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摘要： Epitope-based vaccines are promising therapeutic modalities for infectious diseases and cancer, but identifying immunogenic epitopes is challenging. The vast majority of prediction methods only use amino acid sequence information, and do not incorporate wide-scale structure data and biochemical properties across each peptide-MHC. We present ImmunoStruct, a deep-learning model that integrates sequence, structural, and biochemical information to predict multi-allele class-I peptide-MHC immunogenicity. By leveraging a multimodal dataset of ∼27,000 peptide-MHCs, we demonstrate that ImmunoStruct improves immunogenicity prediction performance and interpretability beyond existing methods, across infectious disease epitopes and cancer neoepitopes. We further show strong alignment with assay results for a set of SARS-CoV-2 epitopes, as well as strong performance in peptide-MHC-based cancer patient survival prediction. Overall, this work also presents a new architecture that incorporates equivariant graph processing and multimodal data integration for the long standing task in immunotherapy.

关键词： Liver cirrhosis   CD8(+) T cell   TCR   Bystander activation   IL-15  

摘要： The development and progression of liver cirrhosis are considerably influenced by immune processes, with CD8 + T cells playing a key role. Notably, cytokines can activate bystander CD38 + HLA-DR + CD8 + T cells without the need for T cell receptor (TCR) stimulation. However, their role in liver fibrosis remains controversial. This study aimed to investigate the pathological role of CD38 + HLA-DR + CD8 + T cells in cirrhosis progression and explore the mechanisms that regulate their functions. Peripheral blood mononuclear cells (PBMCs) were extracted from patients with cirrhosis and healthy donors, and the ratio of CD38(+)HLA-DR(+)CD8(+) T cells was assessed through flow cytometry. The relationship between the prevalence of these cells and certain clinical indicators was investigated. Additionally, CD8(+) T cells from healthy donors were used to examine the impact of cytokine IL-15 on CD38(+)HLA-DR(+)CD8(+) T cells, utilizing flow cytometry and in vitro cytotoxicity assays. Finally, the signaling pathways involved in IL-15 activation of CD38(+)HLA-DR(+)CD8(+) T cells were examined in vitro. The proportion of CD38(+)HLA-DR(+)CD8(+) T cells was significantly increased in patients with cirrhosis compared to healthy donors and exhibited a strong correlation with disease severity, hepatic damage, and inflammation in cirrhosis. IL-15-stimulated CD38(+)HLA-DR(+)CD8(+) T cells from healthy donors demonstrated proliferation and overexpression of cytotoxic molecules, exhibiting NKG2D- and FasL-dependent innate-like cytotoxicity without TCR activation. Notably, IL-15 did not alter the mitochondrial function of these cells. The JAK/STAT5 and PI3K/mTOR pathways were found to play a critical role in IL-15-induced innate-like cytotoxicity. These findings suggested that CD38(+)HLA-DR(+)CD8(+) T cells from patients with cirrhosis contribute to immune-mediated liver injury. Furthermore, the JAK/STAT5 and PI3K/mTOR pathways were essential for IL-15-induced activation of CD38(+)HLA-DR(+

关键词： 急性淋巴细胞白血病   免疫分型   预后   白介素15   基质金属蛋白酶2  

摘要： 目的：研究血清白介素15（IL-15）、基质金属蛋白酶2（MMP-2）水平与儿童急性淋巴细胞白血病（ALL）免疫分型和预后的关系。方法：选取2018年7月至2021年8月在山东第一医科大学附属省立医院就诊的ALL患儿154例为白血病组，根据免疫分型分为早期前B-ALL组（112例）、前B-ALL组（29例）和成熟B-ALL组（13例）。另选取同期在该院体检健康的154例儿童为健康对照组。检测血清IL-15，MMP-2水平；收集白血病组临床资料；随访并统计白血病组患儿的生存情况；采用多因素Cox回归分析白血病组患儿死亡的影响因素；采用Kaplan-Meier法分析血清IL-15，MMP-2表达下白血病组患儿生存率的变化。结果：与健康对照组相比，白血病组血清IL-15水平降低，MMP-2水平升高（P<0.05）。早期前B-ALL组、前B-ALL组、成熟B-ALL组血清IL-15水平依次降低，血清MMP-2水平依次升高（P<0.05）。死亡组患儿有微小残留病变、有MLL基因重排所占比例和血清MMP-2高于生存组患儿，血清IL-15低于生存组患儿（P<0.05）。IL-15低表达患儿的生存率低于IL-15高表达患儿（62.32% vs 80.00%，P<0.05），MMP-2高表达患儿的生存率低于MMP-2低表达患儿（63.01% vs 80.25%，P<0.05）。有微小残留病变（HR=2.476）、有MLL基因重排（HR=2.069）、低水平IL-15（HR=0.462）以及高水平MMP-2（HR=2.855）是ALL患儿死亡的影响因素（P<0.05）。结论：ALL患儿血清IL-15水平较低，MMP-2水平较高，与免疫分型和预后生存有关。

关键词： 慢性阻塞性肺疾病   焦虑抑郁   海马体体积   中性粒细胞与淋巴细胞比  

摘要： 目的 探讨脑海马体体积（HV）、中性粒细胞与淋巴细胞比值（NLR）与慢阻肺合并焦虑和/或抑郁是否存在相关性。方法 选取2023年9月—2024年8月 在云南省第三人民医院呼吸与危重症医学科住院治疗的98例慢阻肺患者为观察对象，其中A组（单纯慢阻肺组）34例和B组（慢阻肺合并焦虑和/或抑郁组）64例，记录并比较两组临床资料及HV、NLR水平，采用Logistic回归模型分析慢阻肺合并焦虑和/或抑郁的影响因素，随后进一步绘制受试者操作特征（ROC）曲线评估预测效能。结果 慢阻肺合并焦虑和/或抑郁组吸烟人数、NEUT、NLR、CRP水平均高于单纯慢阻肺组，FEV1%pred、FEV1/FVC%、HV水平低于单纯慢阻肺组，差异有统计学意义（P＜0.05）。多因素回归分析结果显示NLR、HV均为慢阻肺患者合并焦虑和/或抑郁的影响因素（P＜0.05）。ROC 曲线结果显示，HV、NLR及两者联合的AUC分别为0.720，0.848，0.869，通过最佳截断值得出了HV、NLR及两者联合最佳的灵敏度及特异度，敏感度分别为70.6%，82.8%和92.2%，特异度分别为70.3%，79.4%和70.6%，HV、NLR及二者联合均对慢阻肺患者并发焦虑和/或抑郁具有一定的预测能力（P＜0.05）。结论 慢阻肺患者发生焦虑抑郁与多种因素有关，HV、NLR 联合检测对慢阻肺合并焦虑抑郁的诊断有一定价值。

关键词： SARS-CoV-2   HLA-B allotype   HLA-C allotype   T-cell epitope   vaccine  

摘要： Since the outbreak of novel coronavirus pneumonia (COVID-19), numerous T-cell epitopes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteome have been reported. However, most of the identified CD8+ T-cell epitopes have been restricted primarily by HLA-A allotypes. The epitopes restricted by HLA-B and HLA-C allotypes are limited. This study focuses on the screening of T-cell epitopes restricted by 13 prevalent HLA-B and 13 prevalent HLA-C allotypes, which cover over 70% and 90% of the Chinese and Northeast Asian populations, respectively. Totally, 67 HLA-B restricted and 53 HLA-C restricted epitopes were validated as immunogenic epitopes with a herd predominance rate by peptide-PBMCs ex vivo coculture experiments using the PBMCs from convalescent Chinese cohort. In addition, 26 transfected cell lines expressing indicated HLA-B or HLA-C allotype were established, and used in the competitive peptide binding assays to define the affinities and cross-restriction of each validated epitope binding to HLA-B or HLA-C allotypes. These data will facilitate the design of T-cell-directed vaccines and SARS-CoV-2-specific T-cell detection tools tailored to the Northeast Asian population. The herd test of functionally validated T-cell epitopes, and the competitive peptide binding assay onto cell line array expressing prevalent HLA allotypes may serve as an additional criterion for selecting T-cell epitopes used in vaccine.

摘要： Xanthine oxidoreductase (XOR) inhibitors are used to treat gout, inhibiting uric acid production, which causes clinical symptoms. Commonly used XOR inhibitors are the small molecule febuxostat (Fbx) and the purine analogue allopurinol (Allo). Recent studies show that XOR inhibitors can reduce mature interleukin (IL)-1 beta production by activated macrophages. This effect is not due to reduced uric acid crystal formation, which can induce NLRP3 inflammasome activation, but an independent effect. Fbx and Allo have been used interchangeably in in vitro studies to highlight the role of XOR in pro-inflammatory macrophage function. Here, we analysed the effects of Fbx and Allo on pro-inflammatory macrophage signatures. Both XOR inhibitors maintain pro-inflammatory macrophage metabolic and phenotypic hallmarks. However, only Fbx reduces the activity of caspase-1 and the release of IL-1 beta by preventing inflammasome assembly in macrophages isolated from both mice and humans. Our study identified an Fbx-specific reduction in IL-1 beta production, which could be used clinically to reduce the deleterious effects of macrophage-derived IL-1 beta.

关键词： MHC class II   antigen presentation   ubiquitination  

摘要： MHC class II glycoproteins (MHC-II) bind peptides derived from exogenous antigens and dendritic cells (DCs) present these peptide MHC-II (pMHC-II) complexes to antigen-specific CD4 T cells during immune responses. The turnover of surface pMHC-II on antigen-presenting cells (APCs) is controlled by ubiquitin-mediated degradation of pMHC-II by the E3 ubiquitin ligase March-I. To study March-I protein expression, we have generated a mouse in which a V5 epitope-tag was knocked-in to the endogenous March-I gene, thereby allowing us to follow the fate of March-I using high-affinity anti-V5 antibodies. Quantitative analysis revealed that resting spleen DCs and B cells express only similar to 500 and 125 March-I molecules/cell, respectively. Endogenous March-I protein has a very short half-life in DCs and March-I mRNA, March-I protein, and MHC-II ubiquitination are rapidly terminated upon activation of both DCs and B cells. Like March-I, CD83 is a known regulator of MHC-II expression in APCs and we also show that CD83 suppresses endogenous March-I-dependent MHC-II ubiquitination, endocytosis, and degradation in mouse spleen DCs. Thus, our study reveals molecular mechanisms for both March-I- and CD83-dependent regulation of MHC-II expression in APCs.

关键词： Multiple myeloma   Visfatin   Apoptosis   Interleukin-6   Nuclear factor kappa-B  

摘要： BackgroundMultiple myeloma (MM) is the second most prevalent hematological malignancy that results in the proliferation of malignant plasma cells and the overproduction of monoclonal immunoglobulin. Visfatin plays an important role in the regulation of apoptosis, oxidative stress, and inflammation;however, to this date, the role of visfatin in multiple myeloma is *** explore the role of visfatin in multiple myeloma and find new targets for MM *** this study, expression of visfatin in bone marrow was detected by ELISA. The diagnostic value of visfatin was determined by receiver operating characteristic (ROC) curve analysis. After the quality control by performing western blot to confirm the knockdown of visfatin in two MM cell lines, the phenotype (proliferation and apoptosis) of visfatin in MM was determined by carrying out in vitro experiments, including CCK8, flow cytometry, and western blot. Several cytokines were determined by real-time PCR, followed by in vivo experiments and immunohistochemical assays. I kappa B, NF-kappa bp65, and phosphorylation were determined by western *** found that visfatin level increased in the bone marrow of MM patients compared to controls. ROC curve analysis result showed that bone marrow visfatin was able to distinguish MM patients from controls. In vitro and in vivo, visfatin promotes MM cell proliferation. The production of IL-6 was attenuated by visfatin knockdown. Furthermore, we showed that visfatin could activate IL-6 production via the NF-kappa B signaling *** MM, visfatin promotes tumor progression by upregulating IL-6 production, which may be a novel therapeutic target for the treatment of MM patients.

关键词： monkeypox virus   IFN-α/β   CAST/EiJ mice   rhesus macaques   splenomegaly   STING  

摘要： The recent mpox outbreak underscores the urgent need for more accessible vaccines and treatments. However, the mpox virus (MPXV) clade IIb exhibits milder virulence and fails to develop typical pathological characteristics in mouse models. Herein, we found that CAST/EiJ mice infected intraperitoneally with MPXV clade IIb exhibited more efficient viral replication and experienced splenomegaly. Additionally, MPXV infection triggers the phosphorylation of stimulator of interferon genes (STING), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3) in ex vivo bone marrow-derived macrophages from mice and promotes the transcription of interferon (IFN)-beta via the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway. Notably, IFN-beta treatment significantly reduced viral replication and alleviated splenomegaly in MPXV-infected CAST/EiJ mice. In rhesus macaques, the clinically approved pegylated IFN alpha-2b treatment markedly reduced the severity of MPXV infection by alleviating skin lesions and lowering plasma viremia. These findings demonstrate that MPXV clade IIb activates the cGAS-STING pathway and highlight the potential of type I interferon (IFN-I) treatment in CAST/EiJ mice and rhesus macaques for mpox.

关键词： Centipeda minima (CMX)   brevilin A   tumor necrosis factor-alpha (TNF-alpha)   oxidative stress   extracellular matrix (ECM)   skin aging   inflammation  

摘要： Skin aging and inflammatory skin lesions are exacerbated by reactive oxygen species (ROS) generated in the mitochondria of human dermal fibroblasts (HDFs). These oxidative stressors degrade the extracellular matrix (ECM), promote inflammation, and accelerate skin aging. Antioxidants that suppress reactive oxygen species (ROS) production play a crucial role in mitigating these effects. This study investigated the protective effects of Centipeda minima (CMX) and its active constituent, brevilin A, against tumor necrosis factor-alpha (TNF-alpha)-induced oxidative stress and ECM degradation in normal human dermal fibroblasts (NHDFs). Both CMX and brevilin A significantly inhibited TNF-alpha-induced elevations in ROS, nitric oxide (NO), and prostaglandin E2 (PGE2) levels, thereby reducing oxidative stress and inflammatory responses. Additionally, they effectively suppressed matrix metalloproteinase-1 (MMP-1) expression and restored the procollagen I alpha 1 (COLIA1) levels, indicating their potential to preserve ECM integrity. Mechanistically, brevilin A selectively inhibited ERK phosphorylation in the mitogen-activated protein kinase (MAPK) pathway, suggesting its role in regulating collagen degradation and inflammation. These findings highlight that CMX and brevilin A are promising natural agents for protection against skin aging and inflammation. However, further in vivo studies are necessary to validate their efficacy and explore their potential applications in dermatological formulations.