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关键词： 慢性阻塞性肺疾病   贫血   细胞因子   铁调素   氧化应激  

摘要： 慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）是一种异质性肺部疾病，是由于气道异常（支气管炎、细支气管炎）和/或肺泡异常（肺气肿）引起的慢性呼吸道症状（咳嗽、咳痰、呼吸困难和/或急性加重），导致持续的、进行性加重的气流受限[1]。目前COPD已成为我国第三大死亡原因，我国20岁以上的COPD患病人数为9990万，患病率为8.6％[2]。COPD带来了沉重的经济、社会和医疗保健负担[3]。由于肺部持续炎症迁延发展至全身慢性炎症，COPD患者常伴有多种肺外合并症，包括贫血、心力衰竭、糖尿病、骨质疏松等，其中合并贫血的患病率为7.5％～33％[4-5]。既往多项研究表明，与单纯COPD患者相比，COPD合并贫血患者的呼吸困难更严重，运动耐力下降更明显，住院时长延长，死亡风险增加[6-8]。本文总结了COPD患者发生贫血的危险因素、发病机制，希望为临床治疗COPD合并贫血患者提供新的思路。

关键词： IL-17A   Th17   neurodegenerative diseases   neuro-inflammation   multiple sclerosis   Alzheimer's disease   Parkinson's disease  

摘要： IL-17A has been implicated as a critical pro-inflammatory cytokine in the pathogenesis of autoimmune and neurodegenerative disorders. Emerging evidence indicates its capacity to activate microglial cells and astrocytes, subsequently inducing the production of inflammatory mediators that exacerbate neuronal injury and functional impairment. Clinical observations have revealed a demonstrated association between IL-17A concentrations and blood-brain barrier (BBB) dysfunction, creating a pathological feedback loop that amplifies neuro-inflammatory responses. Recent advances highlight the cytokine's critical involvement in neurodegenerative disorders through multiple molecular pathways. Therapeutic interventions utilizing monoclonal antibodies (mAbs) against IL-17A or its cognate receptor (IL-17R) have shown promising clinical potential. This review systematically examines the IL-17A-mediated neuro-inflammatory cascades;the mechanistic contributions to neurodegenerative pathology in the established disease models including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis;and current therapeutic strategies targeting the IL-17A signaling pathways. The analysis provides novel perspectives on optimizing cytokine-directed therapies while identifying the key challenges and research priorities for translational applications in neurodegeneration.

关键词： machine learning   T-cell response   immunology   predictive modeling  

摘要： Therapeutic proteins are in high demand due to their significant potential, driving continuous market growth. However, a critical concern for therapeutic proteins is their ability to trigger an immune response, while some treatments rely on this response for their therapeutic effect. Therefore, to assess the efficacy and safety of the drug, it is pivotal to determine its immunogenicity potential. Various experimental methods, such as cytokine release or T-cell proliferation assays, are used for this purpose. However, these assays can be costly, time-consuming, and often limited in their ability to screen large peptide sets across diverse major histocompatibility complex (MHC) alleles. Hence, this study aimed to develop a computational classification model for predicting the release of interferon-gamma based on the peptide sequence and the MHC class II (MHC-II) allele pseudo-sequence, which represents the binding environment of the MHC-II molecule. The dataset used in this study was obtained from the Immune Epitope Database and labeled as active or inactive. Among the approaches explored, the random forest algorithm combined with letter-based encoding resulted in the overall best-performing model. Consequently, this model's generalizability to other T-cell activities was further evaluated using a T-cell proliferation dataset. Furthermore, feature importance analysis and virtual single-point mutations were conducted to gain insights into the model's decision-making and to improve the interpretability of the model.

关键词： IL-17RA   colon cancer   EMT   anti-tumor immunity   IL-17   CRC   mycobiome   immunotherapy   inflammation  

摘要： Expression of interleukin (IL)-17 family cytokines is associated with tumor-promoting inflammation. We found that low expression of IL17RA associated with worse prognosis in late-stage colorectal cancer (CRC) patients. Deletion of Il17ra in intestinal epithelial cells (IECs) in a murine model of CRC enhanced epithelialto-mesenchymal transition (EMT) via increased expression of the epidermal growth factor receptor and subsequent activation of the kinase Src. Yet, these mice were protected from metastatic disease;Il17ra deletion impaired intestinal barrier function and enhanced systemic fungal invasion and associated immunity. However, in macrophages, IL-17RA was required for spleen tyrosine kinase (Syk) activation upon fungal-induced dectin-1 engagement, and Il17ra ablation impaired IL-18 release and protective CD8+ T cell-mediated antitumor immunity. Combining recombinant IL-17 and heat-killed Candida albicans rendered colorectal tumors sensitive to a-PD-1 treatment in a model of microsatellite stable (MSS) CRC. Thus, IL-17RA engages two distinct tumor-suppressive mechanisms in CRC, linking EMT and fungal-induced anti-tumor immunity during tumor progression.

关键词： 肥胖   IgA肾病   孟德尔随机化   因果关系   体质量指数  

摘要： 目的：基于孟德尔随机化（MR）分析探讨肥胖相关指标与免疫球蛋白A肾病（IgAN）间潜在的因果关联。方法：提取体质量指数（BMI）、全身脂肪量、体脂率、躯干脂肪量、躯干脂肪率、腰围、臀围、腰臀比和IgAN的大规模全基因组关联研究（GWAS）的汇总数据，以逆方差加权法（IVW）作为主要结果进行双向MR分析。通过Cochran's Q检验、MR-Egger截距检验、MR-PRESSO检验和留一法证实结果的准确性和稳定性。结果：基因预测的BMI(OR=1.202, 95%CI:1.121～1.288, P=2.009×10-7)、全身脂肪量(OR=1.215, 95%CI:1.129～1.307, P=1.827×10-7)、体脂率(OR=1.144, 95%CI:1.023～1.279, P=1.864×10-2)、躯干脂肪量(OR=1.227, 95%CI:1.136～1.326,P=1.994×10-7)、躯干脂肪率（OR=1.113,95%CI:1.011～1.227,P=0.030）、腰围(OR=1.255,95%CI:1.148～1.371,P=5.712×10-7)、臀围(OR=1.175,95%CI:1.085～1.274,P=7.997×10-5)与发生IgAN的风险呈正相关，但尚无证据显示腰臀比（OR=1.081,95%CI:0.855～1.368,P=0.516）与IgAN之间存在可靠的因果关系。这些结果在一系列敏感性分析中是可靠的。此外，反向MR分析显示，IgAN可能不会增加肥胖的风险。结论：肥胖会增加罹患IgAN的风险，预防肥胖可能是降低IgAN风险的重要策略。

关键词： Highlights   immunity  

摘要： Natural killer (NK) cells possess both innate and adaptive features. Here, we investigated NK cell activation across tissues during cytomegalovirus infection, which generates antigen-specific clonal expansion and long-lived memory responses. Longitudinal tracking and single-cell RNA sequencing of NK cells following infection revealed enhanced activation in the spleen, as well as early formation of a CD69lo precursor population that preferentially gave rise to adaptive NK cells. Splenic NK cells demonstrated heightened tumor necrosis factor alpha (TNF-a) signaling and increased expression of the receptor TNFR2, which coincided with elevated TNF-a production by splenic myeloid cells. TNFR2-deficient NK cells exhibited impaired interferon gamma (IFN-g) production and expansion. TNFR2 signaling engaged two distinct nuclear factor kB (NF-kB) signaling arms-innate effector NK cell responses required canonical NF-kB signaling, whereas non-canonical NF-kB signaling enforced differentiation of CD69lo adaptive NK cell precursors. Thus, NK cell priming in the spleen during viral infection promotes an innate-to-adaptive transition, providing insight into avenues for generating adaptive NK cell immunity across diverse settings.

摘要： Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*02:01+ adult patients with mUM. Here we investigate the impact of tumor-associated macrophages (TAM) on ImmTAC activity. In vitro, M2 macrophages inhibit ImmTAC-mediated tumor-killing in a dose-dependent and contact-dependent manner. Accordingly, high baseline intratumoral TAM-to-T cell ratios correlate with shorter OS (HR = 2.09, 95% CI, 1.31-3.33, p = 0.002) in tebentafusp-treated mUM patients from a phase 2 trial. By contrast, IL-2 conditioning of T cells overcomes M2 macrophage-mediated suppression in vitro, while ImmTAC treatment leads to M2-to-M1 macrophage reprogramming both in vitro and in tebentafusp-treated mUM patients. Overall, we show that tebentafusp reshapes the tumor microenvironment to enhance anti-tumor T cell activity, whilst combining tebentafusp with IL-2 may enhance benefit in patients with high levels of TAM.

关键词： 非洲猪瘟病毒   原核表达   pH108R蛋白   多克隆抗体  

摘要： 制备非洲猪瘟病毒（ASFV）pH108R蛋白的多克隆抗体。首先，通过分析H108R基因的跨膜区（TR）并去除该区域，构建了pH108R重组蛋白的原核表达质粒pET-22b-H108RΔTR，并经酶切鉴定验证成功构建此质粒。随后，将质粒转化至大肠杆菌BL21(DE3)感受态细胞中，通过IPTG诱导表达pH108R蛋白。SDS-PAGE检测显示蛋白以包涵体形式表达，经镍柱亲和层析法纯化后，用于免疫豚鼠制备多克隆抗体。免疫印迹、间接免疫荧光和免疫共沉淀试验结果表明，制备的多克隆抗体能够特异地识别ASFV感染的肺泡巨噬细胞中表达的pH108R蛋白。本研究为深入研究ASFV pH108R蛋白的生物学功能提供了有效的检测工具。

关键词： SARS-CoV-2   GWAS   COVID-19   severity   HLA   KIF19  

摘要： The COVID-19 pandemic has had a devastating impact, with more than 7 million deaths worldwide. Advanced age and comorbidities partially explain severe cases of the disease, but genetic factors also play a significant role. Genome-wide association studies (GWASs) have been instrumental in identifying loci associated with SARS-CoV-2 infection. Here, we report the results from a >820 K variant GWAS in a COVID-19 patient cohort from the hospitals associated with IIS Biobizkaia. We compared intensive care unit (ICU)-hospitalized patients with non-ICU-hospitalized patients. The GWAS was complemented with an integrated phenotype and genetic modeling analysis using HLA genotypes, a previously identified COVID-19 polygenic risk score (PRS) and clinical data. We identified four variants associated with COVID-19 severity with genome-wide significance (rs58027632 in KIF19;rs736962 in HTRA1;rs77927946 in DMBT1;and rs115020813 in LINC01283). In addition, we designed a multivariate predictive model including HLA, PRS and clinical data which displayed an area under the curve (AUC) value of 0.79. Our results combining human genetic information with clinical data may help to improve risk assessment for the development of a severe outcome of COVID-19.