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关键词： Autoimmune Diseases   Biomarkers   Inflammation   RNA   Real-Time Polymerase Chain Reaction  

摘要： Rheumatoid arthritis (RA) as a systemic autoimmune disease is often misdiagnosed in its early stages due to vague symptoms, delaying treatment and increasing the likelihood of severe complications including cardiovascular mortality. The main aim of work is to evaluate the serum levels of interleukin 6 (IL-6) and circular RNA DLGAP4 (circRNA-DLGAP4) in RA patients and healthy controls, also analyzing the correlations between all biomarkers to indicate whether those can be used as predictors for early diagnoses of *** hundred subjects were included, they were divided into two equal groups, 50-healthy matched individuals and 50 RA patients. For all participants, a venous blood sample for serum isolation was taken and analyzed for the serum level of IL-6 and circRNA-DLGAP4 as well as laboratory tests. For all patients, full clinical investigations have been performed as well as DAS28 and Modified Larsen radiological scoring have been calculated. Results revealed that there was a significant up-regulation of the concentration level of IL-6 (p=0.0001) and circRNA-DLGAP4 expression (p=0.0001) in the RA group as compared to healthy controls. Moreover, altered expression of circRNA-DLGAP4 showed a slight significant difference between patients with positive deformities with p=0.05. Serum levels of both IL-6 and circRNA-DLGAP4 increased with the severity of RA. Various correlations were detected of both IL-6 and circRNA-DLGAP4 with the associated RA parameters. It can be concluded that IL-6 and circRNA-DLGAP4 could have a potential role in RA pathogenesis and could act as possible biomarkers of RA for further studies to be applied for RA diagnostic purposes.

关键词： TRuC T-cell therapy   CD70   IL-15   renal cell carcinoma   solid tumor   T-cell immunotherapy   fratricide resistant   persistence  

摘要： Introduction Although T-cell immunotherapies have been effective in the treatment of hematological malignancies, solid tumors have proven challenging due to the immunosuppressive microenvironment and lack of viable target antigens. The immune checkpoint ligand CD70, overexpressed in several solid tumors, yet with limited expression in healthy tissue, has emerged as a promising immunotherapeutic *** This study describes the generation and preclinical characterization of ADP-520, a high-affinity, fratricide-resistant, CD70-targeted T-cell receptor fusion construct (TRuC) T-cell therapy enhanced with constitutively expressed mbIL-15, a membrane-bound fusion protein comprising interleukin-15 (IL-15) linked to full-length IL-15 receptor-alpha. The phenotypic distribution, expansion and persistence of ADP-520 TRuC T cells were measured in vitro under autonomous and antigen-dependent conditions, with the contributions of TCR and IL-15 signaling pathways ascertained using inhibition assays. Chronic antigen stimulation was used to evaluate exhaustion-resistance, while anti-tumor potency was explored both in vitro and in *** ADP-520 was found to have potent and antigen-specific activity against hematological and solid CD70-expressing tumors, without apparent fratricide or killing of bystander T cells despite CD70 expression by activated lymphocytes. Engineered co-expression of mbIL-15 augmented antigen-dependent expansion through pro-survival effects and enrichment of an early memory T-cell phenotype, thus enhancing tumor-autonomous, exogenous cytokine-free persistence and bolstering exhaustion resistance during chronic stimulation. mbIL-15 co-expression also enhanced intratumoral T-cell infiltration in vivo for potent and persistent antitumor *** These findings characterize ADP-520 as a first-in-class, CD70-targeted, fratricide-resistant autologous TRuC T-cell therapy leveraging native TCR signaling combined with constitutive IL-15 signalin

关键词： rheumatoid arthritis (RA)   IL-1   autoimmune diseases   cytokines   immunotherapy   monoclonal antibody  

摘要： Rheumatoid arthritis (RA), a chronic autoimmune disorder, imposes a substantial global health burden through elevated disability rates, systemic complications, and socioeconomic consequences. Chronic synovitis and progressive joint destruction characterize this disease, driven by dysregulated innate and adaptive immune responses that amplify synovial inflammation, osteoclastogenesis, and irreversible tissue damage. Aberrant activation of interleukin (IL) -1 family cytokines critically contributes to RA pathogenesis. These cytokines mediate dual mechanisms: pro-inflammatory agonists like IL-1 beta, IL-18, and IL-36 accelerate disease progression, whereas insufficient levels of anti-inflammatory antagonists such as IL-1Ra and IL-37 disrupt the balance required to suppress pathogenic cascades. Clinical trials evaluating IL-1-targeting biologics-including anakinra and canakinumab-have demonstrated robust early efficacy. However, late-stage interventions exhibit diminished therapeutic returns, largely due to irreversible joint damage and compensatory activation of redundant cytokine networks. These findings emphasize the need for precise patient stratification. Single-pathway IL-1 inhibition faces inherent limitations, driving the development of multi-target strategies to counteract cytokine redundancy and reduce therapeutic resistance. This review systematically analyzes the mechanistic roles of IL-1 family cytokines in RA, evaluates clinical outcomes and safety profiles of IL-1-targeted therapies, and proposes innovative strategies to advance RA treatment.

关键词： CXCL11   interferon-gamma   respiratory syncytial virus   T-cell immune response   viral replication  

摘要： Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory infections worldwide. However, no vaccine is available for children, and treatment options are limited. Identification of host factors pivotal to viral replication or immune-inflammatory regulation may inform the development of novel therapies, prophylaxes, or diagnoses. The chemokine (C-X-C motif) ligand 11 (CXCL11), which is drastically increased in RSV-infected respiratory tract samples, was previously found via a metatranscriptome screen, suggesting that CXCL11 may play an important role in RSV infection. In this study, we found that the CXCL11 expression level was negatively associated with the clinical disease severity of RSV infection. Using a CRISPR-Cas9-mediated knockout A549 cell line and a knockout mouse model, we investigated the role of CXCL11 in the pathogenesis of RSV. Our study indicated that CXCL11 restricted RSV infection by interfering with its polymerase activity to inhibit the RSV replication process. Additionally, CXCL11 was crucial for optimizing the IFN-gamma response. With a knockout mouse model, we confirmed that CXCL11 not only restricted RSV infection in vivo but was also associated with the severity of lung pathology. In addition, we found out that CXCL11 was indispensable for regulating Th1/Th2 balance, and the cytotoxic and antiviral phenotypes of the CD8+ T-cell response during RSV infection. Finally, we observed that supplementation with recombinant CXCL11 significantly improved the clinical outcomes of RSV infection in mice, as evidenced by reduced weight loss, lower viral titers, and attenuated lung inflammation. Overall, our studies suggested that CXCL11 functions in controlling RSV infection.

关键词： Helicobacter pylori   outer membrane virulence factor   pyroptosis   programmed cell death   H. pylori-related gastritis   H. pylori-related ulcer  

摘要： Background: This study aims to investigate the association between pyroptosis and the outer membrane virulence factor of H. pylori in patients with gastritis and ulcers. Methods: DNA, RNA, and protein were extracted from a single tissue sample taken from the antrum region of the stomach of volunteer patients. The expression of bacterial outer membrane virulence genes was analyzed at the gene level, and the expression levels of key pyroptosis markers were compared between H. pylori-infected and uninfected gastritis and ulcer patient groups. Results: H. pylori infection induced significant alterations in the expression levels of pyroptosis markers, including ASC, NLRP3, caspase-1, GSDMD, IL-18, and IL-1 beta, indicating a strong association with gastritis and ulcer pathology. Statistically significant correlations were observed between elevated levels of these markers and the activation of caspase-1 across different patient cohorts, supporting effective detection of pyroptosis. Both pro and active forms of caspase-1, GSDMD, IL-18, and IL-1 beta were assessed, revealing pyroptotic activity in specific patient samples. The vacA m2 allele showed a distinct ASC response in gastritis versus ulcer patients and was associated with increased GSDMD expression in ulcerative cases. Along with the babB gene, this allele appears to play a critical role in the interaction between H. pylori virulence and host pyroptotic responses. A statistically significant negative association was identified between the presence of the H. pylori alpA gene and Gasdermin D expression (odds ratio = 0, p < 0.01), suggesting that Gasdermin D was absent in all alpA-positive samples. Conclusion: This study provides novel insights into the interrelation between the virulence factors of H. pylori and pyroptosis in gastritis and ulcer diseases. Our findings demonstrate that H. pylori infection significantly alters the expression levels of pyroptosis markers, including ASC, NLRP3, caspase-1, GSDMD, IL-18, an

关键词： tumor biomarkers   canine lymphoma   recombinant canine interleukin-15   immunotherapy   quality of life  

摘要： Introduction: Canine lymphoma is a common hematopoietic malignancy with variable response to standard chemotherapy. Interleukin-15 (IL-15) is known to enhance cytotoxic lymphocyte activity, and this study aimed to evaluate the efficacy and safety of a recombinant canine IL-15 (rcIL-15) as an adjunct to chemotherapy in dogs with lymphoma. Methods: A total of 61 dogs diagnosed with lymphoma were enrolled in a 12-week clinical study. The test group received rcIL-15 in combination with standard chemotherapy, while the control group received chemotherapy alone. Outcome measures included tumor response rates, tumor biomarker levels (TK-1, LDH, beta 2-microglobulin), quality of life (QOL) assessments, and adverse event monitoring. Results: Of the 61 dogs enrolled, 37 completed the study. The test group demonstrated a higher overall response rate (complete + partial response: 77.8%) compared to the control group (57.9%). Disease progression was observed in 16.7% of dogs in the test group versus 31.6% in controls. Tumor biomarkers were significantly reduced in the test group: TK-1 at 8 weeks (p < 0.0001), LDH at 12 weeks (p = 0.005), and beta 2-microglobulin at both 8 and 12 weeks (p < 0.05). IFN-gamma levels remained stable. QOL parameters, including appetite, activity, and happiness, showed significant improvement. Adverse events were mild, mostly gastrointestinal, and manageable. Discussion: Adjunctive rcIL-15 therapy improved tumor response, reduced biomarker levels, and enhanced QOL with an acceptable safety profile. These findings support the potential of rcIL-15 as a safe and effective immunotherapeutic adjunct for canine lymphoma, meriting further investigation in larger-scale trials.

关键词： Cardiac hypertrophy   IL-21   STAT3  

摘要： Increased cytokine secretion from immune cells is often associated with cardiac remodeling and heart failure due to pressure overload. Several reports suggest that the IL-21/IL-21 receptor (IL-21R) signaling pathway may play a critical role in heart failure progression, but the exact mechanism remains unclear. In this study, isoproterenol (ISO) was used to induce heart failure in mice and found that ISO injection caused significant upregulation of IL-21 and the IL-21R in the heart of mice. Subsequently, IL-21 receptor-deficient (IL-21R-/-) mice were used to evaluate the cardioprotective effects of IL-21/IL-21R. Importantly, we found a significant reduction in myocardial hypertrophy, inflammation, and apoptosis in ISO-treated IL-21R-/- mice compared to WT mice. Furthermore, the frequency of CD4+IFN-gamma+ cells was significantly reduced in ISO-treated IL-21R-/- mice. Co-culture studies showed that the adhesion rate of CD4+ T cells isolated from IL-21R-/- to cardiac fibroblasts was significantly reduced compared to co-cultures isolated from WT mice. Accordingly, significant downregulation of alpha-SMA was detected in cardiac fibroblasts when cocultured with CD4+ T cells isolated from IL-21R-/- mice. Furthermore, IL-21 could directly induce cardiomyocyte hypertrophy and apoptosis and exacerbate ISO-induced myocardial damage through activation of STAT3 signaling pathway. Our study demonstrates the mechanism of IL-21 and its receptor in the progression of myocardial hypertrophy and fibrosis and highlights that the absence of IL-21R may provide protection against myocardial damage, thus providing a new potential therapeutic target for the treatment of heart failure.

关键词： XBP1   Periodontitis   Pyroptosis   Th17/Treg balance   IL-17 Signaling  

摘要： Periodontitis is a long-lasting inflammatory condition that significantly affects people's quality of life. This research focused on examining the function and underlying mechanisms of X-box binding protein 1 (XBP1) in the pathogenesis of periodontitis. In vitro and in vivo models of periodontitis were established using lipopolysaccharide (LPS). The viability and apoptosis of periodontal ligament stem cells (PDLSCs) were assessed using the Cell Counting Kit-8 and flow cytometry assays, respectively. Reverse transcription-quantitative PCR, western blot, and enzyme-linked immunosorbent assays were employed to measure the levels of inflammatory factors and mediators associated with T helper 17 (Th17)/regulatory T cell (Treg) balance, pyroptosis, and the interleukin-17 (IL-17) pathway. Histological and immunohistochemical analyses were conducted to evaluate tissue damage and bone resorption markers. The IL-17 pathway was activated with SR0987 to explore the interactions between XBP1 and IL-17 signaling. XBP1 knockdown reduced apoptosis, pyroptosis, and inflammation, as indicated by lower levels of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1 beta, IL-18) and pyroptosis-related proteins (ASC, GSDMD-N, NLRP3). XBP1 knockdown alleviated tissue damage, inflammatory cell infiltration, and bone destruction in rat models of periodontitis. XBP1 knockdown notably restored the Th17/Treg imbalance by suppressing Th17 differentiation and promoting Treg differentiation. Mechanistically, XBP1 knockdown inhibited the IL-17 signaling pathway, and IL-17Activator SR0987 significantly reversed the beneficial effects of XBP1 knockdown on periodontitis. XBP1 knockdown alleviated periodontitis by inhibiting the IL-17 signaling pathway, implying that XBP1 could serve as a promising therapeutic target for managing periodontal conditions.

关键词： 免疫球蛋白   凝血四项   肾病综合征  

摘要： 探讨在肾病综合征(NS)诊断中,血清免疫球蛋白结合凝血四项的应用价值。方法 选取NS患者62例作为肾病组,30名健康志愿者作为对照组,对入组对象进行血样采集和测定,包括血清免疫球蛋白[免疫球蛋白G(IgG)、免疫球蛋白M(IgM)、免疫球蛋白A(IgA)]、凝血四项[凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血时间(TT)、纤维蛋白原(Fg)]、肾功能指标[肌酐(Cr)、血尿酸(UA)、估算肾小球滤过率(eGFR)]。根据对比结果完成组间对比、相关性和ROC曲线分析。结果 肾病组血清免疫球蛋白三项指标、凝血四项指标与肾功能三项指标测定结果均异于对照组(P<0.05);肾病失代偿组血清免疫球蛋白三项指标、凝血四项指标与肾功能三项指标测定结果均异于代偿组(P<0.05);免疫球蛋白、凝血四项与肾功能指标均表现出相关性(P<0.05);ROC曲线分析,免疫球蛋白联合凝血四项的曲线下面积(AUC)为0.899,敏感度和特异度分别为95.16%、80.65%。结论 免疫球蛋白联合凝血四项在NS诊断中具有较高应用价值。

关键词： COVID-19   代谢组学   细胞因子   犬尿氨酸  

摘要： 目的 分析新型冠状病毒感染（coronavirus disease 2019,COVID-19）患者多种生物标本代谢水平的变化，挖掘COVID-19疾病进展的生物标志物，为构建预测模型和发现潜在治疗靶点提供理论依据。方法 采集2022年12月—2023年1月于北京大学第三医院呼吸与危重症医学科、普外科和重症监护病房住院的45例COVID-19患者的血清、尿液和粪便样本，使用液相色谱质谱联用方法检测标本的代谢物水平。采用差异倍数（fold change,FC）、t检验和Wilcoxon秩和检验筛选差异代谢物。对代谢物与血清细胞因子水平进行相关性分析并计算斯皮尔曼等级相关系数。结果 色氨酸代谢通路的犬尿喹啉酸在重症患者血清中水平上调（FC=2.47,P=0.035），喹啉酸在死亡结局患者血清中水平上调（FC=2.99,P=0.010）。血清犬尿喹啉酸在出现多脏器衰竭（FC=4.74,P=0.013）的患者中代谢水平上调，尿液黄尿酸在出现肾衰竭的患者中代谢水平上调（FC=4.40,P=0.019）。相关性分析结果显示，重症患者血清犬尿喹啉酸与辅助性T细胞（r=-0.75,P<0.001）有较强负相关，死亡结局患者血清喹啉酸和总补体（r=-0.88,P=0.007）有较强负相关。COVID-19患者在血清、尿液和粪便中均表现出犬尿氨酸代谢途径上调的趋势。结论 犬尿氨酸代谢通路在COVID-19疾病进展和免疫调控中具有重要作用，犬尿喹啉酸、喹啉酸等代谢物的水平失调可能与免疫系统激活和不良预后有关。