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摘要： Glaucoma, age-related macular degeneration, and diabetic retinopathy are complex eye diseases that involve inflammation. Several cellular models are developed to study inflammation mechanisms in the posterior segment of the eye. These models, are composed of cells of various origins (human or animal), derived from different tissues (retina, choroid, skin, and umbilical cord) and belonging to different cell types (epithelial, endothelial, vascular, and neuronal). Multiple culture techniques are employed to analyze specific inflammatory responses. Various experimental approaches are used to induce inflammation in these cellular models and identify underlying molecular mechanisms. This review highlights the diversity of cell models used to study posterior ocular inflammation. It emphasizes the use of primary cell cultures, established cell lines, and different co-culture approaches. The goal is to further increase our understanding of these diseases which affect millions of people worldwide.

摘要： Le fonti storico-cliniche del periodo bizantino suggeriscono che differenti forme di gozzo tiroideo erano presenti nella popolazione dei territori dell’Impero. In particolare, Ezio di Amida (VI d.C.), vissuto al tempo dell’Imperatore Giustiniano I, fornisce una classificazione del gozzo che trova numerosi riscontri nelle varianti patologiche che conosciamo oggi e permette di supporre che abbia potuto osservare questi differenti tipi direttamente nella sua pratica clinica. Effettivamente, l’analisi retrospettiva dell’iconografia delle rappresentazioni figurative bizantine mediante Visual Thinking Strategy permette di concludere che il gozzo tiroideo era una patologia diffusa nella popolazione dell’Impero Romano d’Oriente, configurando una possibile epidemiologia indicativa di gozzo endemico.

关键词： MHC-I Antigen Presentation   Immune Escape   GLDC   EGFR Activation   ICB Therapy  

摘要： Inadequate antigen presentation by MHC-I in tumor microenvironment (TME) is a common immune escape mechanism. Here, we show that glycine decarboxylase (GLDC), a key enzyme in glycine metabolism, functions as an inhibitor of MHC-I expression in EGFR-activated tumor cells to induce immune escape by a mechanism independent of its enzymatic activity. Upon EGFR activation, GLDC is phosphorylated by SRC and subsequently translocated to the nucleus in human NSCLC cells. Nuclear GLDC sequesters STAT1 co-activator SMARCE1, inhibiting STAT1-dependent transcription of the inflammatory genes IRF1 and NLRC5. Further, GLDC recruits DNMT1 to the IRF1/NLRC5 promoter inducing DNA hypermethylation, suppressing transcription of downstream MHC-I genes. Inhibition of GLDC restores MHC-I levels in tumor cells, improves tumor-specific CD8+ T cells functions in the TME, and rescues anti-tumor effects of PD-1 blockade therapy in mice. Our findings reveal a non-enzymatic nuclear function for GLDC in the suppression of MHC-I antigen presentation, suggesting new strategies for ICB-based combination immunotherapy.

关键词： HLA-II   esophageal squamous cell carcinoma   neoantigen   immunohistochemistry   transcriptomics   immune microenvironment   prognosis  

摘要： Ectopic expression of human leukocyte antigen class II (HLA-II) on tumor cells correlates with anti-tumor immunity and prognosis in various cancers, but its role in esophageal squamous cell carcinoma (ESCC) remains unclear. Methods: HLA-II expression was evaluated in 34 ESCC tissue sections and a 102-sample tissue microarray (TMA) using immunohistochemistry (IHC) and in 10 ESCC cell lines via flow cytometry. Transcriptome sequencing of KYSE270, KYSE180, KYSE450, and KYSE510 was performed to investigate HLA-II regulatory mechanisms, while tumor samples from 104 ESCC patients were analyzed for neoantigen load. The prognostic significance of neoantigen burden was assessed using Cox regression. Results: HLA-II was ectopically expressed in ESCC, with positivity rates of 20.59% (34 tissues) and 25.49% (TMA). Among 10 ESCC cell lines, only KYSE270 exhibited spontaneous HLA-II expression. Transcriptome analysis revealed 1278 KYSE270-specific genes enriched in immune-related pathways (e.g., "Cytokine-cytokine receptor interaction"), suggesting immune-mediated HLA-II regulation. IFN-gamma stimulation induced HLA-II expression in KYSE180, KYSE450, and KYSE510, indicating broader inducible HLA-II potential. In 104 patients, MHC-II-restricted neoantigen burden varied widely (0-75) and lacked direct correlation with HLA-II expression. Additionally, MHC-II-restricted neoantigen load was not significantly associated with overall survival (p > 0.05). Conclusion: Ectopic HLA-II expression in ESCC may influence the tumor immune microenvironment, while the prognostic value of MHC-II-restricted neoantigen burden in ESCC remains unclear, providing potential implications for immunotherapy strategies.

关键词： CXCL9   Esophageal squamous cell cancer   IFNγ   IKKβ   T cells   early carcinogenesis   inflammation   macrophages  

摘要： Esophageal cancer is a major cause of cancer-related death, often preceded with chronic inflammation and injuries. The NFκB/IKKβ pathway plays a central role in inflammation, yet its role in early esophageal carcinogenesis remains unclear. This study investigated the role of epithelial IKKβ in early esophageal carcinogenesis. Mice were treated with the carcinogen 4-nitroquinoline-1-oxide (4-NQO) or a vehicle for one month to induce precancerous lesions. Esophagi were harvested and examined through histological, protein, flow cytometry, and RNA analyses. Histological analysis revealed that 4-NQO treatment led to increased inflammation, intraepithelial CD45+ immune cells, and elevated IKKβ phosphorylation levels. Mice with esophageal epithelial-specific Ikkβ deletion (4-NQO/IkkβEEC-KO) showed delayed progression to a precancerous state, with reduced immune cell recruitment compared to 4-NQO/controls. Immunophenotyping showed decreased recruitment of T cells, including CD4+, CD8+ and regulatory (Tregs) T cells, and increased recruitment of macrophages in 4-NQO/IkkβEEC-KO mice compared to 4-NQO/controls. RNA sequencing data identified 262 differentially expressed genes in 4-NQO/IkkβEEC-KO mice, implicating pathways related to inflammation and wound healing. Notably, the chemokine CXCL9, a T cell chemoattractant, was significantly upregulated in 4-NQO control mice, but not in 4-NQO/IkkβEEC-KO mice. Further analysis identified IFNγ as an upstream regulator of Cxcl9 expression, and neutralization of IFNγ reduced Cxcl9 expression levels in 4-NQO treated mice. Additionally, in vitro studies demonstrated that IFNγ upregulates Cxcl9 in an NF-ĸB dependent manner in esophageal keratinocytes. These findings suggest that epithelial IKKβ regulates the immune microenvironment in early esophageal carcinogenesis through the IFNγ/CXCL9 axis and influencing T cell recruitment and inflammatory responses.

关键词： IL-6   TGFbeta   airway epithelium   cystic fibrosis  

摘要： Cystic Fibrosis (CF) is characterized by impaired mucociliary clearance and pulmonary infections. Accumulating evidence suggests that fundamentally abnormal inflammatory responses also contribute to CF pathology. TGFβ, a pleiotropic cytokine, is a modifier of CF lung disease; its mechanism of action in CF is unclear. Previous studies have shown that TGFβ induces IL-6 secretion from lung epithelium, which may drive worse pulmonary outcomes in CF and other lung diseases. However, the nature of the TGFβ/IL-6 relationship in CF is not fully understood. In this study, we demonstrated that TGFβ and IL-6 concentration were positively associated in bronchoalveolar lavage fluid from children with CF. Furthermore, pulmonary TGFβ exposure in a CF mouse model induced heightened IL-6 secretion when compared with non-CF mice. CF airway epithelial cells had increased IL-6 secretion and PI3K signaling after TGFβ exposure. In wild type airway epithelium, TGFβ exposure and CFTR inhibition synergistically provoked IL-6 secretion. Restoration of CFTR function by a CFTR modulator and inhibition of PI3K signaling both normalized IL-6 secretion from CF airway epithelial cells. These data indicate that TGFβ drives abnormal IL-6 secretion via the PI3K pathway in the CF airway, demonstrating an inherent inflammatory abnormality in CF and suggesting potential therapeutic targets.

关键词： extracellular vesicles   mesenchymal stem/stromal cells   epidermal growth factor(EGF)   tumor necrosis factor-alpha (TNF-alpha)   hypoxia  

摘要： Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) are promising therapeutic agents for various diseases. However, current methods to improve MSC-EV production are insufficient to meet the clinical demands. Although various strategies have been investigated to enhance MSC-EV production, they are often hampered by limited scalability, loss of stemness, or suboptimal therapeutic outcomes. Our study identified three key stimulators that significantly boosted MSC-EV production: epidermal growth factor (EGF), tumor necrosis factor-alpha (TNF-alpha), and hypoxia. Employing an orthogonal design, we developed an optimized cell culture condition, subsequently referred to as ETH (EGF 10 ng/mL, TNF-alpha 50 ng/mL, and a hypoxic environment of 1% O2) preconditioning. This approach led to a remarkable 4- to 5-fold increase in MSC-EV yield while preserving the stemness of MSCs. Through proteomic analysis, we elucidated the underlying mechanisms of ETH preconditioning, providing insight into the complex processes driving enhanced MSC-EV production. Notably, MSC-EVs generated through ETH preconditioning demonstrated enhanced therapeutic potential including superior angiogenesis, collagen deposition, and regulation of inflammation. These findings present a scalable and effective strategy for elevating MSC-EV production, paving the way for its broader clinical application in regenerative medicine.

关键词： adult worms   extracellular vesicles   IL-10   proteomics   regulatory B cells   Schistosoma mansoni  

摘要： Schistosome parasites are known to modulate host immune responses, which is achieved in part through the release of excretory/secretory (ES) products, including extracellular vesicles (EVs). During chronic schistosomiasis, increased regulatory responses are found, which include enhanced IL-10 production by B (Breg) cells. ES products from schistosome eggs are able to induce IL-10 production by B cells. However, since infection with male worms only (without egg production) also promotes IL-10 producing B cells, we here studied the stimulatory effects of adult worm ES and EVs on murine and human B cells. Worm ES increased IL-10 release by mouse splenic B cells;this activity was concentrated in defined size-separated fractions of adult worm ES. Interestingly, mass spectrometry of the fractions that induced the highest IL-10 response revealed an enrichment of EV-associated proteins. Indeed, highly purified adult worm EVs could interact with mouse splenic B cells, visualised by binding of a schistosome-specific tetraspanin (TSP2) targeting antibody. Furthermore, purified adult worm EVs induced IL-10 release in both mouse splenic and human peripheral blood B cells, suggesting that adult worm EVs can play a role in immune regulatory processes within their host.

关键词： HLA class   NGS   novel allele  

摘要： We identified seven novel HLA class I alleles by NGS.

摘要： BackgroundGX-I7 (rhIL-7-hyFc, efineptakin alfa) is a hybrid Fc-fused long-acting interleukin-7 (IL-7) with the aim of correcting T-cell deficiency, thereby strengthening the immune response to fight against cancer. This Phase 1b, dose-escalation study was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GX-I7 in patients with locally advanced or metastatic solid *** study, conducted in patients with advanced solid tumours at three hospitals in Korea, involved intramuscular GX-I7 administration across eight dose levels (60-1700 mu g/kg) in 3- and 6-week cohorts. A dose-expansion phase at 720 and 1200 mu g/kg further assessed GX-I7's safety and ***-tumour responses showed either stable disease (SD) or disease progression (PD). GX-I7 demonstrated dose-dependent increases in the maximum serum concentration (Cmax) and area under the curve up to the last measurable concentration (AUClast). In addition, a dose-dependent increase in circulating CD8+/CD4+ T cells was observed. In five patients who consented for biopsy, a statistically significant increase in tumour-infiltrating lymphocytes (TILs) followed GX-I7 *** suggest GX-I7 is a safe T cell-amplifying agent with peripheral immune activation. Ongoing studies are exploring its ability to enhance immune responses in peripheral immune cells and tumour cells when combined with other anti-cancer *** Trial registrationNCT03478995