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Cellular immune response to the anti-SARS-CoV-2 BNT162b2 mRNA vaccine in pediatric autoimmune inflammatory rheumatic disease patients and controls. 小儿自身免疫性炎症性风湿病患者和对照组对抗 SARS-CoV-2 BNT162b2 mRNA 疫苗的细胞免疫反应。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-12 DOI: 10.1093/cei/uxae044
Tali Eviatar, Adi Pappo, Tal Freund, Yishai Friedlander, Ori Elkayam, David Hagin, Merav Heshin-Bekenstein

This paper aims to compare the cellular immune response to the SARS-CoV-2 BNT162b2 vaccine of pediatric patients with autoimmune inflammatory rheumatic disease (pAIIRD) and healthy controls. A prospective longitudinal study was conducted between April 2021 and December 2022 at the Tel Aviv Medical Center. Children <18 years, with pediatric-onset AIIRD and healthy controls, who have received at least two doses of the BNT162b2 vaccine, were included. Humoral response was evaluated by serum levels of anti-SARS-CoV-2 receptor-binding domain antibodies. Cellular response was evaluated by flow cytometry, measuring IFNγ and TNFα production by CD4+ T cells following stimulation with SARS-CoV-2 Spike peptide mix. The study included 20 pAIIRD patients and 11 controls. The mean age of participants was 12.6 ± 2.94 years, with 58.1% females. The cellular response to the BNT162b2 vaccine was statistically similar in both groups. However, the humoral response was statistically lower in pAIIRD compared with the healthy control group. There was no statistically significant correlation between the humoral response and cellular response. During the study period, 43.75% of AIIRD children and 72.7% of controls had a breakthrough COVID-19 infection (P = 0.48). Bivariate models examining the effect of the cellular response and presence of an AIIRD on breakthrough infections found no effect. Compared with healthy controls, pAIIRD demonstrated similar cellular responses. Patients showed reduced humoral response compared with healthy adolescents, but similar breakthrough infection rates. These findings may support the importance of the cellular response in protecting against COVID-19 infections.

本文旨在比较自身免疫性炎症性风湿病(pAIIRD)儿科患者和健康对照组对 SARS-CoV2 BNT162b2 疫苗的细胞免疫反应。一项前瞻性纵向研究于 2021 年 4 月至 2022 年 12 月在特拉维夫医疗中心进行。儿童
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引用次数: 0
Effector CD4+ T-cell subsets in Takayasu arteritis-differences between the peripheral blood and the aorta. 高安动脉炎的效应 CD4+ T 细胞亚群--外周血和主动脉之间的差异。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-12 DOI: 10.1093/cei/uxae046
Bruna Savioli, Heron Fernandes Vieira Torquato, Edgar Julian Paredes-Gamero, Andréia Fabiana do Vale Franco, Carolina de Oliveira Gigek, Ricardo Artigiani Neto, Alexandre Wagner Silva de Souza

Takayasu arteritis (TAK) is a granulomatous vasculitis that affects large arteries. T cells are important in TAK pathophysiology as these cells orchestrate granulomatous infiltration in arteries. This study aims to evaluate effector CD4+ T cells in the peripheral blood and the aortic wall of TAK patients and to analyze associations with disease activity and therapy. We performed a longitudinal study including 30 TAK patients and 30 controls. CD3+ T cells, CD3+CD4- T cells, CD4+ T cells, and Th1, Th2, and Th17 cells were evaluated in peripheral blood by flow cytometry, and the expression of CD4, CD8, Tbet, GATA-3, and RORγT was analyzed in the aorta of six patients by immunohistochemistry. TAK patients presented lower CD3+ T cells and CD4+ T cells (P = 0.031 and P = 0.039, respectively) than controls. Patients with active disease and those in remission had higher proportions of Th17 cells than controls (P = 0.016 and P = 0.004, respectively). Therapy for TAK did not result in significant differences concerning CD4+ effector T-cell subpopulations. Disease duration correlated with the number and percentage of Th2 cells (rho = -0.610 and rho = -0.463, respectively) and with Th17 cells (rho = -0.365 and rho = -0.568). In the aorta, the expression of CD8 was higher than CD4, whereas GATA-3, Tbet, and RORγT were expressed in this order of frequency. In conclusion, TAK patients present an increased Th17 response in the peripheral blood regardless of disease activity, whereas in the aortic tissue CD8 cells and the Th2 response were predominant.

高安动脉炎(TAK)是一种影响大动脉的肉芽肿性血管炎。T细胞在TAK病理生理学中起着重要作用,因为这些细胞能协调动脉中的肉芽肿浸润。本研究旨在评估 TAK 患者外周血和主动脉壁中的效应 CD4+ T 细胞,并分析其与疾病活动和治疗的关系。我们进行了一项纵向研究,其中包括 30 名 TAK 患者和 30 名对照组。通过流式细胞术评估了外周血中的CD3+ T细胞、CD3+CD4- T细胞、CD4+ T细胞以及Th1、Th2和Th17细胞,并通过免疫组化分析了6名患者主动脉中CD4、CD8、Tbet、GATA-3和RORγT的表达。与对照组相比,TAK 患者的 CD3+ T 细胞和 CD4+ T 细胞数量较低(分别为 p=0.031 和 p=0.039)。活动期患者和缓解期患者的Th17细胞比例高于对照组(分别为p=0.016和p=0.004)。TAK治疗并未导致CD4+效应T细胞亚群的显著差异。疾病持续时间与Th2细胞的数量和百分比相关(rho=-0.610和rho=-0.463),与Th17细胞相关(rho=-0.365和rho=-0.568)。在主动脉中,CD8的表达高于CD4,而GATA-3、Tbet和RORγT的表达频率依次为CD4、Tbet和RORγT。总之,无论疾病活动如何,TAK 患者外周血中 Th17 反应增加,而在主动脉组织中 CD8 细胞和 Th2 反应占主导地位。
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引用次数: 0
Impact on in-depth immunophenotyping of delay to peripheral blood processing. 外周血处理延迟对深入免疫分型的影响。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-12 DOI: 10.1093/cei/uxae041
Lauren E Higdon, Sheila Scheiding, Anna M Kus, Noha Lim, S Alice Long, Mark S Anderson, Alice E Wiedeman

Peripheral blood mononuclear cell (PBMC) immunophenotyping is crucial in tracking activation, disease state, and response to therapy in human subjects. Many studies require the shipping of blood from clinical sites to a laboratory for processing to PBMC, which can lead to delays that impact sample quality. We used an extensive cytometry by time-of-flight (CyTOF) immunophenotyping panel to analyze the impacts of delays to processing and distinct storage conditions on cell composition and quality of PBMC from seven adults across a range of ages, including two with rheumatoid arthritis. Two or more days of delay to processing resulted in extensive red blood cell contamination and increased variability of cell counts. While total memory and naïve B- and T-cell populations were maintained, 4-day delays reduced the frequencies of monocytes. Variation across all immune subsets increased with delays of up to 7 days in processing. Unbiased clustering analysis to define more granular subsets confirmed changes in PBMC composition, including decreases of classical and non-classical monocytes, basophils, plasmacytoid dendritic cells, and follicular helper T cells, with each subset impacted at a distinct time of delay. Expression of activation markers and chemokine receptors changed by Day 2, with differential impacts across subsets and markers. Our data support existing recommendations to process PBMC within 36 h of collection but provide guidance on appropriate immunophenotyping experiments with longer delays.

外周血单核细胞(PBMC)免疫分型对于跟踪人体活化、疾病状态和治疗反应至关重要。许多研究需要将血液从临床地点运送到实验室处理成 PBMC,这可能会导致延误,影响样本质量。我们使用了大量的飞行时间细胞计数法(CyTOF)免疫表型面板来分析延迟处理和不同储存条件对细胞组成和 PBMC 质量的影响,这些样本来自七个不同年龄段的成年人,其中包括两名类风湿性关节炎患者。延迟两天或两天以上处理会导致大量红细胞污染和细胞计数变异性增加。虽然记忆细胞、幼稚 B 细胞和 T 细胞总数得以保持,但延迟四天处理会降低单核细胞的频率。处理时间延迟七天,所有免疫亚群的变异都会增加。通过无偏聚类分析确定更细粒度的亚群,证实了 PBMC 组成的变化,包括经典和非经典单核细胞、嗜碱性粒细胞、浆细胞树突状细胞和滤泡辅助 T 细胞的减少,每个亚群都在不同的延迟时间受到影响。活化标志物和趋化因子受体的表达在第二天发生了变化,不同亚群和标志物受到的影响也不同。我们的数据支持现有的建议,即在采集后 36 小时内处理 PBMC,但也为延迟更长时间进行适当的免疫分型实验提供了指导。
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引用次数: 0
Correction to: Type 1 interferon auto-antibodies are elevated in patients with decompensated liver cirrhosis. 更正为肝硬化失代偿期患者的 1 型干扰素自身抗体升高。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-12 DOI: 10.1093/cei/uxae024
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引用次数: 0
NK-cell receptor modulation in viral infections. 病毒感染中的 NK 细胞受体调节。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-12 DOI: 10.1093/cei/uxae045
Marzena Lenart, Magdalena Rutkowska-Zapała, Maciej Siedlar

Natural killer (NK) cells play a crucial role in controlling viral infections. The ability to kill infected cells without prior immunization, yet being tolerant to self, healthy cells, depends on the balance of germ-line encoded surface receptors. NK-cell receptors are divided into either activating, leading to activation of NK cell and its cytotoxic and pro-inflammatory activity, or inhibitory, providing tolerance for a target cell. The signals from inhibitory receptors dominate and NK-cell activation requires stimulation of activating receptors. In viral infections, NK-cell interaction with infected cells can result in activation, memory-like NK-cell differentiation, or NK-cell exhaustion, which constitutes one of the viral immune evasion mechanisms. All of these states are associated with the modulation of NK-cell receptor expression. In this review, we summarize the current knowledge of NK-cell receptors and their role in viral infection control, as well as the alterations of their expression observed in acute or chronic infections. We present recently discovered SARS-CoV-2-mediated modulation of NK-cell receptor expression and compare them with other human viral infections. Finally, since modulation of NK-cell receptor activation gives a promising addition to currently used antiviral therapies, we briefly discuss the clinical significance and future perspective of the application of agonists or antagonists of activating and inhibitory receptors, respectively. In sum, our review shows that although much is known about NK-cell receptor biology, a deeper understanding of NK-cell receptors role in viral infections is still needed.

自然杀伤(NK)细胞在控制病毒感染方面发挥着至关重要的作用。能否在不事先免疫的情况下杀死受感染的细胞,同时又对自身的健康细胞具有耐受性,这取决于种系编码的表面受体的平衡。NK 细胞受体分为激活型和抑制型,激活型受体可导致 NK 细胞活化并产生细胞毒性和促炎活性,抑制型受体则可提供对靶细胞的耐受性。抑制性受体发出的信号占主导地位,NK 细胞的激活需要激活性受体的刺激。在病毒感染中,NK 细胞与受感染细胞的相互作用可导致激活、记忆型 NK 细胞分化或 NK 细胞衰竭,这构成了病毒免疫逃避机制之一。所有这些状态都与 NK 细胞受体表达的调节有关。在这篇综述中,我们总结了目前关于 NK 细胞受体及其在病毒感染控制中作用的知识,以及在急性或慢性感染中观察到的受体表达变化。我们介绍了最近发现的 SARS-CoV-2 介导的 NK 细胞受体表达调节,并将其与其他人类病毒感染进行了比较。最后,由于对 NK 细胞受体活化的调节有望为目前使用的抗病毒疗法提供新的补充,我们简要讨论了分别应用活化受体和抑制受体的激动剂或拮抗剂的临床意义和未来前景。总之,我们的综述表明,尽管人们对 NK 细胞受体生物学知之甚少,但仍需要更深入地了解 NK 细胞受体在病毒感染中的作用。
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引用次数: 0
T Cells Immune Imbalance Present in Patients With Multiple Intracranial Aneurysms. 多发性颅内动脉瘤患者的 T 细胞免疫失衡。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-11 DOI: 10.1093/cei/uxae058
Chuming Tao, Chenglong Liu, Peicong Ge, Liujia Chan, Yuheng Pang, Junsheng Li, Qiheng He, Wei Liu, Siqi Mou, Zhiyao Zheng, Bojian Zhang, Zhikang Zhao, Wei Sun, Qian Zhang, Rong Wang, Yan Zhang, Wenjing Wang, Dong Zhang, Jizong Zhao

Growing evidence suggests that systemic immune and inflammatory responses may play a critical role in the formation and development of aneurysms. Exploring the differences between single intracranial aneurysm (SIA) and multiple IAs (MIAs) could provide insights for targeted therapies. However, there is a lack of comprehensive and detailed characterization of changes in circulating immune cells in MIAs. Peripheral blood mononuclear cell (PBMC) samples from patients with SIA (n = 16) or MIAs (n = 6) were analyzed using high-dimensional mass cytometry to evaluate the frequency and phenotype of immune cell subtypes. A total of 25 cell clusters were identified, revealing that the immune signature of MIAs included cluster changes. Compared to patients with SIA, patients with MIAs exhibited immune dysfunction and regulatory imbalance in T-cell clusters. They also had reduced numbers of CD8+ T cells and their subgroups CD8+ Te and CD8+ Tem cells, as well as reduced numbers of the CD4+ T-cell subgroup CD27-CD4+ Tem cells. Furthermore, compared to SIA, MIAs were associated with enhanced T-cell immune activation, with elevated expression levels of CD3, CD25, CD27, CCR7, GP130, and interleukin 10. This study provides insights into the circulating immune cell profiles in patients with MIAs, highlighting the similarities and differences between patients with SIA and those with MIAs. Furthermore, the study suggests that circulating immune dysfunction may contribute to development of MIAs.

越来越多的证据表明,全身免疫和炎症反应可能在动脉瘤的形成和发展中起着至关重要的作用。探索单发颅内动脉瘤(SIA)和多发动脉瘤(MIA)之间的差异可为靶向治疗提供启示。然而,目前还缺乏对多发性动脉瘤中循环免疫细胞变化的全面而详细的描述。研究人员使用高维质谱仪分析了SIA(16例)或MIA(6例)患者的外周血单核细胞(PBMC)样本,以评估免疫细胞亚型的频率和表型。共鉴定出 25 个细胞集群,揭示出 MIAs 的免疫特征包括集群变化。与SIA患者相比,MIA患者表现出免疫功能紊乱和T细胞群调节失衡。他们的CD8+ T细胞及其亚群CD8+ Te和CD8+ Tem细胞数量减少,CD4+ T细胞亚群CD27-CD4+ Tem细胞数量减少。此外,与 SIA 相比,MIA 与 T 细胞免疫活化增强有关,CD3、CD25、CD27、CCR7、GP130 和白细胞介素 10 的表达水平升高。这项研究深入揭示了多发性骨髓瘤患者的循环免疫细胞特征,强调了SIA患者与多发性骨髓瘤患者之间的异同。此外,该研究还表明,循环免疫功能失调可能会导致 MIAs 的发生。
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引用次数: 0
A homogeneous bioluminescent inhibition immunoassay to detect anti-interferon gamma antibodies. 检测抗干扰素 gamma 抗体的均相生物发光抑制免疫分析法。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-08 DOI: 10.1093/cei/uxae055
Peter Bradhurst, Alex Stoyanov, Arnone Nithichanon, Christine Bundell, Nicolás Urriola

Adult-onset immunodeficiency with antibodies to interferon-γ (AOID with AIGA), is a rare, acquired immunodeficiency causing susceptibility to disseminated non-tuberculous mycobacteria and other intracellular opportunistic infections. The diagnosis depends on demonstrating the presence of endogenous anti-interferon-γ antibodies (AIGA) that suppress Th1 cell mediated immunity. Bioluminescent immunoassays are a newly emerging immunoassay format which utilise the action of bioluminescent enzymes on a substrate for specific analyte detection. In-short, detecting antibodies are conjugated with a bioluminescent enzyme. The detecting antibodies bind the analyte of interest and produce light (luminescence) after addition of a substrate. The purpose of this study was to evaluate two newly developed bioluminescent immunoassays using Lumit® (Promega) technology as a diagnostic test for AOID with AIGA. Specific aims included the clinical validation of a new inhibition bioluminescent immunoassay technique to detect AIGA which block detection of interferon-γ (IFN-γ) in-vitro and correlation of inhibition bioluminescent immunoassay results with AOID with AIGA disease status. Two bioluminescent inhibition immunoassays were developed. One which adapted an existing kit from Promega (Lumit® Human IFN-γ Immunoassay) and one which was developed in-house. 87 healthy controls and 48 patients with previously diagnosed AOID with AIGA were recruited and tested using these two methods. Results showed both bioluminescent inhibition immunoassays were able to clearly discriminate between AOID with AIGA patients and healthy controls. The mean inhibition percentage between patient groups correlated with disease activity. Both assays appeared to be more sensitive when compared to the existing inhibition ELISA.

带有干扰素-γ抗体的成人型免疫缺陷病(AOID with AIGA)是一种罕见的获得性免疫缺陷病,可导致对播散性非结核分枝杆菌和其他细胞内机会性感染的易感性。诊断取决于是否存在抑制 Th1 细胞介导免疫的内源性抗干扰素-γ 抗体(AIGA)。生物发光免疫测定是一种新兴的免疫测定方法,它利用生物发光酶对底物的作用来检测特定的分析物。简言之,检测抗体与生物发光酶结合。检测抗体与感兴趣的分析物结合,并在加入底物后产生光(发光)。本研究的目的是评估使用 Lumit® (Promega) 技术新开发的两种生物发光免疫测定,作为 AIGA 的 AOID 诊断测试。具体目标包括:对检测 AIGA 的新型抑制生物发光免疫测定技术进行临床验证,该技术可在体外阻断干扰素-γ(IFN-γ)的检测;以及抑制生物发光免疫测定结果与 AOID 和 AIGA 疾病状态的相关性。我们开发了两种生物发光抑制免疫测定。一种是对 Promega 公司现有试剂盒(Lumit® 人类 IFN-γ 免疫测定)的改良,另一种是自行开发的。招募了 87 名健康对照者和 48 名先前诊断为 AIGA 的 AOID 患者,并使用这两种方法进行了检测。结果表明,这两种生物发光抑制免疫测定法都能清楚地区分 AOID 伴 AIGA 患者和健康对照组。患者组之间的平均抑制百分比与疾病活动相关。与现有的抑制酶联免疫吸附测定法相比,这两种测定法似乎更加灵敏。
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引用次数: 0
The neutrophil extracellular traps in neurological diseases: An update. 神经系统疾病中的中性粒细胞胞外捕获器:最新进展。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-08 DOI: 10.1093/cei/uxae057
Xiaoping Yu, Zhaoyan Chen, Wei Bao, Yaqing Jiang, Fei Ruan, Di Wu, Kai Le

Neutrophil extracellular traps released by neutrophils are web-like DNA structures adhered to granulin proteins with bactericidal activity and can be an important mechanism for preventing pathogen dissemination or eliminating microorganisms. However, they also play important roles in diseases of other systems, such as the central nervous system. We tracked the latest advances and performed a review based on published original and review articles related to neutrophil extracellular traps and neurological diseases. Generally, neutrophils barely penetrate the blood-brain barrier into the brain parenchyma, but when pathological changes such as infection, trauma, or neurodegeneration occur, neutrophils rapidly infiltrate the central nervous system to exert their defensive effects. However, neutrophils may adversely affect the host when they uncontrollably release neutrophil extracellular traps upon persistent neuroinflammation. This review focused on recent advances in understanding the mechanisms and effects of neutrophil extracellular traps release in neurological diseases, and we also discuss the role of molecules that regulate neutrophil extracellular traps release in anticipation of clinical applications in neurological diseases.

中性粒细胞释放的细胞外捕获器是一种网状 DNA 结构,附着在具有杀菌活性的颗粒蛋白上,是防止病原体传播或消灭微生物的重要机制。然而,它们在中枢神经系统等其他系统疾病中也发挥着重要作用。我们追踪了最新进展,并根据已发表的与中性粒细胞胞外捕获物和神经系统疾病相关的原创文章和综述文章进行了综述。一般情况下,中性粒细胞几乎不会穿透血脑屏障进入脑实质,但当感染、创伤或神经变性等病理变化发生时,中性粒细胞会迅速浸润中枢神经系统,发挥其防御作用。然而,如果中性粒细胞在神经炎症持续存在时不受控制地释放中性粒细胞胞外捕获物,则可能对宿主产生不利影响。本综述重点介绍了神经系统疾病中嗜中性粒细胞胞外捕获物释放机制和影响的最新研究进展,并探讨了调控嗜中性粒细胞胞外捕获物释放的分子的作用,以期待在神经系统疾病中的临床应用。
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引用次数: 0
Reduced IFNL1 and/or IFNL2, but not IFNL3 is associated with worse outcome in patients with COVID-19. IFNL1 和/或 IFNL2(而非 IFNL3)的降低与 COVID-19 患者的预后较差有关。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-02 DOI: 10.1093/cei/uxae047
Elena Woods, Adriana Mena, Sophie Sierpinska, Emily Carr, Richard Hagan, John Crowley, Colm Bergin, David Clark, Caroline Brophy, Derek Macallan, Clair M Gardiner

The recent pandemic was caused by the emergence of a new human pathogen, SARS-CoV-2. While the rapid development of many vaccines provided an end to the immediate crisis, there remains an urgent need to understand more about this new virus and what constitutes a beneficial immune response in terms of successful resolution of infection. Indeed, this is key for development of vaccines that provide long lasting protective immunity. The interferon lambda (IFNL) family of cytokines are produced early in response to infection and are generally considered anti-viral and beneficial. However, data regarding production of IFNL cytokines in COVID-19 patients is highly variable, and generally from underpowered studies. In this study, we measured all three IFNL1, IFNL2 and IFNL3 cytokines in plasma from a well characterised, large COVID-19 cohort (n=399) that included good representation from patients with a more indolent disease progression, and hence a beneficial immune response. While all three cytokines were produced, they differed in both the frequency of expression in patients, and the levels produced. IFNL3 was produced in almost all patients but neither protein level nor IFNL3/IFNL4 SNPs were associated with clinical outcome. In contrast, both IFNL1 and IFNL2 levels were significantly lower, or absent, in plasma of patients that had a more severe disease outcome. These data are consistent with the concept that early IFNL1 and IFNL2 cytokine production is protective against SARS-CoV-2 infection.

最近的大流行是由一种新的人类病原体 SARS-CoV-2 引起的。虽然许多疫苗的快速开发结束了这场直接危机,但人们仍然迫切需要更多地了解这种新病毒,以及什么是成功解决感染的有益免疫反应。事实上,这是开发可提供长期保护性免疫的疫苗的关键。λ干扰素(IFNL)系列细胞因子在感染早期就会产生,通常被认为是抗病毒和有益的。然而,有关 COVID-19 患者 IFNL 细胞因子产生情况的数据变化很大,而且一般都是来自幂等不足的研究。在这项研究中,我们测量了一个特征明确、规模庞大的 COVID-19 患者群(人数=399)血浆中的所有三种 IFNL1、IFNL2 和 IFNL3 细胞因子,其中包括病情发展较为缓和的患者,因此他们的免疫反应是有益的。虽然所有三种细胞因子都会产生,但它们在患者体内的表达频率和产生水平都有所不同。几乎所有患者都会产生 IFNL3,但蛋白水平和 IFNL3/IFNL4 SNPs 都与临床结果无关。相比之下,在病情较重的患者血浆中,IFNL1 和 IFNL2 的水平明显较低或不存在。这些数据与早期 IFNL1 和 IFNL2 细胞因子的产生对 SARS-CoV-2 感染具有保护作用的观点一致。
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引用次数: 0
Catalase inhibition can modulate the ability of peripheral blood T cells to undergo apoptosis in Crohn's disease. 抑制过氧化氢酶可调节克罗恩病患者外周血 T 细胞的凋亡能力。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-06-20 DOI: 10.1093/cei/uxad134
Inés Moret-Tatay, Pilar Nos, Marisa Iborra, Francisco Rausell, Belén Beltrán

Crohn's disease (CD) is a chronic relapsing inflammatory disorder in which defective apoptosis of mucosal T cells is postulated to produce sustained inflammation and reactive oxygen species accumulation. Whether CD T cells are intrinsically resistant to apoptosis or whether this resistance is acquired at the intestinal site needs to be clarified, as the cellular mechanisms modulate the impaired apoptosis in these cells. Here, we analysed peripheral blood T cells from patients naïve to specific CD treatment at the onset and from healthy controls. Non-activated freshly purified lymphocytes were cultured and submitted to in vitro protocols for activation (CD3/CD28 antibodies) and apoptosis (Fas antibody). Cells were analysed by flow cytometry. Caspases (3, 8, and 9) and catalase activity were measured; protein levels of bax, Bcl-2, and NF-kB were detected by western blotting, and cytokines by Luminex-based assays. The results showed that CD4 T cells from CD patients are less prone to apoptosis before they can migrate to the intestinal mucosa. Caspase-9, FasR, sIL-2Rα, IL-17A, IFNγ, IL-6, TNF-α, and IL-10 were shown to be significantly different in CD but not for the rest of the analysed biological elements. Catalase activity was significantly reduced in CD T cells, which was confirmed in ex vivo experiments in which catalase inhibition in T cells from healthy controls triggered apoptosis inhibition in a dose-dependent manner. In conclusion, apoptosis inhibition of CD T cells is a feature of these cells before they can migrate to the intestinal mucosa. Noteworthy, the impaired apoptosis of T cells can be directly influenced by catalase inhibition.

克罗恩病(Crohn's disease,CD)是一种慢性复发性炎症性疾病,据推测,粘膜 T 细胞凋亡缺陷会产生持续的炎症和活性氧积累。CD的T细胞是否对凋亡具有内在抵抗力,或者这种抵抗力是否是在肠道部位获得的,这些都需要加以澄清,因为细胞机制会调节这些细胞凋亡受损的情况。在这里,我们分析了发病时未接受特定 CD 治疗的患者和健康对照组的外周血 T 细胞。我们培养了未活化的新鲜纯化淋巴细胞,并对其进行了体外活化(CD3/CD28 抗体)和凋亡(Fas 抗体)检测。细胞通过流式细胞术进行分析。对 Caspases(3、8 和 9)和过氧化氢酶活性进行了测定;通过 Western 印迹法检测了 bax、Bcl-2 和 NF-kB 的蛋白水平;通过基于 Luminex 的检测法检测了细胞因子。结果显示,CD患者的CD4 T细胞在迁移到肠道粘膜之前不易发生凋亡。结果显示,CD患者的Caspase-9、FasR、sIL-2Rα、IL-17A、IFNγ、IL-6、TNF-α和IL-10有显著差异,而其他被分析的生物因子则无显著差异。CD T细胞的过氧化氢酶活性明显降低,这一点在体外实验中得到了证实,在健康对照组的T细胞中抑制过氧化氢酶会以剂量依赖的方式引发细胞凋亡抑制。总之,CD T 细胞的凋亡抑制是这些细胞迁移到肠道粘膜之前的一个特征。值得注意的是,过氧化氢酶抑制剂可直接影响 T 细胞的凋亡。
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Clinical and experimental immunology
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