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摘要： Lung transplantation (LTx) is an effective treatment option for patients suffering from end-stage lung disease; however, its success is hindered by chronic lung allograft dysfunction (CLAD), which remains the leading cause of long-term mortality. ...

关键词： IL-6/STAT3   Rheumatoid arthritis   Immune adaptation   Synovial fibroblasts   Chronic inflammation   non-coding RNAs   Epigenetic plasticity  

摘要： The IL-6/STAT3 signaling cascade is a well-known cause of chronic inflammation and joint destruction in rheumatoid arthritis (RA). However, existing medicines targeting IL-6 or JAKs frequently fail to induce long-term remission, suggesting a deeper level of immunological plasticity, which may involve complex epigenetic changes and RNA interactions, underlying disease recurrence. We proposed that the IL-6/STAT3 signaling pathway functions as an "autoimmune adaptability axis" that extends beyond its classical pro-inflammatory role in rheumatoid arthritis (RA). This axis enables immune cells and synovial fibroblasts to dynamically alter their phenotype in response to environmental cues, thereby promoting persistence of inflammation and resistance to therapy. This adaptability is driven by coordinated regulation of gene expression, chromatin state, and noncoding RNAs including lncRNAs and potentially circRNAs that sustain disease-associated cellular programs. The axis includes cytokines (IL-6), transcription factors (STAT3), and regulatory RNAs that improve harmful cell conditions. A dynamic feedback system stabilises inflammatory phenotypes and aids immune escape in this framework, which interacts with established RA pathways. Further experimental validation is needed to delineate the specific interactions within this axis and to determine how it may be targeted for therapeutic modulation. We hypothesise that IL-6/STAT3 signalling serves as a 'decision-making centre' for gene expression programs that control immune evasion, fibroblast invasiveness, and treatment resistance. This approach advances the emphasis from linear inflammatory signalling to an intelligent immune adaptability model, offering up novel possibilities for precision therapeutics that intercept disease plasticity at the molecular level.

关键词： HLA   HLA-DPA1*02:113   new allele   next-generation sequencing  

摘要： The HLA-DPA1*02:113 allele differs from the HLA-DPA1*02:02:02:01 allele by a single nucleotide at codon-3 in exon 1.

关键词： Interleukin-27   BCG   Tuberculosis   Vaccine   Neonatal  

摘要： Tuberculosis (TB) is the leading cause of death due to a pathogen. The live-attenuated BCG vaccine is the only approved vaccine to prevent TB, but it fails to confer long-term protection. We hypothesize that the immunosuppressive cytokine IL-27 may contribute to the inefficacies of the BCG vaccine. IL-27 is elevated in neonates, the population most commonly administered BCG, and levels increase further upon vaccination. IL-27 interferes with the phagolysosomal pathway, suggesting it may limit the diversity of antigens processed and presented to T cells. We hypothesized that in the absence of IL-27 signaling, BCG vaccination induces antigen-specific T cells that recognize a greater number of antigens and provide enhanced protection during M. tuberculosis (Mtb) challenge. CD3+ T cells isolated from IL-27R alpha KO mice vaccinated with BCG as neonates were more responsive to BCG and a Mtb peptide pool than T cells from vaccinated WT mice. Adoptive transfer of IL-27R alpha KO T cells provided more consistent protection against Mtb than WT, but this was not observed in TCR alpha- /- mice. A principal component analysis suggested a more consistent multifunctional cytokine response was associated IL27R alpha KO T cells. These findings enhance our understanding of IL-27 during neonatal vaccination and development of protective immunity.

关键词： Diabetic foot ulcer   HIF-1 alpha   MMP-9   IL-8   biomarkers  

摘要： Diabetic foot ulcers (DFUs) are a serious complication of diabetes, leading to high morbidity and mortality rates. Early diagnosis of DFUs is critical for improving patients' quality of life and reducing the burden on healthcare systems. This study aimed to identify biomarkers that can predict the early development of DFUs and evaluate their potential for clinical applications. The study included three groups: diabetic patients with DFUs, diabetic patients without ulcers and healthy individuals. Serum levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha), matrix metallopeptidase 9 (MMP-9) and IL-8 were measured in blood samples and these biomarkers were compared with acute phase reactants such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and procalcitonin. The diagnostic values of these biomarkers were assessed using receiver operating characteristic (ROC) analysis. HIF-1 alpha levels were found to be significantly elevated in patients with DFUs and ROC analysis revealed that this biomarker had the highest diagnostic sensitivity and specificity [area the under curve (AUC= 0.99, p= 0.001)]. The increase in HIF-1 alpha levels suggested that hypoxic responses remain active during the early stages of DFU but decrease in advanced stages due to impaired tissue response to hypoxia. MMP-9 levels were observed to increase proportionally with Wagner stages and were positively correlated with ESR, indicating its role in chronic inflammation and tissue damage. IL-8 levels were significantly elevated in DFU patients, yet their lack of correlation with other inflammatory markers suggested that IL-8 might have a more specific role in the inflammatory process. HIF-1 alpha emerges as a key biomarker in the early detection of DFUs due to its central role in hypoxia-driven tissue repair and angiogenesis. Owing to its high specificity and sensitivity (AUC= 0.99), it should be considered a promising biomarker for routine clinical monitoring. The role of MMP-9 in

关键词： flow cytometry crossmatch   HLA   interference   solid organ transplantation   vedolizumab  

摘要： In organ transplantation, immunological risk assessment uses cell crossmatch (XM) results, which can be altered by several drugs. We observed two recipients awaiting kidney and liver transplantation with positive flow cytometry XM (FCXM) on T-cells in the absence of Donor Specific Antibodies (DSA). Both were treated with vedolizumab (VDZ) for an inflammatory bowel disease (IBD). VDZ is an IgG1 directed against integrin alpha 4 beta 7, expressed on T and B cell subsets, we therefore suspected that VDZ interfered with XM. We tested with Luminex screening and single antigen assays and with auto- and allo-FCXM on different HLA-typed cells several sera from the two recipients, collected before and during treatment with VDZ. To assess the intensity and the kinetics of the interference, the sera collected during VDZ treatment were from the induction and the maintenance phases at different times post-injection. All sera were DSA-negative with Luminex assays, indicating the absence of interference of VDZ with virtual XM. IgG allo-FCXM on T cells was positive during the maintenance phase while it was randomly positive on B cells. On T cells, the ratio was between 1.6 and 4.4 times the negative control (positivity threshold of 1.5) for the two recipients, and did not depend on the time between collection and injection. Unique T cell populations express Integrin alpha 4 beta 7, then we did not observe a global shift for T cells in the presence of VDZ but a shift for a small subset which was sufficient to induce a positive FCXM. VDZ treatment did not interfere with complement-dependent cytotoxicity XM or with IgM FCXM. Pronase treatment abrogated VDZ interference. In the event of unexpected positive FCXM on T cells in a recipient with IBD, the transplant team should seek VDZ treatment and interference.

关键词： Porcine pancreatic elastase (PPE)   Emphysema   Siglec-F+ neutrophils   IL-17A   G-CSF   gamma delta(+) T cells   Epithelial/stromal cells   G-CSF receptor signaling  

摘要： Neutrophils play a pivotal role in the progression of IL-17-mediated airway inflammation, but the mechanisms underlying their pathological differentiation remain poorly understood. In this study, we identified a distinct population of lung-specific pathogenic Siglec-F+ neutrophils in a porcine pancreatic elastase (PPE)-induced mouse model of emphysema. Compared with conventional neutrophils, these Siglec-F+ neutrophils exhibited increased phagocytic activity, increased extracellular trap formation, increased production of proinflammatory cytokines, and reduced IL-10 levels. During the early phase of acute inflammation following PPE instillation, IL-17A levels in the lungs increase, which is driven primarily by gamma delta(+) T cells. IL-17A stimulated lung epithelial/stromal cells to secrete granulocyte colony-stimulating factor (G-CSF), which promoted the differentiation of Siglec-F+ neutrophils via the JAK2/STAT3 pathway and the PI3K-independent mTOR and p38 MAPK signaling pathways. Neutralizing G-CSF or inhibiting JAK2/STAT3, mTOR or p38 MAPK signaling significantly suppressed Siglec-F+ neutrophil development, resulting in the alleviation of emphysematous symptoms. Our findings underscore the crucial role of Siglec-F+ neutrophils in the pathogenesis of PPE-induced emphysema and suggest that targeting the IL-17A/G-CSF axis or G-CSF receptor downstream signaling pathways may represent a promising therapeutic strategy for treating emphysema.

关键词： NK cells   Hemorrhagic fever with renal syndrome   Flow cytometry   Cloning   Gene expression   Blood   Cell staining   Cell binding  

摘要： NK cells could participate in the pathogenesis process of virus infectious diseases through the inhibitory receptor CD94/NKG2A interacting with HLA-E/virus-derived peptide complex. However, the effects and mechanisms of NKG2A-HLA-E axis-mediated NK cell responses in hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV) infection remain unclear. Single-cell RNA sequencing and flow cytometry were employed to analyze the phenotype and function of different NK cell subsets in HFRS patients. The K562/HLA-E cells binding assay was used for peptide affinity detection. The binding capacity of HLA-E/peptide-CD94/NKG2A was detected using ligand-receptor binding assay and tetramer staining. The cytotoxicity assay of NK cells against peptide-pulsed K562/HLA-E cells was conducted for functional evaluation. In this study, CD56dimCD16+NKG2A+ NK cells were the main subset in HFRS patients, showing activation and proliferation phenotypes with NKG2C-CD57- and the ability to secrete tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and cytotoxic mediators. Notably, none of the four identified HTNV epitopes presented by HLA-E could be recognized by CD94/NKG2A on CD56dimNKG2A+ NK cells. Furthermore, the subset of CD56dimNKG2A+ NK cells showed the enhanced cytolytic capacity against HTNV peptide pulsed K562/HLA-E cells ex vivo. Taken together, the findings demonstrate that HTNV-derived peptides presented by HLA-E could "abrogate" the inhibition of CD56dimNKG2A+ NK cells, contributing to the antiviral immune response in HFRS patients.

关键词： Apigenin   human lung cancer A549   apoptosis   signaling pathway  

摘要： Background/Aim: Apigenin, found in a variety of vegetables and fruits, exhibits anti-oxidant, anti-inflammatory and anticancer effects. Recently, we reported the possibility that apigenin induces apoptosis in human lung adenocarcinoma A549 cells through the miR-34a-5p/SNAI1/caspase-3/-7 pathway. Understanding how apigenin triggers apoptosis in cancer cells will help lay the groundwork for developing effective cancer treatments. Materials and Methods: The lung adenocarcinoma A549 Cell line was used. To determine whether caspase-8 or caspase-9 is activated, we performed a caspase activity assay. Real-time qRT-PCR was performed to identify mRNAs that may stimulate the upstream pathways, including tumor necrosis factor-a (TNF-a), spondin-2 (SPON2), and interferon-a2 (IFNA2), which are known to be involved in apoptosis in various cancer cell lines. Results: In apigenin-treated cells, early-stage apoptosis was observed at 24 h, with increased activity of caspase-8 at 18 h and again at 24 h, and caspase-9 at 24 h and further at 48 h. However, mRNA levels of caspase-8 and caspase-9 significantly decreased after 24 h. Real-time RT-qPCR analysis revealed increased mRNA levels of TNF-a, spondin-2, and interferon-a2 after 24 h of apigenin treatment in A549 cells, whereas treatment for 48 h led to decreased expression of SPON2 and IFNA2. Conclusion: Apigenin promotes apoptosis in A549 cells by modulating various signaling pathways at different time points.