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关键词： adipose tissue IL-23   FBG   HbA1c   HOMA-IR   inflammatory markers   obesity  

摘要： IL-23, a proinflammatory cytokine, plays a role in the development of inflammatory diseases. However, the association between IL-23 expression in adipose tissue (AT) and glycemic changes in obesity remains unclear. This cross-sectional study aimed to examine the relationship of adipose tissue IL-23 (AT-IL-23) expression with other inflammatory mediators within the same compartment and insulin resistance markers fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) in overweight/obese individuals. Fat biopsies were collected from 10 individuals with a body mass index (BMI) < 25kg/m2 and 51 individuals with a BMI > 25kg/m2 and were analyzed for IL-23 and other inflammatory markers using qRT-PCR. Inflammatory markers, including CD16, CD11c, CCR2, CCR5, TNF-alpha, IL-1 beta, IL-2, IL-12, CCL8, CCL19, and CXCL9, were positively correlated with IL-23 in the AT-compartment in the obesity context. Notably, AT-IL-23 was correlated positively with FBG, HbA1c, and homeostasis model assessment of insulin resistance (HOMA-IR), while negatively correlating with adiponectin. These findings suggest that AT-IL-23 is associated with metabolic inflammation and insulin resistance in obesity, suggesting it may be of interest for future biomarker studies.

关键词： Infectious disease and host defense   Innate immunity and inflammation   Mucosal immunology  

摘要： Respiratory viral infections establish tissue-resident memory T cells (TRM) in the lung, which provide optimal protection against subsequent infections, though the underlying mechanisms are incompletely understood. Here, we demonstrate in a mouse model of heterosubtypic influenza infection that lung TRM attenuate inflammation by macrophages during secondary versus primary responses, in part, through production of the immunoregulatory cytokine IL-10. During secondary infections, lung TRM were the predominant producers of early IL-10;inhibiting early IL-10 signaling resulted in increased macrophage-mediated inflammation, morbidity, and lung pathology. Moreover, lung TRM were shown to directly modulate lung macrophage responses and polarization in depletion experiments. Finally, IL-10 enhanced IFN-gamma production by lung memory CD8+ T cells. Human influenza-specific TRM isolated from lungs recapitulated robust IL-10 expression associated with augmented effector responses of murine TRM. These data support a dual role of TRM in coordinating in situ secondary responses-augmenting effector responses for robust viral clearance while dampening inflammation to limit tissue damage.

关键词： IFN gamma   immunotherapy   melanoma   NK cells  

摘要： Melanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)-based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer-(NK) cells is increasingly recognized. However, resistance mechanisms to both CTL- and NK-cell-mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK-cells in anti-melanoma immunity, we performed 2D and 3D co-culture-based cytotoxicity assays under varying conditions. Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK-cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK-cell-mediated killing (NKmK). We found that cytokines such as IFN gamma play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFN gamma, significantly reduced melanoma cell resistance to NKmK. This study provides potential strategies to overcome resistance to NK-cell-based immunotherapies and offers novel insights into melanoma immune escape mechanisms.

关键词： 反复种植失败   子宫内膜容受性   白介素IL-1β   核因子NF-κB   血清糖皮质激素诱导激酶1   同源框基因A10  

摘要： 目的 探讨白介素IL-1β及血清糖皮质激素诱导激酶1（SGK1）在反复种植失败（RIF）患者子宫内膜组织中的表达特征及其通过HOXA10调控子宫内膜容受性的分子机制。方法 收集2021年1月至2022年12月在常州市妇幼保健院就诊的RIF患者（试验组，n=9）或因男方因素不孕但成功妊娠女性（对照组，n=8）的分泌中期子宫内膜组织。采用qPCR检测两组子宫内膜组织中IL-1β的mRNA水平以及IL-1β和SGK1对HOXA10表达的影响；蛋白质印迹技术检测两组子宫内膜组织中SGK1和HOXA10的蛋白水平以及Ishikawa细胞中p65、p-p65、SGK1、HOXA10蛋白在相应刺激下的表达水平。结果 与对照组相比，试验组分泌中期子宫内膜组织中IL-1β mRNA及SGK1的蛋白水平升高（1.000 ± 0.043 vs 1.619 ± 0.075，P<0.001；0.656 ± 0.053 vs 1.091 ± 0.064，P<0.001）；而HOXA10的蛋白水平降低（1.159 ± 0.115 vs 0.595 ± 0.060，P<0.001）。IL-1β以浓度依赖性方式激活NF-κB p65磷酸化并上调SGK1的表达，而NF-κB活性抑制剂PDTC可逆转此效应。SGK1抑制Ishikawa细胞中HOXA10 mRNA和蛋白的表达，SGK1特异性siRNA可部分挽救IL-1β对HOXA10的抑制作用。结论 RIF患者分泌中期子宫内膜组织中异常高表达的IL-1β，可能通过激活NF-κB/SGK1通路抑制HOXA10的表达，损害子宫内膜的容受性，导致反复种植失败的发生。

关键词： NK cell   CAR NK cell   Cord blood   Progenitor cell   IL-15   Adoptive cell therapy  

摘要： Cord blood (CB)-derived chimeric antigen receptor (CAR) natural killer (NK) cells have demonstrated significant antitumor efficacy. We recently reported that CB-derived CAR NK cells predominantly originate from CD7+CD56-CD34-HLA-DR-Lin- NK cell precursors in CB. Here, we demonstrate that stimulating the interleukin (IL)-15 receptor on these NK precursors enhances the production of CAR NK cells from CB cells. In CB CD56-CD34-HLA-DR-Lin- cells, the IL-15 receptor was exclusively expressed on CD7+ NK cell precursors. Using K562 feeder cells that express not only 4-1BB ligand and membrane-bound (mb) IL-21 but also mbIL-15 significantly increased the production of mature NK cells from the purified NK cell precursors or T cell-depleted CB cells. The in vitro and in vivo antitumor effects of CAR NK cells generated using K562 feeder cells that express mbIL-15 were comparable to those of CAR NK cells produced using K562 feeder cells that do not express mbIL-15. These results suggest that K562 feeder cells expressing 4-1BBL, mbIL-21, and mbIL-15 can increase the production of CAR NK cells from CB cells while maintaining their cytotoxic potential. This method could also be useful for expanding NK cells from CB for any type of adoptive NK cell therapy with or without CAR transduction.

摘要： Background:Thyroid nodules are common in clinical practice, with malignancy detected in about 5% of cases. Current risk-stratification approaches, which rely on sonographic features and cytopathological assessment, have notable limitations, especially for indeterminate nodules categorized as Bethesda III. Aims:To address these diagnostic challenges, this study evaluated the utility of preoperative serum interleukin (IL)-17A and calprotectin levels as potential biomarkers for distinguishing malignant from benign Bethesda III thyroid nodules. Study Design:This single-center prospective methodological study. Methods:In this prospective study, 76 patients with Bethesda III nodules scheduled for thyroidectomy were enrolled. Based on histopathological findings, nodules were classified as benign (n = 41) or malignant (n = 35). Comprehensive patient information was collected, including demographics, medical history, and detailed clinical parameters related to nodule characteristics and laboratory results. Circulating biomarkers measured included thyroid-stimulating hormone, free T3, free T4, thyroglobulin (TG), anti-TG, anti-thyroid peroxidase, calcitonin, IL-17A, and calprotectin. Results:Patients with malignant nodules (n = 35) exhibited significantly higher preoperative IL-17A and calprotectin levels compared with those with benign nodules (n = 41) ( < 0.001 and = 0.038, respectively). receiver operating characteristic analysis demonstrated promising diagnostic performance for IL-17A [area under the curve (AUC) = 0.733] and calprotectin (AUC = 0.639). Conclusion:IL-17A and calprotectin emerge as promising biomarkers for refining Bethesda III nodule stratification. Incorporating these inflammatory markers into existing diagnostic protocols may substantially reduce unnecessary surgical interventions, thereby alleviating patient anxiety, surgical risks, and healthcare costs.

摘要： Background We sought to determine the prevalence, clinical impact, neutralizing capacity, and cross-reactivity of pre-existing antibodies to infliximab and adalimumab in antitumor necrosis factor (TNF) treatment-naive patients with active luminal crohn disease. Methods The prevalence of antibodies to infliximab and adalimumab at entry to the "Personalised Anti-TNF Therapy in Crohn's Disease Study" (PANTS) were measured using the drug-tolerant IDKmonitor Total antidrug antibody ELISAs. Neutralizing capacity in positive cases was determined using iLite (TM) cell-based assays. Results Pre-existing antibodies to infliximab were more common (6.3%, 96/1525 vs 2.4%, 36/1525, P < 0.01) and detectable at higher concentrations [median (IQR) 23.9 (14.2-55.2) AU/mL vs 7.2 (6.3-10.4) AU/mL, P < 0.0001] to infliximab than adalimumab. A few patients [1.3% (95% CI 0.6-1.8) 20/1525] had antidrug antibody reactivity to both drugs. None of the detected antidrug antibodies had demonstrable anti-TNF neutralizing capacity. No associations were seen between pre-existing antibody positivity, adverse drug reactions, drug levels, or response status at weeks 14 or 54 or subsequent immunogenicity. Cross-reactivity with rheumatoid factor and antimouse antibodies was detected (>10 IU/mL) in 6.6% (95% CI 3.2-13.0) (7/106) and 17.0% (95% CI 10.5-25.2) (19/112) of patients with pre-existing antibodies. Conclusions Pre-existing antidrug antibodies are common but do not neutralize anti-TNF drug activity in vitro, promote drug clearance, or influence clinical response to anti-TNF drugs. Further work is required to understand this cross-reactivity and to determine the exact nature of the antibodies detected in drug-naive individuals.