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关键词： 吉兰-巴雷综合征   补体   抗体   免疫治疗   协同致病机制  

摘要： 目前临床实践发现吉兰-巴雷综合征（GBS）患者体液中抗神经节苷脂抗体存在异质性，常规免疫治疗对部分GBS临床亚型的疗效有限。参考其他神经免疫疾病的治疗方案，针对抗体与补体系统的靶向调控已成为GBS治疗研究的重要方向。本文通过梳理补体、抗体及其相关炎性因子介导的免疫应答机制，探讨GBS免疫治疗领域的新策略，旨在为该病的个体化治疗提供理论依据和研究切入点。

关键词： Diamine oxidase   IFN-gamma   NK cells   Inflammation  

摘要： Aims: Diamine oxidase (DAO), a well-established biomarker for intestinal damage, histamine intolerance or tumorigenesis, has rarely been reported in immune regulation. This study aimed to identify DAO as a critical enhancer of abnormal inflammation by promoting interferon-gamma (IFN-gamma) production from natural killer (NK) cells. Main methods: Clinical bioinformatics analyzed aoc1 (DAO-coding gene) expression in PBMCs from patients with inflammatory diseases. Murine models (LPS-induced systemic inflammation, sepsis, DSS-induced colitis) using DAO-/- mice, alongside DAO-/- NK92 cells and DAO inhibitor DIZE, were employed for phenotypic validation. Cellular profiling, bone marrow chimeras, reciprocal transplantation, RNA-sequence, non-targeted metabolomics, and flow cytometry were utilized to dissect DAO's mechanisms in NK cells. Key findings: DAO deficiency protected mice from inflammatory pathology by suppressing IFN-gamma production. NK cells were identified as the primary target cells during the process, with DAO acting intracellularly to promote IFN-gamma via a reactive oxygen species (ROS)-autophagy axis. DAO-derived ROS, distinct from mitochondrial or NOX2 sources, enhanced autophagic flux during NK activation, enabling IFN-gamma biosynthesis. DAO did not affect NK homeostasis, including maturation, proliferation, or receptor expressions. Significance: DAO is a novel risk factor in inflammatory diseases, driving IFN-gamma production through ROSautophagy signaling in NK cells. Targeting DAO may offer therapeutic strategies for conditions involving dysregulated IFN-gamma responses, including sepsis, colitis, and autoimmune disorders.

关键词： Neurodegeneration   Noradrenergic   Axon   Acrylamide   Microglia   Oxidative stress   TNF-alpha  

摘要： Environmental toxicants such as acrylamide or 1-bromopropane induce cognitive dysfunction in humans. We previously reported specific noradrenergic neuronal degeneration induced by acrylamide or 1-bromopropane in rodents. In this study, we applied in vivo and in vitro models as well as bulk and single-cell transcriptomic analyses to uncover the underlying mechanisms. RNA-seq of brains of acrylamide-exposed mice revealed a transcriptomic profile involving genes related to multiple neurodegenerative diseases and oxidative stress pathways. Single-cell RNA-seq for microglia identified upregulation of immunoregulation-, inflammation-, and oxidative stress- related pathways, and identified the upregulation of Tnfaip2 (a TNF-alpha effector), in multiple microglial sub-clusters. Further results of our in vitro interaction model showed that compared to direct acrylamide exposure, exposure to conditioned medium (CM) of acrylamide-exposed BV2 microglia significantly decreased 1C11NE axon density, and RNA-seq for 1C11NE identified similar transcriptomic profiles to those of brains of acrylamide-exposed mice. RNA-seq for BV2 microglia showed upregulation of various oxidative stress related genes. Further inhibition experiments demonstrated that TNF-alpha inhibition or anti-oxidation alleviated acrylamide-induced axonal degeneration in 1C11NE neurons. Finally, in vivo TNF-alpha knockout alleviated acrylamide-induced neurotoxicity. Our study demonstrated that acrylamide-induced noradrenergic axon degeneration is promoted via a non-cell autonomous mechanism, involving microglial Tnfaip2/TNF-alpha and

关键词： Mammals  

摘要： The gut microbiota and its associated micro-ecosystem are closely related to the onset and development of ulcerative colitis (UC). It is known that Corynebacterium glutamicum (C. glutamicum) helps rebuild gut eubiosis from diabetes dysbiosis;however, its effects on UC remain unknown. This study aims to investigate the therapeutic effects and mechanisms of C. glutamicum on UC. In this study, C. glutamicum was encapsulated with thiolated hyaluronic acid (HA-SH) to form a hydrogel, termed as CG-HA-SH. The adhesion and distribution of CG-HA-SH in the intestine were evaluated, along with its therapeutic effects on UC mice, including its impact on the gut microbiota. Additionally, changes in short-chain fatty acids (SCFAs) in the intestines of UC mice were analyzed, and RNA sequencing (RNA-Seq) was employed to investigate the mechanisms by which C. glutamicum alleviated inflammation. HA-SH enhanced the resistance of C. glutamicum in gastric and intestinal fluids, providing approximately 12 hours of adhesion at colitis inflammation sites. C. glutamicum reduced the levels of pro-inflammatory factors such as IL-1 beta (by 97.31%) and TNF-alpha (by 90.10%) while increasing anti-inflammatory IL-10 levels (by 197.59%) in the colon. It also increased the abundance of E. fissicatena, Muribaculum, and butyrate and enhanced intestinal tight junctions (OCC, by 318.93%) and the mucus barrier (MUC2, by 515.93%). The mRNA levels of cIAP1/2 decreased by 4.33-fold, and their protein expression levels were reduced by 36.97% correspondingly. The enrichment of the TNF pathway was the most significant. Therefore, C. glutamicum exhibited remarkable efficacy in alleviating inflammation and reshaping dysbiotic gut microbiota by downregulating the cIAP1/2-mediated TNF signaling pathway and NF-kappa B signaling pathway. cIAP1 and cIAP2 might serve as effective therapeutic targets.

关键词： Alzheimer's disease   inflammatory factor   Mendelian randomization   severe asthma   single-cell RNA sequencing analysis  

摘要： Purpose Epidemiological investigation has revealed a higher incidence of Alzheimer's disease (AD) in individuals with severe asthma. However, the causality of this relationship remains uncertain. The current research aimed to examine the potential link between genetically predicted moderate to severe asthma and the risk of AD using Mendelian randomization (MR) analysis. Methods Summary statistics obtained from genome-wide association studies of AD (n = 455,258) and moderate to severe asthma (n = 57,695) in individuals of European ancestry were utilized in this MR study. SMR analysis was also performed to investigate whether the expression of these genes was correlated with AD or moderate to severe asthma outcomes to detect a causal relationship between moderate to severe asthma and AD. Genome-wide genetic correlation between moderate to severe asthma and AD was estimated using linkage disequilibrium score regression (LDSC). Single-cell RNA sequencing (scRNA-seq) datasets of asthma-related peripheral blood mononuclear cell (PBMC) data and AD cerebrospinal fluid (CSF) were obtained to further investigate the crosstalk between the different biological pathways in asthma and AD. Results The impact of moderate to severe asthma on AD risk persisted (ORIVW = 1.01, 95% CI = 1.00-1.02, p = 3.85 x 10(-3)) after controlling for confounder risk factors in multivariable MR analyses. Additionally, the study showed that 1.8% of the total effect (moderate to severe asthma) was mediated by eosinophils. SMR analysis and the gene-wide MR analysis revealed numerous gene targets linked to the susceptibility of AD and moderate to severe asthma. Among these targets, FPR1 (Formyl Peptide Receptor 1), IL1RAP (Interleukin 1 Receptor Accessory Protein), IL7R (Interleukin 7 Receptor), and IL18RAP (Interleukin 18 Receptor Accessory Protein) warrant additional exploration as potential therapeutic targets for AD and moderate to severe asthma. LDSC analysis revealed no significant overlap between

关键词： sarcoma   cytokines   IL-1B   luminex   immunotherapy   biomarkers   pediatric cancer   osteosarcoma   Ewing sarcoma  

摘要： Background: Sarcomas are a heterogeneous group of mesenchymal tumors frequently diagnosed in pediatric and young adult patients. These tumors respond poorly to conventional immunotherapy, although the precise reason for this is not known. We sought to characterize the systemic immune response to sarcomas by measuring the levels of circulating cytokines in the plasma of newly diagnosed sarcoma patients, testing the hypothesis that the nature of a patient's immune response to their tumor directly affects outcome. Methods: Plasma was collected from newly diagnosed, treatment-naive pediatric sarcoma patients participating in an ongoing clinical trial, MCC20320. A panel of 18 cytokines was selected, and cytokine levels were measured using the Luminex platform. Cytokine levels were analyzed based on clinicopathological parameters such as gender, age, stage, and survival. Results: We found that the cytokine profile in patients newly diagnosed with sarcoma is distinct from healthy controls, but different sarcomas were not distinguishable. Patients with osteosarcoma who had elevated levels of multiple cytokines had inferior overall survival compared to those with fewer or no elevated levels. Similarly, elevated levels of individual cytokines and chemokines, including IL-24, CXCL5, and CXCL10, were associated with inferior event-free or overall survival in patients with osteosarcoma. Perhaps most significantly, elevated IL-1 beta at diagnosis was associated with metastatic presentation and inferior event-free survival in patients with osteosarcoma. Conclusions: These findings suggest that pediatric sarcoma patients mount a systemic immune response that may affect event-free or overall survival. IL-1 beta in particular may be a valuable therapeutic target for osteosarcoma patients.

关键词： span>biological therapyJanus kinase inhibitorscyclosporinesurveillancescreeninginflammatory skin diseasestuberculosistuberculin testinterferon-gamma release testhealth services researchpublic healthinfection  

关键词： 膀胱癌   免疫检查点抑制剂   免疫性心肌炎   甲泼尼龙   免疫球蛋白   英夫利昔单抗   托法替布   呼吸功能衰竭  

摘要： 目的 探讨免疫检查点抑制剂(ICI)治疗膀胱癌患者相关免疫性心肌炎患者的临床特征及临床诊疗方案。方法 回顾性收集2020年1月2024年5月南京医科大学第一附属医院泌尿外科收治的213例行ICIs治疗的膀胱癌患者的临床与随访资料,其中7例(3.3%)患者出现ICIs相关免疫性心肌炎,收集并分析7例患者的临床及随访资料。结果 7例患者中,女性2例,男性5例,中位年龄72岁。其中4例患者无明显症状,3例症状主要表现为胸闷、呼吸困难、端坐呼吸等。7例患者均有高敏肌钙蛋白T显著升高,仅2例患者N末端B型脑钠肽前体明显升高。4例患者心电图无明显改变,2例的患者超声心动图提示左室心肌应变明显减低,心脏磁共振提示急性心肌炎。所有患者明确诊断后均立即停用ICIs并给予一线甲泼尼龙治疗,2例患者一线治疗5 d后病情未改善给予二线治疗,1例患者加用免疫球蛋白与英夫利昔单抗后未见好转,三线治疗加用托法替布后好转;另1例患者加用免疫球蛋白后突发呼吸功能衰竭转至重症监护室治疗10 d后因多器官功能衰竭死亡。结论 ICIs治疗相关免疫性心肌炎是膀胱癌综合治疗过程中的一种相对罕见但具有独特临床特征的免疫相关不良反应,甲泼尼龙是该疾病治疗的一线用药,而对于危重型及激素抵抗型患者,常需基于患者的具体情况并经过多学科讨论后早期联用其他免疫抑制剂。

摘要： Protein secretion plays a crucial role in maintaining immune homeostasis, yet the molecular interactions governing this process remain incompletely understood. While transcriptional and post-transcriptional regulation of protein expression is well characterized, the subcellular interactions between secreted proteins and trafficking machinery are less explored. To address this, we systematically mapped protein-protein interactions (PPIs) involved in the secretion of interleukin-2 (IL-2) from human T cells using proximity-based labeling coupled with mass spectrometry. Our analysis revealed significant enrichment of proteins associated with conventional secretory pathways, including ER-to-Golgi transport, protein folding, and vesicle-mediated trafficking. Functional validation confirmed that several of these proteins are critical for IL-2 secretion, underscoring their direct roles in cytokine processing. In addition, time-resolved profiling of PPIs and transcriptomic changes following T cell stimulation revealed dynamic remodeling of the cytokine secretion machinery, reflecting multilayered regulation at both the protein and gene expression levels. These findings offer a systems-level understanding of IL-2 secretion and identify new molecular components that can be targeted to modulate immune responses. This work provides a framework for dissecting complex secretory processes and has broad implications for therapeutic strategies in immune-related diseases.