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关键词： B locus   IBDV   MHC   infectious bursal disease virus   major histocompatibility complex  

摘要： Seven lines of major histocompatibility complex (MHC)-B congenic specific pathogen free (SPF) chickens and two lines of non-B congenic SPF chickens with similar B haplotype but differing non-MHC genes were utilized to investigate the effect of the B locus on infectious bursal disease (IBD) development. In initial experiments, chickens were challenged at 28 days of age with the variant infectious bursal disease virus (IBDV) strain AL-2, classical IBDV strain STC, or very virulent (vv) IBDV strain rA. IBD severity was evaluated throughout the seven-day course of infection by assessing survivability and histopathological analysis of bursal lesion scores. Follow up studies investigated the effects of varying STC challenge doses on IBD development. Results demonstrated that the challenge strain of IBDV has a large impact on B locus-based genetic resistance. The most significant differences in survivability and bursal lesions were noted after challenge with the vvIBDV strain, with MHC-B congenic chicken lines B*13 and B*19 being the most susceptible. Based on survivability, the B*19 chicken line was also characterized as the most susceptible after challenge with high doses (10 EID) of the STC strain. No differences in survivability were detected among the chicken lines when challenged with the variant strain AL-2. Based on the results with these chicken lines, B locus-based genetic resistance to IBDV is mainly associated with survival during the early stages of infection and has minimal association with bursal damage and bursal lymphocyte depletion. Non-B locus-based genetic differences also have a significant impact on survival during early IBDV infection.

关键词： Carbohydrate antigen   Conversion immunochemotherapy   Gastric cancer   Hypertension   IL-10   Prediction model   Serum albumin  

摘要： BACKGROUND:Conversion immunochemotherapy may enable curative surgery in patients with initially unresectable locally advanced gastric cancer, but its response rate remains low. Little evidence has shown how to easily predict therapeutic efficacy from hematological biomarkers, apart from tissue biomarkers. This study aimed to identify predictive factors for treatment response from hematological biomarkers and propose strategies for non-responsive patients. METHODS:Clinical and laboratory data from 153 PD-L1 negative and microsatellite stable advanced gastric cancer patients treated with conversion immunochemotherapy followed by radical gastrectomy were retrospectively analyzed. Correlations between key indicators and treatment outcomes were assessed, and a nomogram was developed to predict tumor regression grade (TRG). RESULTS:TRG was strongly associated with the prognosis of advanced gastric cancer treated with conversion immunochemotherapy. Factors significantly related to TRG included hypertension, pre-treatment serum albumin levels, tumor size, post-treatment serum IL-10, IFN-γ, TNF-α, and changes in tumor-associated carbohydrate antigens before and after treatment. Hypertension, pre-treatment serum albumin levels, post-treatment IL-10 levels, and restoration in tumor-associated carbohydrate antigens were identified as independent predictors of TRG. CONCLUSION:Dynamic monitoring of serum albumin, IL-10, and tumor-associated carbohydrate antigens can help assess treatment response and identify patients sensitive to conversion immunochemotherapy. For non-responsive patients, strategies such as the associations observed require validation in prospective interventional trials before specific interventions can be recommended.

关键词： CD4 + T cell   Diffuse large b-cell lymphoma   IFN-γ/IL-4 ratio   Immune related prognostic model   International prognostic index  

摘要： BACKGROUND:Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous B-cell malignancy influenced by immune dysregulation, posing significant clinical challenges. Lymphocyte subsets (e.g., CD4 + T helper 1/ T helper 2 cells) and their cytokines (IFN-γ/IL-4) are readily measurable immune markers involved in DLBCL pathogenesis and may independently predict prognosis. However, the prognostic value of these two combined clinical laboratory findings in newly diagnosed DLBCL patients remains uninvestigated. METHOD:Here, we retrospectively analyzed 94 newly diagnosed DLBCL patients treated at our institution between 2017 and 2023. The prognostic influences of lymphocyte subsets, cytokines levels and other factors on progression-free survival (PFS) and overall survival (OS) were studied by Kaplan-Meier analysis and Cox regression (univariate/multivariate). Then we constructed an immune-related prognostic score model (IRPS) and validated it in another independent cohort. RESULTS:The results suggested that a high IFN-γ/IL-4 ratio and elevated CD4 + T cell count were favorable risk variables for both PFS and OS in DLBCL patients. Besides, multivariate analysis showed that age was marginally associated with the worse OS whereas low CD8 + T cell count was associated with the inferior PFS. Moreover, elevated pretreatment IFN-γ/IL-4 ratio was significantly correlated with better clinical response efficacy. Compared to those treatment-responsive patients, lower level of IFN-γ/IL-4 ratio was discovered in patients experienced with progression during the subsequent treatment cycles. Additionally, a new immune-related prognostic score model was constructed based on age, CD4 + T cell count and IFN-γ/IL-4 ratio, where high-risk patients had worse overall survival than low-risk patients. Meanwhile, the IRPS could refine the International Prognostic Index (IPI) score well and validation of the IRPS in another independent cohort confirmed its effectiveness. CONCLUSION:IFN-γ/IL-4 rati

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

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-α (TNF-α), and hypoxia. Employing an orthogonal design, we developed an optimized cell culture condition, subsequently referred to as ETH (EGF 10 ng/mL, TNF-α 50 ng/mL, and a hypoxic environment of 1% O) 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： candidiasis   head-neck irradiation   interleukin-23   irradiation   oral mucositis  

摘要： Targeted head and neck irradiation (HNI) used for cancer therapy causes mucosal damage and immune dysregulation, leaving cancer patients highly susceptible to infections of the oral mucosa. Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by , a commensal fungus found in up to 80% of the population at any given time. High colonization levels of are known to worsen damage caused by HNI. The interleukin-23 (IL-23)-T-helper 17 (Th17) axis is a central and non-redundant mediator of immunity to OPC, and anti-cytokine biologics targeting IL-23 have come into widespread clinical use for treating various autoimmune conditions. Here, we sought to understand the consequences of IL-23 deficiency in the setting of HNI, taking advantage of a mouse model of radiation-induced oral mucositis (OM) which we combined with fungal infection. Surprisingly, mice lacking IL-23 did not show increased signs of injury to the oral mucosa when subjected to HNI. However, in mice subjected to HNI and exposed to oral , damage to the oral mucosa was markedly exacerbated, accompanied by substantially increased fungal susceptibility when IL-23 was absent. Thus, IL-23-driven control of fungal infections is needed to mitigate susceptibility to OM in the high proportion of individuals who carry in the ***-23 plays key roles in expanding the T-helper 17 (Th17) cell subset during differentiation and promoting expression of cytokines, including the subset-defining cytokine IL-17 (IL-17A). While the effector cytokines produced by Th17 cells are required for host defense against extracellular microbes, especially , these can also be pathogenic during inflammatory and autoimmune disorders including psoriasis, psoriatic arthritis, and ankylosing spondylitis, among others. While IL-23 and IL-17 are similarly required for protection against oropharyngeal candidiasis (OPC), they can exert divergent functions in other forms of immune-mediated inflammation; for example, anti-IL-

关键词： TNF‐α   blood glucose   clinical trial   glycated albumin   hemodialysis day   insulin dose adjustment   interleukin‐6  

摘要： BACKGROUND:Previous studies suggested adjusting insulin doses during hemodialysis to reduce intra- and post-hemodialysis hypoglycemia. However, the impact of insulin adjustment on cardiovascular morbidity and mortality in diabetic patients with end-stage renal disease (ESRD) remains unclear. Although reducing hypoglycemia is a well-documented benefit of insulin dose modification in this population, the broader metabolic and inflammatory consequences-particularly those related to cardiovascular risk-are not well understood. This study aimed to investigate the effects of a 25% reduction in total daily insulin dose on hemodialysis days in T2DM patients with ESRD, focusing on daily blood glucose profiles, glycated albumin, IL-6, and TNF-α. METHODS:A multicenter study with clinical trials was designed in five hemodialysis centers. It was a 4-week clinical trial involving 17 eligible type 2 diabetic patients with ESRD on insulin therapy and regular hemodialysis. Self-monitoring blood glucose was performed seven times a day before, during, and 1 month after the intervention. Blood samples were collected before and after the intervention. The Wilcoxon test was used to assess differences in daily glucose profiles, glycated albumin, IL-6, and TNF-α before and after insulin dose adjustment. RESULTS:After 1 month of adjusting total daily insulin dose during hemodialysis, no statistically significant difference was observed in daily blood glucose, IL-6, and TNF-α levels. However, glycated albumin levels increased both before and after the insulin dosage modification. CONCLUSIONS:Reducing the total daily insulin dose by 25% during hemodialysis day effectively reduces hypoglycemia incidence intra- and post-hemodialysis in T2DM patients with ESRD without impacting pro-inflammatory factors IL-6 and TNF-α, which are associated with increased cardiovascular morbidity and mortality risk.

关键词： NK cells   IL-15   cytokine signaling   tumor immunology   innate immunity   post-translational modifications   core fucosylation  

摘要： Natural killer (NK) cell homeostasis and effector functions require context-dependent signaling via numerous receptors, including the interleukin-15 receptor (IL-15R). Post-translational modifications can regulate receptor signaling, impacting receptor turnover and trafficking. Core fucosylation is one such modification known to impact receptor expression and is uniquely mediated by fucosyltransferase 8 (FUT8). We identified FUT8 as an essential gene required for IL-15R responsiveness in a human NK cell genome-wide CRISPR screen. To further validate core fucosylation in IL-15R signaling and NK cell biology, mice lacking Fut8 in NK cells (Fut8fl/flNcr1cre/+) were generated. The loss of core fucose in murine NK cells resulted in severe NK cell lymphopenia, with a reduction in IL-15R beta (IL-2RB/CD122) expression, impairing in vivo homeostatic proliferation. The loss of FUT8 also decreased NK cell cytotoxicity, tumor immunity, and early viral immunity. Taking these results together, we have identified FUT8 as a key modulator of NK cell biology by regulating their development, IL-15R expression, and signaling.

摘要： BACKGROUND:Eplets, acting as specificity determinants on donor HLA antigen molecules, may induce the formation of de novo donor-specific antibodies (dnDSAs) by the recipient's B cells posttransplantation. HLA-DQ DSAs are the most common type of DSAs that target mismatched donor HLA-DQ antigens. The HLA-DQ protein exists as a heterodimer, consisting of HLA-DQA1 and HLA-DQB1 molecules. The specific risk of each mismatched HLA-DQ dimer contributing to dnDSA formation remains underexplored. METHODS:A total of 434 kidney transplant donor/recipient pairs from Zheng Zhou University First Affiliated Hospital, who underwent the transplant procedure between September 2016 and November 2020, were included in this analysis. All were DSA-negative pretransplant. For each HLA-DQ heterodimer, the total incidence of dnDSA, alpha chain-specific dnDSA, and beta chain-specific dnDSA after kidney transplant was analyzed. The dnDSA formation rates of different mismatched HLA-DQ dimers were compared and their haplotype association with specific HLA-DRB1 protein were determined. RESULTS:In this study, 38 HLA-DQ dnDSAs were detected, with 28 to HLA-DQB1 and 10 to HLA-DQA1. HLA-DQA1*03:02-DQB1*03:03 dimer had the highest dnDSA formation rate of 28.3%. The HLA-DQA1*05:xx-DQB1*03:01 and HLA-DQA1*05:xx-DQB1*02:xx, which are known for their high immunogenicity in previous studies, showed a relatively low DSA formation rate of 4.3%. The common DQB1*01:xx-DQB1*05:xx and DQA1*01:xx-DQB1*06:xx dimers had DSA formation rates of 1.8% and 3.9%, respectively. The high immunogenic HLA-DQA1*03:02-DQB1*03:03 dimer formed haplotype with DRB1*09:01 (98%), whereas the low immunogenic HLA-DQA1*02:01-DQB1*03:03 dimer formed exclusively haplotype with DRB1*07:01. CONCLUSIONS:The DQA1*03:02-DQB1*03:03 dimer and the HLA-DRB1*09:01-HLA-DQA1*03:02-DQB1*03:03 haplotype turned out to be the most immunogenic in inducing HLA-DQ dnDSA in this Northern Han Chinese cohort.

关键词： inflammation   atopic dermatitis   neutrophilic asthma   Staphylococcus aureus   immunotherapeutic   atopic march   NETs   IL-36   skin   lung  

摘要： Patients with atopic dermatitis exhibit abundant Staphylococcus aureus skin colonization and an increased risk of atopic march diseases, including allergic rhinitis, food allergies, and asthma. We have previously shown that S. aureus skin exposure exacerbates allergic lung inflammation in an interleukin-36 receptor (IL-36R)-dependent manner. However, the cellular and molecular mechanisms by which S. aureus skin exposure and IL-36R signaling orchestrate the progression from skin to lung inflammation are unclear. Using a preclinical model of the atopic march, we found that S. aureus skin exposure promoted robust neutrophilic lung inflammation via keratinocyte-and lung epithelia-specific IL-36R signaling. Unexpectedly, neutrophil IL-36R signaling triggered neutrophil extracellular trap (NET) formation and augmented lung pathology. Importantly, anti-IL-36R monoclonal antibody (mAb) treatment prevented the development of neutrophilic lung inflammation. Collectively, our findings suggested that S. aureus skin exposure exacerbates lung inflammation via distinct IL-36R signaling mechanisms on epithelia and neutrophils, which has therapeutic potential in halting the progression of the atopic march.