicity assay, electron microscopy, ELISA, and immunofluorescence were utilized to investigate IL-8-induced pyroptosis and GC resistance in hNECs, alongside the examination of the involved signaling pathways via western blot and immunofluorescence. In a murine model, hematoxylin-eosin staining and immunohistochemistry clarified relationship between pyroptosis and GC ***-8 and pyroptotic biomarker expression were significantly higher in nasal polyp-derived tissues and hNECs compared to controls. IL-8 showed a positive correlation and co-localized with the pyroptotic biomarkers. IL-8 triggered pyroptosis in hNECs by activating the ERK signaling pathway, leading to increased IL-1 beta and IL-18 secretion. Moreover, IL-8-induced pyroptosis was found to contribute to GC resistance by affecting phosphorylation of GC receptor Ser211. Inhibition of pyroptotic proteins mitigated IL-8-induced GC resistance both in vitro and in *** IL-8 facilitates pyroptosis via the ERK signaling pathway and plays a significant role in GC resistance in nasal polyps.

关键词： DNA extraction   Microtube   PCR-SSOP   HLA typing  

摘要： Background The purity of the extracted DNA is critical for successful molecular testing. This study aimed to compare the effect of various DNA extraction methods, extraction processes, and sources of consumables, such as microtubes, on PCR results. Methods DNA extraction from whole blood was performed using four different approaches utilizing four types of microtubes: chloroform-based, sodium perchlorate-based, heat-assisted salting out, and solid-phase extraction. Extracted DNA was evaluated by nanodrop spectrophotometry and used in PCR-based methods for human leukocyte antigens (HLA) typing. Results The lowest and highest concentrations of extracted DNA were observed in the column-based and heat-assisted methods, respectively. The mean ratios of A260/A230, represents chemical contamination, were significantly lower in all extraction methods using all types of microtubes versus "A" microtube. We observed the highest mean ratio of A260/A230 (> 1.9) in the sodium perchlorate method by using the "A" microtube compared to other types of microtubes and extraction methods. Extracted DNA samples using microtube "A" showed acceptable results for HLA typing compared to other microtubes that represented uninterpretable results in the PCR using the sequence-specific oligonucleotide probe (PCR-SSOP) method. Conclusion Our findings indicate that the chemical contaminations derived mainly from microtubes can decrease the quality of DNA and consequently interfere with the amplification or hybridization reactions in the PCR-SSOP method for HLA typing. Although, technical issues and extraction processes may also influence the quality of DNA.

关键词： Microchimerism   HLA   Autoimmune disease  

摘要： Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.

关键词： Renal ischemia/reperfusion   Remote ischemic pre-conditioning   Apelin   Inflammation   Oxidative stress  

摘要： Background Remote limb ischemic pre-conditioning (RIPreC) can invoke potent renal protection. The involvement of oxidative stress and inflammatory pathways in renal ischemia/reperfusion injury (I/RI) was also confirmed. This study was designed to investigate the RIPreC effects on IRI-induced kidney dysfunction in rats through NF kappa B/TNF-alpha/TGF-beta/apelin signaling *** Renal I/RI was induced by occluding the kidney arteries for 45 min, then reperfusion for 24 h. Four similar cycles of left femoral artery ischemia (2 min)/reperfusion (3 min) before the onset of kidney ischemia were performed to create RIPreC. Animals were randomly divided into three groups: sham, I/R, and RIPreC + I/R. Following the reperfusion phase, urine and blood samples were taken, and the kidney was removed for functional, molecular, and histological *** When compared to sham rats, renal IRI resulted in decreased creatinine clearance and increased sodium fractional excretion, lower antioxidant enzyme activities, higher malondialdehyde content and higher nuclear factor-kappa B (NF-kappa B), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-betta (TGF-beta), and Apelin expression levels, and histologically damaged kidney tissue. All of the alterations, as mentioned earlier, were alleviated using the RIPreC *** Thus, RIPreC can protect against renal dysfunction after renal I/RI via modulation of the TNF-alpha/NF-kappa B/TGF-beta Apelin signaling pathway and strengthening the antioxidant defense system.