Immunobiology最新文献_第3页

Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation 内皮细胞线粒体DNA激活cGAS-STING通路，调控肺移植后肺缺血再灌注损伤的焦亡。

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2025-01-01 DOI: 10.1016/j.imbio.2024.152865

Ying-nan Ju , Hu Li , Zi-peng Zhuo , Qing Yang , Wei Gao

Objective

Cell dysfunction and death induced by lung ischaemia–reperfusion injury (LIRI) are the main causes of death in transplant patients. Activation of the cGAS-STING-induced immune response and death plays a critical role in multiple organ injuries. However, no study has yet investigated the role of the cGAS-STING pathway in LIRI after lung transplantation.

Methods

Sprague-Dawley (SD) rats were subjected to left lung transplantation and administered inhibitors of cGAS and STING. The expression of cGAS-STING-TBK1-IRF3, histological injury, pulmonary permeability, and the levels of cytokines and pyroptotic proteins in transplanted lungs were tested. Endothelial cells were subjected to hypoxemia and reoxygenation and treated with inhibitors of cGAS and STING. Mitochondrial DNA (mtDNA), the cGAS-STING axis and cytokine levels in cells, cellular activity and death were evaluated. Moreover, after the administration of deoxyribonuclease (DNase) I, the reoxygenated endothelial cells were also examined for cellular function and inflammatory factor expression. Finally, we administered an agonist of STING and an inhibitor of cathepsin B to the normal endothelium and investigated pyroptosis and pyroptotic proteins.

Results

After 24 h of reperfusion, the expression of cGAS-STING-TBK1-IRF3 and pyroptotic proteins was significantly increased, and inhibitors of cGAS or STING ameliorated lung injury and reduced pyroptotic protein levels. In vitro, the inhibition of cGAS and STING reduced the activation of TBK and IRF3 and reduced cellular injury and death. The activation of cGAS-STING and cellular inflammation were suppressed by DNase I. Cathepsin B and NLRP3 were upregulated by an agonist of STING, and an inhibitor of cathepsin B reduced NLRP3 levels.

Conclusion

cGAS-STING participated in LIRI by promoting endothelial cell pyroptosis via cathepsin B.

目的：肺缺血再灌注损伤（LIRI）所致的细胞功能障碍和死亡是移植患者死亡的主要原因。激活cgas - sting诱导的免疫反应和死亡在多器官损伤中起关键作用。然而，尚未有研究调查cGAS-STING通路在肺移植术后LIRI中的作用。方法：SD大鼠左肺移植后给予cGAS和STING抑制剂。检测移植肺组织cGAS-STING-TBK1-IRF3的表达、组织损伤、肺通透性、细胞因子和焦亡蛋白水平。内皮细胞进行低氧血症和再氧化，并使用cGAS和STING抑制剂处理。观察线粒体DNA （mtDNA）、细胞内cGAS-STING轴和细胞因子水平、细胞活性和死亡情况。此外，在给予脱氧核糖核酸酶（DNase） I后，还检测了再氧化内皮细胞的细胞功能和炎症因子的表达。最后，我们给正常内皮注射了STING激动剂和组织蛋白酶B抑制剂，并研究了焦亡和焦亡蛋白。结果：再灌注24 h后，cGAS-STING- tbk1 - irf3及焦亡蛋白表达显著升高，cGAS或STING抑制剂可改善肺损伤，降低焦亡蛋白水平。在体外，抑制cGAS和STING可降低TBK和IRF3的激活，减轻细胞损伤和死亡。dna酶i可抑制cGAS-STING的激活和细胞炎症。STING激动剂可上调组织蛋白酶B和NLRP3水平，组织蛋白酶B抑制剂可降低NLRP3水平。结论：cGAS-STING通过组织蛋白酶B促进内皮细胞焦亡参与LIRI。

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引用次数: 0

STING modulates HBV-related acute-on-chronic liver failure by mediating autophagy and macrophage polarization STING通过介导自噬和巨噬细胞极化调节hbv相关的急慢性肝衰竭。

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2025-01-01 DOI: 10.1016/j.imbio.2024.152860

Hao Zhang , Teng Liang , Wanlu Duan , Futing Liu , LiPing Li , Qian Liu , Jianfei Li , Qiyin Zong , Lei Jin , Qin Wang , Qiang Zhou

Background & Aims

HBV-related acute-on-chronic liver failure (HBV-ACLF) is a severe acute liver injury secondary to HBV-related chronic liver disease (with or without cirrhosis) and is characterized by a high short-term mortality rate. Presently, there is a paucity of experimental models that specifically focus on HBV-ACLF based on chronic hepatitis B. Therefore, this study aimed to establish an experimental mouse model of HBV-ACLF using chronic hepatitis B (CHB) as a basis and investigate the impact of STING activation on the disease.

Methods

To simulate HBV-ACLF conditions, a model was constructed by combining chronic HBV replication (caudal vein high-pressure hydrodynamic injection of pAAV/HBV1.2 plasmid) and acute hepatic insult (intraperitoneal injection of Acetaminophen (APAP)). Then, model mice were administered either a STING agonist or STING inhibitor. Liver injury, STING pathway, autophagy flux, and macrophage polarization were assessed to elucidate the potential role of STING.

Results

The mouse model developed chronic hepatitis B and acute liver injury, partially reflecting features of clinical HBV-ACLF based on CHB. STING activation, autophagy, and macrophage polarization were found to be involved in the disease process. During the early stage (6 h) of the STING agonist treatment group, the STING pathway was activated, autophagy flux was up-regulated, and liver inflammation and injury were alleviated. Contrastingly, at the late stage of STING agonist treatment (24 h, 48 h), macrophages were polarized to the M1 phenotype, exacerbating liver inflammatory infiltration and injury. However, treatment with a STING covalent inhibitor reversed these effects.

Conclusions

Sting-induced autophagy exerts a protective effect on liver injury during the early stage. However, in later stages, STING may aggravate liver injury by shifting liver macrophage polarization to the M1 phenotype, thereby enhancing the inflammatory response.

背景与目的：hbv相关的急性慢性肝衰竭（HBV-ACLF）是一种继发于hbv相关的慢性肝病（伴或不伴肝硬化）的严重急性肝损伤，其特点是短期死亡率高。目前，专门针对慢性乙型肝炎HBV-ACLF的实验模型缺乏。因此，本研究旨在以慢性乙型肝炎（chronic hepatitis B， CHB）为基础，建立小鼠HBV-ACLF实验模型，探讨STING激活对该疾病的影响。方法：建立慢性HBV复制（尾静脉高压流体动力注射pAAV/HBV1.2质粒）和急性肝损伤（腹腔注射对乙酰氨基酚（APAP））相结合的模型，模拟HBV- aclf条件。然后，给模型小鼠注射STING激动剂或STING抑制剂。通过评估肝损伤、STING通路、自噬通量和巨噬细胞极化来阐明STING的潜在作用。结果：小鼠模型发生慢性乙型肝炎和急性肝损伤，部分反映了以慢性乙型肝炎为基础的临床HBV-ACLF特征。发现STING激活、自噬和巨噬细胞极化参与了疾病过程。在STING激动剂治疗组的早期（6 h）， STING通路被激活，自噬通量上调，肝脏炎症和损伤减轻。相反，在STING激动剂治疗的后期（24 h, 48 h），巨噬细胞极化到M1表型，加剧了肝脏炎症浸润和损伤。然而，用STING共价抑制剂治疗逆转了这些作用。结论：蜇伤诱导的自噬对早期肝损伤具有保护作用。然而，在后期，STING可能通过使肝巨噬细胞极化向M1表型转变，从而增强炎症反应，从而加重肝损伤。

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引用次数: 0

Downregulating LKB1 in bone marrow mesenchymal stem cells could inhibit CD4+ T cell proliferation via the PD-1/PD-L1 signaling pathway 下调骨髓间充质干细胞中的 LKB1 可通过 PD-1/PD-L1 信号通路抑制 CD4+ T 细胞增殖。

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-10-02 DOI: 10.1016/j.imbio.2024.152856

Yaqin Zhang , Jingyi Ren , Zhongxian Liao, Xiaoyu Li, Chunying Zhang, Bihan Huang, Yingping Cao, Jiadi Chen

Background

Our previous research has shown that LKB1 in amniotic mesenchymal stem cells (MSCs) serves as a vital regulator of regulatory T cell differentiation and T cell proliferation, which may have a similar role in bone marrow MSCs (BMMSCs). Therefore, we investigated the role of LKB1 in BMMSCs for regulating CD4⁺ T cell proliferation in the bone micro-environment of AML.

Methods

RT-PCR was used to assessed LKB1 expression in BMMSCs derived from AML patients and healthy controls. Subsequently, LKB1 was knocked down in the BMMSCs line HS-5 (HS-5-LKB1^KD). Co-cultures in vitro were established to analyze the effect of HS-5-LKB1^KD on CD4⁺ T cell. Flow cytometry was employed to measure PD-L1 and CD4⁺ T cell proliferation levels. Western blot was utilized to detect related proteins.

Results

The expression of LKB1 in BMMSCs derived from AML patients was decreased. Knockdown of LKB1 in HS-5 resulted in upregulation of PD-L1 expression. Co-culture of peripheral blood CD4⁺ T cell with HS-5-LKB1^KD exhibited reduced CD4⁺ T cell proliferation compared to co-culture with HS-5-LKB1^con. Furthermore, blocking PD-L1 in the co-culture conditions could restore the reduced CD4⁺ T cell proliferation. Additionally, it was found that upregulation of the Wnt signaling pathway-related proteins following LKB1 knockdown in HS-5, indicating that downregulating LKB1 could promote PD-L1 expression through activation of the Wnt signaling pathway.

Conclusions

The decreased expression of LKB1 in BMMSCs may activate the Wnt signaling pathway, leading to increased PD-L1 expression. This inhibited CD4⁺ T cell proliferation, which might lead to impaired anti-tumor immunity in AML patients and promote AML progression.

背景：我们之前的研究表明，羊膜间充质干细胞（MSCs）中的LKB1是调节T细胞分化和T细胞增殖的重要调节因子，它在骨髓间充质干细胞（BMMSCs）中可能也有类似的作用。因此，我们研究了LKB1在骨髓间充质干细胞中调节AML骨微环境中CD4+ T细胞增殖的作用：方法：采用 RT-PCR 技术评估 LKB1 在 AML 患者和健康对照组 BMMSCs 中的表达。随后，在 BMMSCs 株系 HS-5 中敲除 LKB1（HS-5-LKB1KD）。体外共培养分析了HS-5-LKB1KD对CD4+ T细胞的影响。采用流式细胞术测量 PD-L1 和 CD4+ T 细胞增殖水平。Western blot用于检测相关蛋白：结果：来自 AML 患者的 BMMSCs 中 LKB1 表达减少。在 HS-5 中敲除 LKB1 会导致 PD-L1 表达上调。与HS-5-LKB1KD共培养外周血CD4+ T细胞相比，与HS-5-LKB1con共培养的CD4+ T细胞增殖减少。此外，在共培养条件下阻断 PD-L1 可以恢复降低的 CD4+ T 细胞增殖。此外，研究还发现，在敲除 HS-5 中的 LKB1 后，Wnt 信号通路相关蛋白上调，这表明下调 LKB1 可通过激活 Wnt 信号通路促进 PD-L1 的表达：结论：LKB1在BMMSCs中的表达减少可能会激活Wnt信号通路，导致PD-L1表达增加。结论：BMMSCs 中 LKB1 表达的减少可能会激活 Wnt 信号通路，导致 PD-L1 表达增加，从而抑制 CD4+ T 细胞的增殖，这可能会导致 AML 患者的抗肿瘤免疫功能受损，并促进 AML 的进展。

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引用次数: 0

Pan-cancer analysis of ADAR1 with its prognostic relevance in low-grade glioma ADAR1 的泛癌分析及其在低级别胶质瘤中的预后相关性

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-09-24 DOI: 10.1016/j.imbio.2024.152855

Qin Yang , Xin Li

ADAR1, known as the primary enzyme for adenosine-to-inosine RNA editing, has recently been implicated in cancer development through both RNA editing-dependent and −independent pathways. These discoveries suggest that ADAR1′s functions may extend beyond our current understanding. A pan-cancer analysis offers a unique opportunity to identify both common and distinct mechanisms across various cancers, thereby advancing personalized medicine. Low-grade glioma (LGG), characterized by a diverse group of tumor cells, presents a challenge in risk stratification, leading to significant variations in treatment approaches. Recently discovered molecular alterations in LGG have helped to refine the stratification of of these tumors and offered novel targets for predicting likely outcomes. This study aims to provide a detailed analysis of ADAR mRNA across multiple cancers, emphasizing its prognostic significance in LGG. We observed inconsistent mRNA and consistent protein expression patterns of ADAR1/ADAR in pan-cancer analyses that across tumor types. ADAR mRNA expression did not always correlate with ADAR1 protein expression. Nevertheless, the transcript levels correlated significantly with genetic alterations, tumor mutation burden, microsatellite instability, overall survival, recurrence-free survival, immune marker presence, immune infiltration, and the survival of patients undergoing immunotherapy in select cancers. Furthermore, ADAR and its top 50 associated genes were primarily involved in mRNA-related events, as identified through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Utilizing the Cox proportional hazards model, we developed a 3-gene signature (ADAR, HNRNPK, and SMG7), which effectively stratified patients into high- and low-risk groups, with high-risk patients exhibiting poorer overall survival, higher tumor grades, and a greater number of non-codeletions. Overall, this signature was inversely related to immune infiltration across cancers. Transcription factor SPI1 and miR-206, potential upstream regulators of the signature genes, were closely linked to patient survival in LGG. The promoter regions of these genes were hypermethylated, further associating them with patient outcomes. Additionally, these genes displayed consistent drug susceptibility patterns. In conclusion, our findings reveal multiple aspects of ADAR1′s role in cancer and underscore its prognostic value in LGG, offering insights into potential therapeutic targets and strategies.

ADAR1 是腺苷酸-肌苷酸 RNA 编辑的主要酶，最近它通过 RNA 编辑依赖性和非依赖性途径与癌症的发生发展有关。这些发现表明，ADAR1 的功能可能超出了我们目前的理解范围。泛癌症分析为确定各种癌症的共同和不同机制提供了一个独特的机会，从而推动了个性化医疗的发展。低级别胶质瘤（LGG）的特点是肿瘤细胞的多样性，这给风险分层带来了挑战，导致治疗方法的显著差异。最近发现的低级别胶质瘤分子改变有助于完善这些肿瘤的分层，并为预测可能的结果提供了新的靶点。本研究旨在对多种癌症的 ADAR mRNA 进行详细分析，强调其在 LGG 中的预后意义。在跨肿瘤类型的泛癌症分析中，我们观察到 ADAR1/ADAR 的 mRNA 表达模式不一致，而蛋白表达模式则一致。ADAR mRNA表达并不总是与ADAR1蛋白表达相关。不过，转录本水平与基因改变、肿瘤突变负荷、微卫星不稳定性、总生存期、无复发生存期、免疫标记物存在、免疫浸润以及接受免疫疗法的特定癌症患者的生存期有显著相关性。此外，通过基因本体和京都基因与基因组百科全书分析发现，ADAR及其前50个相关基因主要参与mRNA相关事件。利用Cox比例危险模型，我们建立了一个3基因特征（ADAR、HNRNPK和SMG7），它能有效地将患者分为高危和低危两组，其中高危患者的总生存率较低，肿瘤分级较高，非编码缺失的数量较多。总体而言，这一特征与各种癌症的免疫浸润成反比。转录因子 SPI1 和 miR-206 是特征基因的潜在上游调控因子，它们与 LGG 患者的生存密切相关。这些基因的启动子区域发生了高甲基化，进一步将它们与患者的预后联系在一起。此外，这些基因显示出一致的药物易感性模式。总之，我们的研究结果揭示了 ADAR1 在癌症中的多方面作用，并强调了它在 LGG 中的预后价值，为潜在的治疗目标和策略提供了启示。

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引用次数: 0

Comparison of urine and serum IgG detection ELISA for tegumentary leishmaniasis diagnosis and prognosis 尿液和血清 IgG 检测 ELISA 在利什曼病诊断和预后方面的比较

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-09-17 DOI: 10.1016/j.imbio.2024.152853

Raquel S.B. Câmara , Isabela A.G. Pereira , Daniela P. Lage , Danniele L. Vale , Fernanda Ludolf , Nathália C. Galvani , Camila S. Freitas , João A. Oliveira-da-Silva , Bárbara P.N. Assis , Ana T. Chaves , Mário S. Giusta , Grasiele S.V. Tavares , César N. Pereira , Alexsandro S. Galdino , Unaí Tupinambás , Miguel A. Chávez-Fumagalli , Vanessa P.M. Pascoal , Marcela T.C. Eller , Manoel O. da Costa Rocha , Myron Christodoulides , Eduardo A.F. Coelho

Laboratorial diagnosis of tegumentary leishmaniasis (TL) is hampered by variable sensitivity and/or specificity of the tests, which are still hampered by blood́ invasive collection. In this context, in the present study, we develop a serum- and urine-based ELISA to TL diagnoses. A recombinant protein (rLiHyA), which was previously showed to be antigenic for the disease, as well as a B-cell epitope produced as synthetic peptide and a Leishmania antigenic extract (SLA), were used as antigens. A total of paired 205 urine and serum samples were used, which were comprised by samples from cutaneous (n = 30) and mucosal (n = 30) leishmaniasis patients, as well as from healthy individuals living in endemic region of disease (n = 45), of patients with Chagas disease (n = 30), leprosy (n = 35), malaria (n = 15) or HIV-infected (n = 20). Results showed that serum-based ELISA presented sensitivity of 24.0 %, 100 % and 41.0 %, when SLA, rLiHyA and synthetic peptide were used as antigens, and specificity of 98.4 %, 98.4 % and 98.4 %, respectively. The area under the curve (AUC) was calculated and results were 0.74, 1.0, and 0.71, respectively, when SLA, rLiHyA and synthetic peptide were used as antigens. Performing an urine-based ELISA, sensitivity was 28.0 %, 100 % and 75.0 %, respectively, when SLA, rLiHyA, and synthetic peptide were used, while specificity values were of 98.4 %, 98.4 % and 98.4 %, respectively. In addition, the AUC values were 0.82, 1.0, and 0.94, respectively. A significant drop in specific antibodies levels in both patientś serum and urine samples was found six months after treatment, suggesting a prognostic role of rLiHyA for TL. In conclusion, preliminary data suggest the potential of use patient urine to TL diagnoses.

皮损利什曼病（TL）的实验室诊断因检测灵敏度和/或特异性的不同而受到阻碍，而血液的侵入性采集仍阻碍着实验室诊断。在这种情况下，我们在本研究中开发了一种基于血清和尿液的酶联免疫吸附试验（ELISA）来诊断利什曼病。我们使用了一种重组蛋白（rLiHyA）作为抗原，该蛋白之前已被证明对该疾病具有抗原性，同时还使用了一种以合成肽形式产生的 B 细胞表位和一种利什曼病抗原提取物（SLA）作为抗原。共使用了 205 份成对的尿液和血清样本，其中包括皮肤利什曼病患者（30 份）和粘膜利什曼病患者（30 份）的样本，以及生活在疾病流行区的健康人（45 份）、南美锥虫病患者（30 份）、麻风病患者（35 份）、疟疾患者（15 份）或 HIV 感染者（20 份）的样本。结果显示，当使用 SLA、rLiHyA 和合成肽作为抗原时，基于血清的 ELISA 的灵敏度分别为 24.0%、100% 和 41.0%，特异性分别为 98.4%、98.4% 和 98.4%。当使用 SLA、rLiHyA 和合成肽作为抗原时，曲线下面积（AUC）的计算结果分别为 0.74、1.0 和 0.71。在尿液酶联免疫吸附试验中，使用 SLA、rLiHyA 和合成肽时，灵敏度分别为 28.0%、100% 和 75.0%，特异性分别为 98.4%、98.4% 和 98.4%。此外，AUC 值分别为 0.82、1.0 和 0.94。治疗 6 个月后，患者血清和尿液样本中的特异性抗体水平明显下降，这表明 rLiHyA 对 TL 有预后作用。总之，初步数据表明，患者尿液具有诊断 TL 的潜力。

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引用次数: 0

The role of CD24hiCD27+ regulatory B cells in human chronic rhinosinusitis with/without nasal polyps CD24hiCD27+ 调节性 B 细胞在伴有/不伴有鼻息肉的人类慢性鼻窦炎中的作用

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-09-16 DOI: 10.1016/j.imbio.2024.152854

Shiyu Tian , Jiao Xia , Ke Liu , Youxiang Ma , Hao Tian , Weiwei Wang , Ruxiang Zhang , Chunli Zhao , Shusheng Gong

Background

Regulatory B cells (Bregs) reduce allergic and autoimmune inflammation. However, their role in chronic rhinosinusitis (CRS) remains unknown. This study investigated the frequency and function of Breg subsets in the peripheral blood of patients with CRS.

Methods

The demographic and clinical characteristics were compared among control, CRSsNP, neCRSwNP, and eCRSwNP groups. The expression of various Breg subtypes was evaluated in peripheral blood mononuclear cells (PBMCs) of patients with eosinophilic CRS with nasal polyps (eCRSwNP), non-eosinophilic CRS with nasal polyps (neCRSwNP), CRS without nasal polyps (CRSsNP). CD19⁺CD24^hiCD27⁺ B cells (B10 cells) were isolated by flow cytometry, followed by RNA sequencing (RNA-seq). Finally, IL-10 secreted by B10 cells were evaluated through the intracellular stain.

Results

A higher number of eosinophils in peripheral blood and nasal polyps were found in eCRSwNP compared with neCRSwNP, CRSsNP, and control groups. The frequency of B10 in the peripheral blood B cells (B10%) of patients with eCRSwNP was significantly lower than that in the neCRSwNP and control groups. B10% was negatively correlated with the quantity of tissue eosinophils, and the percentage and absolute value of peripheral blood eosinophils. The eCRSwNP, neCRSwNP and control groups had 1403 differentially expressed genes, 35 of which were identified in four highly enriched pathways. Additionally, the frequency of IL-10⁺B10 cells in peripheral blood was lower in patients with eCRSwNP than in the neCRSwNP and control groups.

Conclusion

This study is the first to reveal differences in both the quantity and IL-10 secretion of B10 cells in patients with eCRSwNP and neCRSwNP. These variations were strongly negatively associated with eosinophils in nasal polyps and peripheral blood. IL-10⁺B10 cells may play a key role in the pathological mechanisms of CRS, particularly the recurrence of eCRSwNP.

背景调节性 B 细胞（Bregs）能减轻过敏性和自身免疫性炎症。然而，它们在慢性鼻炎（CRS）中的作用仍然未知。本研究调查了CRS患者外周血中Breg亚群的频率和功能。方法比较了对照组、CRSsNP组、neCRSwNP组和eCRSwNP组的人口统计学和临床特征。方法比较了对照组、CRSsNP 组、neCRSwNP 组和 eCRSwNP 组患者的人口统计学和临床特征，评估了嗜酸性粒细胞性 CRS 伴鼻息肉（eCRSwNP）、非嗜酸性粒细胞性 CRS 伴鼻息肉（neCRSwNP）和无鼻息肉性 CRS（CRSsNP）患者外周血单核细胞（PBMC）中各种 Breg 亚型的表达情况。通过流式细胞术分离 CD19+CD24hiCD27+ B 细胞（B10 细胞），然后进行 RNA 测序（RNA-seq）。结果与 neCRSwNP、CRSsNP 和对照组相比，eCRSwNP 组外周血和鼻息肉中嗜酸性粒细胞的数量更高。eCRSwNP 患者外周血 B 细胞中 B10 的频率（B10%）明显低于 neCRSwNP 组和对照组。B10% 与组织嗜酸性粒细胞的数量、外周血嗜酸性粒细胞的百分比和绝对值呈负相关。eCRSwNP组、neCRSwNP组和对照组共有1403个差异表达基因，其中35个基因在四条高度富集的通路中被确定。此外，eCRSwNP 患者外周血中 IL-10+B10 细胞的频率低于 neCRSwNP 组和对照组。这些变化与鼻息肉和外周血中的嗜酸性粒细胞呈强负相关。IL-10+B10 细胞可能在 CRS 的病理机制中发挥关键作用，尤其是在 eCRSwNP 的复发中。

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引用次数: 0

Retraction notice to “Increased levels of Th17 cells are associated with non-neuronal acetylcholine in COPD patients” [Immunobiology 219(5) (2014) 392–401] 慢性阻塞性肺病患者Th17细胞水平升高与非神经元乙酰胆碱有关》的撤稿通知[《免疫生物学》219（5）（2014）392-401]。

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-09-01 DOI: 10.1016/j.imbio.2024.152806

引用次数: 0

A study on the efficacy and Safety Evaluation of a novel PD-1/CTLA-4 bispecific antibody 新型 PD-1/CTLA-4 双特异性抗体的疗效和安全性评估研究。

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-08-30 DOI: 10.1016/j.imbio.2024.152844

Qi Song , Meiling Jiang , Xinrong Pan , Guanyue Zhou , Xiaomeng Zhang

Tumors constitute a significant health concern for humans, and PD-1 and CTLA-4 monoclonal antibodies have been proven effective in cancer treatment. Some researchers have identified that the combination of PD-1 and CTLA-4 dual blockade demonstrates superior therapeutic efficacy. However, the development of PD-1/CTLA-4 bispecific antibodies faces challenges in terms of both safety and efficacy. The present study discloses a novel PD-1/CTLA-4 bispecific antibody, designated as SH010. Experimental validation through surface plasmon resonance (SPR) confirmed that SH010 exhibits favorable binding activity with both PD-1 and CTLA-4. Flow cytometry analysis demonstrated stable binding of SH010 antibody to CHOK1 cells overexpressing human or cynomolgus monkey PD-1 protein and to 293F cells overexpressing human or cynomolgus monkey CTLA-4 protein. Moreover, it exhibited excellent blocking capabilities in protein binding between human PD-1 and PD-L1, as well as human CTLA-4 and CD80/CD86. Simultaneously, in vitro experiments indicate that SH010 exerts a significant activating effect on hPBMCs. In murine transplant models of human prostate cancer (22RV1) and small cell lung cancer (NCI-H69), administration of varying concentrations of the bispecific antibody significantly inhibits tumor growth. MSD analysis revealed that stimulation of hPBMCs from three different donors with SH010 did not induce the production of cytokine release syndrome. Furthermore, Single or repeated intravenous administrations of SH010 in cynomolgus monkeys show favorable systemic exposure without noticeable drug accumulation or apparent toxicity. In conclusion, SH010 represents a novel cancer therapeutic drug poised to enter clinical trials and obtain market approval.

肿瘤是人类健康的重大隐患，PD-1 和 CTLA-4 单克隆抗体已被证明在癌症治疗中有效。一些研究人员发现，PD-1和CTLA-4双重阻断的组合具有更优越的疗效。然而，PD-1/CTLA-4 双特异性抗体的开发在安全性和有效性方面都面临着挑战。本研究揭示了一种新型 PD-1/CTLA-4 双特异性抗体，命名为 SH010。通过表面等离子体共振（SPR）进行的实验验证证实，SH010 与 PD-1 和 CTLA-4 都具有良好的结合活性。流式细胞仪分析表明，SH010 抗体能与过表达人或猴 PD-1 蛋白的 CHOK1 细胞以及过表达人或猴 CTLA-4 蛋白的 293F 细胞稳定结合。此外，它还在人 PD-1 和 PD-L1 蛋白结合以及人 CTLA-4 和 CD80/CD86 蛋白结合方面表现出卓越的阻断能力。同时，体外实验表明，SH010 对 hPBMCs 有显著的激活作用。在人类前列腺癌（22RV1）和小细胞肺癌（NCI-H69）的小鼠移植模型中，施用不同浓度的双特异性抗体可显著抑制肿瘤生长。MSD 分析表明，用 SH010 刺激来自三个不同供体的 hPBMCs 不会诱导细胞因子释放综合征的产生。此外，单次或多次静脉注射 SH010 对猴显示出良好的全身暴露，没有明显的药物蓄积或毒性。总之，SH010 是一种新型癌症治疗药物，有望进入临床试验阶段并获得市场批准。

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引用次数: 0

Myeloperoxidase-deficient mice exposed to Zymosan exhibit severe neutrophilia and anemia with enhanced granulopoiesis and reduced erythropoiesis, accompanied by pulmonary inflammation 髓过氧化物酶缺乏的小鼠暴露于 Zymosan 后会出现严重的中性粒细胞增多和贫血，粒细胞生成增强，红细胞生成减少，并伴有肺部炎症

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-08-25 DOI: 10.1016/j.imbio.2024.152843

Misaki Yoshikawa , Yuki Sato , Mayu Sasaki , Yasuaki Aratani

We previously reported that myeloperoxidase-deficient (MPO^-/-) mice develop more severe neutrophil-rich lung inflammation than wild-type mice following intranasal Zymosan administration. Interestingly, we found that these mutant mice with severe lung inflammation also displayed pronounced neutrophilia and anemia, characterized by increased granulopoiesis and decreased erythropoiesis in the bone marrow, compared to wild-type mice. This condition was associated with higher concentrations of granulocyte-colony stimulating factor (G-CSF) in both the lungs and serum, a factor known to enhance granulopoiesis. Neutrophils accumulating in the lungs of MPO^-/- mice produced greater amounts of G-CSF than those in wild-type mice, indicating that they are a significant source of G-CSF. In vitro experiments using signal transduction inhibitors and Western blot analysis revealed that MPO^-/- neutrophils express higher levels of G-CSF mRNA in response to Zymosan, attributed to the upregulation of the IκB kinase/nuclear factor (NF)-κB pathway and the extracellular-signal-regulated kinase/NF-κB pathway. These findings highlight MPO as a critical regulator of granulopoiesis and erythropoiesis in inflamed tissues.

我们以前曾报道过，与野生型小鼠相比，髓过氧化物酶缺陷（MPO-/-）小鼠在鼻内注射 Zymosan 后会出现更严重的富含中性粒细胞的肺部炎症。有趣的是，我们发现与野生型小鼠相比，这些患有严重肺部炎症的突变小鼠还表现出明显的中性粒细胞增多和贫血，其特点是骨髓中粒细胞生成增加，红细胞生成减少。这种情况与肺部和血清中粒细胞集落刺激因子（G-CSF）浓度升高有关，G-CSF 是一种已知能促进粒细胞生成的因子。积聚在 MPO-/- 小鼠肺部的中性粒细胞比野生型小鼠产生更多的 G-CSF，这表明它们是 G-CSF 的重要来源。使用信号转导抑制剂和 Western 印迹分析进行的体外实验显示，MPO-/- 中性粒细胞对 Zymosan 的反应中表达更高水平的 G-CSF mRNA，这归因于 IκB 激酶/核因子（NF）-κB 通路和细胞外信号调节激酶/NF-κB 通路的上调。这些发现凸显了 MPO 是炎症组织中粒细胞生成和红细胞生成的关键调节因子。

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引用次数: 0

Dexmedetomidine induces IL-10 secretion by B lymphocytes in the peripheral blood of patients with hepatocellular carcinoma 右美托咪定可诱导肝细胞癌患者外周血中的 B 淋巴细胞分泌 IL-10

IF 2.5 4区医学 Q3 IMMUNOLOGY

Immunobiology

Pub Date : 2024-08-13 DOI: 10.1016/j.imbio.2024.152842

Miaomiao Qin , Yining Chen , Xinxin Wang , Xiaobao Zhang , Xiongxiong Pan

Background/aim

To investigate the distribution of subpopulations of peripheral blood B lymphocytes in individuals with hepatocellular carcinoma (HCC), and to evaluate the effect of dexmedetomidine (DEX) on B lymphocyte differentiation in patients with HCC in vitro.

Methods

Peripheral blood mononuclear cells (PBMCs) were collected from the HCC group and the healthy group, and the distribution of peripheral blood B-lymphocyte subpopulations in the two groups was examined by Flow Cytometry (FCM). B lymphocytes extracted from the peripheral blood of the HCC group were divided into D0, D1, D2 and D4 groups according to the different dose of DEX in the culture medium (0 μM, 1 μM, 2 μM and 4 μM). After 72 h of in vitro culture, FCM was used to detect differences in the percentage of apoptotic B lymphocytes and the percentage of B lymphocytes that can express interleukin 10(IL-10) and transforming growth factor-β (TGF-β) in each group.

Results

In contrast to the healthy group, the HCC group exhibited a statistically significant increase in the proportion of CD19 + CD73 + B lymphocyte subpopulation (P<0.05). In the in vitro culture experiment, the differences in apoptosis of B lymphocytes and the percentage of TGF-β expression in each group were not statistically significant; When compared to the control group, there was a significant increase in the percentage of B lymphocytes expressing IL-10 across the D1, D2, and D4 groups (P<0.05).

Conclusion

The peripheral blood of HCC patients is characterized by an elevated presence of CD19 + CD73 + B lymphocyte subpopulations; DEX may have an immunosuppressive effect by promoting IL-10 secretion from peripheral blood B lymphocytes of HCC patients.

背景/目的研究肝细胞癌（HCC）患者外周血B淋巴细胞亚群的分布，并评估右美托咪定（DEX）对HCC患者体外B淋巴细胞分化的影响。方法收集 HCC 组和健康组的外周血单核细胞（PBMCs），用流式细胞术（FCM）检测两组外周血 B 淋巴细胞亚群的分布。根据培养基中 DEX 的不同剂量（0 μM、1 μM、2 μM 和 4 μM），将 HCC 组外周血中提取的 B 淋巴细胞分为 D0、D1、D2 和 D4 组。结果与健康组相比，HCC 组 CD19 + CD73 + B 淋巴细胞亚群比例的增加有统计学意义（P<0.05）。在体外培养实验中，各组 B 淋巴细胞凋亡率和 TGF-β 表达比例差异无统计学意义；与对照组相比，D1、D2 和 D4 组 B 淋巴细胞表达 IL-10 的比例显著增加（P<0.05）。结论 HCC 患者外周血中 CD19 + CD73 + B 淋巴细胞亚群升高；DEX 可能通过促进 HCC 患者外周血 B 淋巴细胞分泌 IL-10 而产生免疫抑制作用。

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引用次数: 0