Pub Date : 2025-05-01DOI: 10.1016/j.cellimm.2025.104945
Simon Fillatreau
{"title":"Immunity in children: How does it begin?","authors":"Simon Fillatreau","doi":"10.1016/j.cellimm.2025.104945","DOIUrl":"10.1016/j.cellimm.2025.104945","url":null,"abstract":"","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"411 ","pages":"Article 104945"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01DOI: 10.1016/j.cellimm.2025.104961
Isadora M. de Oliveira , Mariana M. Chaves
The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) through pattern recognition receptors (PRRs). Inflammasomes, cytoplasmic protein complexes, are activated in response to PAMPs and DAMPs, leading to the release of inflammatory cytokines such as IL-1β and IL-18. NLRP3 inflammasome is one of the best characterized inflammasomes and recently its activation has been associated with granuloma formation, structures that aggregate immune cells in response to infections, such as those caused by bacteria, fungi and parasites, and autoinflammatory diseases, such as sarcoidosis. Activation of NLRP3 inflammasomes in macrophages induces the release of cytokines that recruit immune cells, such as monocytes and lymphocytes, to the site of infection. Neutrophils, monocytes, T and B lymphocytes are important in the formation and maintenance of granulomas. Although NLRP3 plays a key role in the immune response, cell recruitment and granuloma formation, many aspects of its function in different cell types remain to be elucidated. In this review, we aim to outline the NLRP3 inflammasome not only as a protein complex that aids innate immune cells in combating intracellular pathogens but also as a platform with broader implications in orchestrating immune responses. This underexplored aspect of the NLRP3 inflammasome presents a novel perspective on its involvement in immunity. Thus, we review the current understanding of the role of the NLRP3 inflammasome in immune cell infiltration and its significance in the organization and formation of granulomas in inflammatory diseases.
{"title":"The NLRP3 Inflammasome in inflammatory diseases: Cellular dynamics and role in granuloma formation","authors":"Isadora M. de Oliveira , Mariana M. Chaves","doi":"10.1016/j.cellimm.2025.104961","DOIUrl":"10.1016/j.cellimm.2025.104961","url":null,"abstract":"<div><div>The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) through pattern recognition receptors (PRRs). Inflammasomes, cytoplasmic protein complexes, are activated in response to PAMPs and DAMPs, leading to the release of inflammatory cytokines such as IL-1β and IL-18. NLRP3 inflammasome is one of the best characterized inflammasomes and recently its activation has been associated with granuloma formation, structures that aggregate immune cells in response to infections, such as those caused by bacteria, fungi and parasites, and autoinflammatory diseases, such as sarcoidosis. Activation of NLRP3 inflammasomes in macrophages induces the release of cytokines that recruit immune cells, such as monocytes and lymphocytes, to the site of infection. Neutrophils, monocytes, T and B lymphocytes are important in the formation and maintenance of granulomas. Although NLRP3 plays a key role in the immune response, cell recruitment and granuloma formation, many aspects of its function in different cell types remain to be elucidated. In this review, we aim to outline the NLRP3 inflammasome not only as a protein complex that aids innate immune cells in combating intracellular pathogens but also as a platform with broader implications in orchestrating immune responses. This underexplored aspect of the NLRP3 inflammasome presents a novel perspective on its involvement in immunity. Thus, we review the current understanding of the role of the NLRP3 inflammasome in immune cell infiltration and its significance in the organization and formation of granulomas in inflammatory diseases.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"411 ","pages":"Article 104961"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01DOI: 10.1016/j.cellimm.2025.104956
Jinyi Yan , Kalam Choi , Peicai Fu, Mengge Yang, Jing Lin, Mengcui Gui, Yue Li, Bitao Bu, Zhijun Li
Background
Corticosteroids are crucial for managing acute exacerbation symptoms and preventing relapses in myasthenia gravis (MG) patients.
Methods
Between April 15–30, 2024, 2368 online self - report questionnaires were distributed. Eventually, 444 MG patients who had received corticosteroid therapy completed the survey.
Results
Self-reported adverse events (AEs) were observed in 97.5 % of the respondents. Among them, 72.5 % (322 patients) reported experiencing more than four AEs. The quality of life (QOL) of patients with MG was significantly impacted, with average MG-QOL scores of 18.07 ± 12.03. Patients with a cumulative dosage exceeding 20 g experienced the highest incidence of various AEs compared to those with lower cumulative dosages (5–20 g and less than 5 g). Additionally, a longer duration of corticosteroid exposure was associated with a higher reported incidence of AEs. Cox risk regression modeling revealed that a longer disease course, a history of myasthenic crisis, and the average daily dose of steroids (exceeding 5 mg/d), were independent predictors of corticosteroid-associated AEs. The study revealed in a single MG center, the awareness of these AEs was low among Chinese patients.
Conclusion
This study systematically assessed the incidence and risk factors of corticosteroid-related AEs in Chinese MG patients. The study found that the occurrence of AEs was associated with the cumulative dosage and duration of corticosteroid use. Additionally, long disease duration, a history of myasthenic crises, and an average daily dosage exceeding 5 mg/d are identified as risk factors for corticosteroid-related AEs in patients with MG.
{"title":"The real-world impact of corticosteroid-associated adverse events in myasthenia gravis: A patient-reported survey analysis","authors":"Jinyi Yan , Kalam Choi , Peicai Fu, Mengge Yang, Jing Lin, Mengcui Gui, Yue Li, Bitao Bu, Zhijun Li","doi":"10.1016/j.cellimm.2025.104956","DOIUrl":"10.1016/j.cellimm.2025.104956","url":null,"abstract":"<div><h3>Background</h3><div>Corticosteroids are crucial for managing acute exacerbation symptoms and preventing relapses in myasthenia gravis (MG) patients.</div></div><div><h3>Methods</h3><div>Between April 15–30, 2024, 2368 online self - report questionnaires were distributed. Eventually, 444 MG patients who had received corticosteroid therapy completed the survey.</div></div><div><h3>Results</h3><div>Self-reported adverse events (AEs) were observed in 97.5 % of the respondents. Among them, 72.5 % (322 patients) reported experiencing more than four AEs. The quality of life (QOL) of patients with MG was significantly impacted, with average MG-QOL scores of 18.07 ± 12.03. Patients with a cumulative dosage exceeding 20 g experienced the highest incidence of various AEs compared to those with lower cumulative dosages (5–20 g and less than 5 g). Additionally, a longer duration of corticosteroid exposure was associated with a higher reported incidence of AEs. Cox risk regression modeling revealed that a longer disease course, a history of myasthenic crisis, and the average daily dose of steroids (exceeding 5 mg/d), were independent predictors of corticosteroid-associated AEs. The study revealed in a single MG center, the awareness of these AEs was low among Chinese patients.</div></div><div><h3>Conclusion</h3><div>This study systematically assessed the incidence and risk factors of corticosteroid-related AEs in Chinese MG patients. The study found that the occurrence of AEs was associated with the cumulative dosage and duration of corticosteroid use. Additionally, long disease duration, a history of myasthenic crises, and an average daily dosage exceeding 5 mg/d are identified as risk factors for corticosteroid-related AEs in patients with MG.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"411 ","pages":"Article 104956"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-22DOI: 10.1016/j.cellimm.2025.104958
Zhe Peng , Dewen Ru , Guangpeng Leng , Jinghua Peng , Meng Zhang , Bin Cai
Background
Ischemic stroke is a major cause of mortality and disability, with neuroinflammation driving secondary brain injury. Microglial activation contributes to neuronal apoptosis, BBB disruption, and prolonged neurological deficits. Apelin-13, an endogenous peptide, has demonstrated neuroprotective potential, but its precise mechanisms remain unclear. This study investigates how Apelin-13 modulates neuroinflammation and the molecular pathways involved in ischemic stroke.
Methods
Mice underwent middle cerebral artery occlusion-reperfusion (MCAO/R) to model ischemic stroke, followed by Apelin-13 administration. Neurological function was assessed using Garcia scoring, adhesive removal, rotarod, and grid-walking tests. Infarct volume was quantified via TTC staining, and MRI evaluated cerebral edema. Immunofluorescence staining and Western blotting were used to assess neuronal apoptosis and BBB integrity. Microglial activation and polarization were analyzed via Iba1 co-immunostaining with CD16 (pro-inflammatory) and Arg1 (anti-inflammatory) markers. In vitro, primary microglia and BV2 cells were exposed to oxygen-glucose deprivation (OGD) to mimic ischemia, and Apelin-13's effects on inflammatory signaling were examined. The role of the SIRT1/NF-κB axis was evaluated using the SIRT1 inhibitor EX-527.
Results
Apelin-13 significantly improved post-stroke neurological function, reduced infarct volume, and alleviated cerebral edema. It preserved BBB integrity by reducing vascular leakage and albumin extravasation and suppressed neuronal apoptosis by downregulating cleaved caspase-3. Apelin-13 also mitigated neuroinflammation by decreasing microglial activation and shifting polarization toward an anti-inflammatory phenotype, as evidenced by reduced CD16+ and increased Arg1+ microglia. In vitro, Apelin-13 suppressed OGD-induced pro-inflammatory cytokine release while promoting anti-inflammatory responses. Mechanistically, Apelin-13 upregulated SIRT1, inhibiting NF-κB signaling and reducing inflammatory mediator expression. SIRT1 inhibition with EX-527 reversed these effects, restoring NF-κB activation and pro-inflammatory microglial polarization.
Conclusions
Apelin-13 exerts neuroprotective effects in ischemic stroke by preserving BBB integrity, reducing neuronal apoptosis, and suppressing neuroinflammation. These effects are mediated through SIRT1 activation and NF-κB inhibition. Targeting the Apelin-13/SIRT1/NF-κB axis may offer a promising therapeutic strategy for mitigating neuroinflammation and improving stroke recovery.
{"title":"Apelin-13 enhances neurofunctional recovery and suppresses neuroinflammation via the SIRT1/NF-κB axis in ischemic stroke","authors":"Zhe Peng , Dewen Ru , Guangpeng Leng , Jinghua Peng , Meng Zhang , Bin Cai","doi":"10.1016/j.cellimm.2025.104958","DOIUrl":"10.1016/j.cellimm.2025.104958","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic stroke is a major cause of mortality and disability, with neuroinflammation driving secondary brain injury. Microglial activation contributes to neuronal apoptosis, BBB disruption, and prolonged neurological deficits. Apelin-13, an endogenous peptide, has demonstrated neuroprotective potential, but its precise mechanisms remain unclear. This study investigates how Apelin-13 modulates neuroinflammation and the molecular pathways involved in ischemic stroke.</div></div><div><h3>Methods</h3><div>Mice underwent middle cerebral artery occlusion-reperfusion (MCAO/R) to model ischemic stroke, followed by Apelin-13 administration. Neurological function was assessed using Garcia scoring, adhesive removal, rotarod, and grid-walking tests. Infarct volume was quantified via TTC staining, and MRI evaluated cerebral edema. Immunofluorescence staining and Western blotting were used to assess neuronal apoptosis and BBB integrity. Microglial activation and polarization were analyzed via Iba1 co-immunostaining with CD16 (pro-inflammatory) and Arg1 (anti-inflammatory) markers. In vitro, primary microglia and BV2 cells were exposed to oxygen-glucose deprivation (OGD) to mimic ischemia, and Apelin-13's effects on inflammatory signaling were examined. The role of the SIRT1/NF-κB axis was evaluated using the SIRT1 inhibitor EX-527.</div></div><div><h3>Results</h3><div>Apelin-13 significantly improved post-stroke neurological function, reduced infarct volume, and alleviated cerebral edema. It preserved BBB integrity by reducing vascular leakage and albumin extravasation and suppressed neuronal apoptosis by downregulating cleaved caspase-3. Apelin-13 also mitigated neuroinflammation by decreasing microglial activation and shifting polarization toward an anti-inflammatory phenotype, as evidenced by reduced CD16+ and increased Arg1+ microglia. In vitro, Apelin-13 suppressed OGD-induced pro-inflammatory cytokine release while promoting anti-inflammatory responses. Mechanistically, Apelin-13 upregulated SIRT1, inhibiting NF-κB signaling and reducing inflammatory mediator expression. SIRT1 inhibition with EX-527 reversed these effects, restoring NF-κB activation and pro-inflammatory microglial polarization.</div></div><div><h3>Conclusions</h3><div>Apelin-13 exerts neuroprotective effects in ischemic stroke by preserving BBB integrity, reducing neuronal apoptosis, and suppressing neuroinflammation. These effects are mediated through SIRT1 activation and NF-κB inhibition. Targeting the Apelin-13/SIRT1/NF-κB axis may offer a promising therapeutic strategy for mitigating neuroinflammation and improving stroke recovery.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104958"},"PeriodicalIF":3.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-19DOI: 10.1016/j.cellimm.2025.104955
Ruyin Liu , Zongjin Yue , Jia'an Dong , Cheng Zhang , Chuanghao Guo , Xinli Wang
Spinal cord injury (SCI) often results in severe disability or even death, with inflammation playing a critical role in hindering recovery. Although Lupeol is known for its potent anti-inflammatory properties, its specific role in SCI-induced inflammation remains underexplored. In this study, an in vitro inflammation model was established using LPS-stimulated BV2 microglia. Lupeol treatment effectively counteracted LPS-induced reductions in Na+/K+-ATPase (NKA) activity, suppression of mitophagy, M1 polarization of microglia, release of inflammatory factors, and increased pyroptosis. Mechanistically, Lupeol alleviated microglial inflammation by enhancing mitophagy through the activation of NKA activity. Furthermore, Lupeol upregulated NKA activity and mitophagy by activating the AMPKα2-mTOR-TFEB pathway. In vivo, a mouse model of SCI was established, and Lupeol was administered daily via intraperitoneal injection. Lupeol treatment significantly reduced neuronal loss, promoted microglial polarization from the M1 to the M2 phenotype, attenuated inflammation, and improved motor function recovery in SCI mice. In conclusion, Lupeol promotes mitophagy by enhancing NKA activity via the AMPK–mTOR–TFEB pathway, thereby suppressing the pro-inflammatory phenotype of microglia and mitigating SCI progression.
{"title":"Lupeol mitigates spinal cord injury by modulating microglial M1/M2 polarization via Na+/K+-ATPase-mediated mitophagy","authors":"Ruyin Liu , Zongjin Yue , Jia'an Dong , Cheng Zhang , Chuanghao Guo , Xinli Wang","doi":"10.1016/j.cellimm.2025.104955","DOIUrl":"10.1016/j.cellimm.2025.104955","url":null,"abstract":"<div><div>Spinal cord injury (SCI) often results in severe disability or even death, with inflammation playing a critical role in hindering recovery. Although Lupeol is known for its potent anti-inflammatory properties, its specific role in SCI-induced inflammation remains underexplored. In this study, an in vitro inflammation model was established using LPS-stimulated BV2 microglia. Lupeol treatment effectively counteracted LPS-induced reductions in Na<sup>+</sup>/K<sup>+</sup>-ATPase (NKA) activity, suppression of mitophagy, M1 polarization of microglia, release of inflammatory factors, and increased pyroptosis. Mechanistically, Lupeol alleviated microglial inflammation by enhancing mitophagy through the activation of NKA activity. Furthermore, Lupeol upregulated NKA activity and mitophagy by activating the AMPKα2-mTOR-TFEB pathway. In vivo, a mouse model of SCI was established, and Lupeol was administered daily via intraperitoneal injection. Lupeol treatment significantly reduced neuronal loss, promoted microglial polarization from the M1 to the M2 phenotype, attenuated inflammation, and improved motor function recovery in SCI mice. In conclusion, Lupeol promotes mitophagy by enhancing NKA activity via the AMPK–mTOR–TFEB pathway, thereby suppressing the pro-inflammatory phenotype of microglia and mitigating SCI progression.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"411 ","pages":"Article 104955"},"PeriodicalIF":3.7,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-15DOI: 10.1016/j.cellimm.2025.104954
Zhifeng Chen , Yulin Shang , Yu Yuan , Xiaoying Ji , Subo Gong , Qingping Zeng , Xudong Xiang
Th17 cells are involved in the pathogenesis of elderly asthma. Bronchial epithelial cells (BECs) can act as antigen-presenting cells, and our previous studies have shown that methyl-CPG binding domain protein 2 (MBD2) in BECs can promote Th17 cell differentiation in asthma. However, the effect of BECs from different age groups (young and old) on Th17 cells remains unclear. In this study, BECs were co-cultured with CD4+ T cells, and it was found that BECs from young mice promoted the biased differentiation of Th2 cells, while BECs from older mice facilitated the biased differentiation of Th17 cells. Interestingly, MBD2 was highly expressed in BECs from older mice compared to BECs from young mice. MBD2 silencing induced inhibition of Th17 cell differentiation, while MBD2 overexpression reversed this change and promoted Th cell differentiation into Th17 cells. Soluble inducible T cell costimulator ligand (sICOSL) is mainly involved in the regulation of T cells after activation. In this study, we found that sICOSL levels were lower in BECs of old mice compared to BECs of young mice. Mechanistically, sICOSL levels increased with MBD2 silencing and decreased with MBD2 overexpression. As expected, the addition of anti-sICOSL antibodies significantly enhanced Th17 cell differentiation and suppressed Th2 cell differentiation, while exogenous sICOSL supplementation promoted Th2 cell differentiation and inhibited Th17 cell differentiation. However, neither anti-sICOSL nor exogenous sICOSL affected the expression of MBD2. Taken together, these results suggest that BECs from older mice regulate Th17 cell differentiation via the MBD2-sICOSL axis. These findings provide new insights into the pathogenesis of Th17-activated asthma in elderly patients.
Th17细胞参与了老年哮喘的发病机制。支气管上皮细胞（BECs）可作为抗原提呈细胞，我们前期研究发现BECs中甲基化cpg结合域蛋白2 （MBD2）可促进哮喘Th17细胞分化。然而，来自不同年龄组（年轻人和老年人）的BECs对Th17细胞的影响尚不清楚。本研究将BECs与CD4+ T细胞共培养，发现来自年轻小鼠的BECs促进Th2细胞的偏分化，而来自老年小鼠的BECs促进Th17细胞的偏分化。有趣的是，与年轻小鼠的BECs相比，MBD2在老年小鼠的BECs中高度表达。MBD2沉默诱导Th17细胞分化受到抑制，而MBD2过表达逆转这一变化，促进Th细胞向Th17细胞分化。可溶性诱导T细胞共刺激配体（Soluble inducible T cell costimulator ligand, sICOSL）主要参与T细胞活化后的调控。在这项研究中，我们发现老年小鼠BECs中的sICOSL水平低于年轻小鼠BECs。机制上，sICOSL水平随着MBD2沉默而升高，随着MBD2过表达而降低。正如预期的那样，抗sICOSL抗体的加入显著增强了Th17细胞的分化，抑制了Th2细胞的分化，而外源性sICOSL的补充促进了Th2细胞的分化，抑制了Th17细胞的分化。然而，抗sICOSL和外源性sICOSL均不影响MBD2的表达。综上所述，这些结果表明来自老年小鼠的BECs通过MBD2-sICOSL轴调节Th17细胞分化。这些发现为老年患者th17活化哮喘的发病机制提供了新的见解。
{"title":"Aged mice-derived bronchial epithelial cells regulate Th17 cell differentiation in asthma via the MBD2-sICOSL axis","authors":"Zhifeng Chen , Yulin Shang , Yu Yuan , Xiaoying Ji , Subo Gong , Qingping Zeng , Xudong Xiang","doi":"10.1016/j.cellimm.2025.104954","DOIUrl":"10.1016/j.cellimm.2025.104954","url":null,"abstract":"<div><div>Th17 cells are involved in the pathogenesis of elderly asthma. Bronchial epithelial cells (BECs) can act as antigen-presenting cells, and our previous studies have shown that methyl-CPG binding domain protein 2 (MBD2) in BECs can promote Th17 cell differentiation in asthma. However, the effect of BECs from different age groups (young and old) on Th17 cells remains unclear. In this study, BECs were co-cultured with CD4<sup>+</sup> T cells, and it was found that BECs from young mice promoted the biased differentiation of Th2 cells, while BECs from older mice facilitated the biased differentiation of Th17 cells. Interestingly, MBD2 was highly expressed in BECs from older mice compared to BECs from young mice. MBD2 silencing induced inhibition of Th17 cell differentiation, while MBD2 overexpression reversed this change and promoted Th cell differentiation into Th17 cells. Soluble inducible T cell costimulator ligand (sICOSL) is mainly involved in the regulation of T cells after activation. In this study, we found that sICOSL levels were lower in BECs of old mice compared to BECs of young mice. Mechanistically, sICOSL levels increased with MBD2 silencing and decreased with MBD2 overexpression. As expected, the addition of anti-sICOSL antibodies significantly enhanced Th17 cell differentiation and suppressed Th2 cell differentiation, while exogenous sICOSL supplementation promoted Th2 cell differentiation and inhibited Th17 cell differentiation. However, neither anti-sICOSL nor exogenous sICOSL affected the expression of MBD2. Taken together, these results suggest that BECs from older mice regulate Th17 cell differentiation via the MBD2-sICOSL axis. These findings provide new insights into the pathogenesis of Th17-activated asthma in elderly patients.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"411 ","pages":"Article 104954"},"PeriodicalIF":3.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-15DOI: 10.1016/j.cellimm.2025.104950
Xiuying Liu , Yaru Feng , Zhiru Song , Jingjing Liu , Zhiqiang Luo , Guohua Yu , Jianxun Wang
Targeting CD19 with chimeric antigen receptor (CAR)-T cells is clinically effective, but tumor immune escape and tumor recurrence still occur. Designing CAR-T cells that target multiple antigens simultaneously is a viable approach for inhibiting tumor immune escape, and promising findings have been reported. In this study, we designed new CD19 and CD38 dual-target CAR-T cells that are strongly cytotoxic to target cells expressing CD19 or CD38. In vitro studies, compared with single-target CAR-T cells or CD19/CD38 tandem (Tan) CAR-T cells, CD38/CD19 Tan CAR-T cells presented similar CAR expression, superior cytotoxicity and antigen-stimulated T-cell proliferation. In vivo studies, CD38/CD19 Tan CAR-T cells demonstrated the same efficacy and safety as single-target CAR-T. These CD19/CD38 Tan CAR-T cells are fully compatible with existing clinical-grade T-cell manufacturing procedures and can be implemented using current clinical protocols. In summary, our findings provide an effective solution to the challenge of tumor immune escape in anti-CD19 CAR-T-cell therapy.
用嵌合抗原受体（CAR）-T 细胞靶向 CD19 在临床上是有效的，但肿瘤免疫逃逸和肿瘤复发仍时有发生。设计能同时靶向多种抗原的 CAR-T 细胞是抑制肿瘤免疫逃逸的一种可行方法，而且已经有了很有前景的研究结果。在这项研究中，我们设计了新型 CD19 和 CD38 双靶点 CAR-T 细胞，它们对表达 CD19 或 CD38 的靶细胞具有很强的细胞毒性。在体外研究中，与单靶点CAR-T细胞或CD19/CD38串联（Tan）CAR-T细胞相比，CD38/CD19 Tan CAR-T细胞具有相似的CAR表达、卓越的细胞毒性和抗原刺激T细胞增殖。在体内研究中，CD38/CD19 Tan CAR-T 细胞表现出与单靶点 CAR-T 细胞相同的疗效和安全性。这些 CD19/CD38 Tan CAR-T 细胞与现有的临床级 T 细胞制造程序完全兼容，可以使用当前的临床方案实施。总之，我们的研究结果为抗 CD19 CAR-T 细胞疗法中肿瘤免疫逃逸的挑战提供了有效的解决方案。
{"title":"Novel and effective tandem CD38 and CD19 targeting CAR-T cells inhibit hematological tumor immune escape","authors":"Xiuying Liu , Yaru Feng , Zhiru Song , Jingjing Liu , Zhiqiang Luo , Guohua Yu , Jianxun Wang","doi":"10.1016/j.cellimm.2025.104950","DOIUrl":"10.1016/j.cellimm.2025.104950","url":null,"abstract":"<div><div>Targeting CD19 with chimeric antigen receptor (CAR)-T cells is clinically effective, but tumor immune escape and tumor recurrence still occur. Designing CAR-T cells that target multiple antigens simultaneously is a viable approach for inhibiting tumor immune escape, and promising findings have been reported. In this study, we designed new CD19 and CD38 dual-target CAR-T cells that are strongly cytotoxic to target cells expressing CD19 or CD38. <em>In vitro</em> studies, compared with single-target CAR-T cells or CD19/CD38 tandem (Tan) CAR-T cells, CD38/CD19 Tan CAR-T cells presented similar CAR expression, superior cytotoxicity and antigen-stimulated T-cell proliferation. <em>In vivo</em> studies, CD38/CD19 Tan CAR-T cells demonstrated the same efficacy and safety as single-target CAR-T. These CD19/CD38 Tan CAR-T cells are fully compatible with existing clinical-grade T-cell manufacturing procedures and can be implemented using current clinical protocols. In summary, our findings provide an effective solution to the challenge of tumor immune escape in anti-CD19 CAR-T-cell therapy.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"411 ","pages":"Article 104950"},"PeriodicalIF":3.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-12DOI: 10.1016/j.cellimm.2025.104953
Yuling Zhang , Mengzhe Yang , Yan Li , Zaichuan Wang , Shujian Zhang , Limin Zhao , Yingyue Liu , Xinyi Li , Xue Wang , Feng Lan , Luo Zhang
Heterogeneity of monocyte-derived macrophages (MDMs) is gradually recognized in polyp tissue of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the contributions of MDM subsets for sustaining inflammation remain unclear. This study therefore aimed to characterize MDM subsets in polyp tissues and estimate their functions. We identified MDM subsets in polyp tissues by flow cytometry, and analyzed the correlation between the expression of these subsets and disease severity. We also explored the similarities and differences between tissue MDMs and classical ex vivo polarized MDMs. By using appropriate substitutes for tissue MDMs, we investigated the function of MDMs. MDM1 (lin−CD44+CD64+) and MDM3 (lin−CD44+CCR2+CD64−) were identified in polyp tissues by flow cytometry. Recurrent CRSwNP patients exhibited higher levels of MDM3 compared to non-recurrent patients. This increase in MDM3 was positively correlated with the Lund-Mackay score, the number of infiltrated tissue eosinophils, and IL-5 expression levels. Ex vivo polarized alternatively activated (M2a) macrophage preferentially expressed MDM3 marker genes, which can be used as the substitute for MDM3 within the polyp tissues. M2a macrophages engulfed more Staphylococcus aureus than classically activated (M1) macrophages. However, interferon lambda 1 (IFN-λ1) did not alter the bacterial killing efficiency of M2a macrophages, nor did it affect the activation of reactive oxidase substrate (ROS) and signal transducer and activator of transcription 1 (STAT1) pathway and viability. The increase in MDM3 within polyp tissues, similar to classical M2a macrophages, acted as bacterial reservoirs and contributed to persistent inflammation, offering insights into the underlying mechanisms of CRSwNP.
{"title":"Role of CD44+CCR2+CD64−monocyte-derived macrophage in chronic rhinosinusitis with nasal polyps","authors":"Yuling Zhang , Mengzhe Yang , Yan Li , Zaichuan Wang , Shujian Zhang , Limin Zhao , Yingyue Liu , Xinyi Li , Xue Wang , Feng Lan , Luo Zhang","doi":"10.1016/j.cellimm.2025.104953","DOIUrl":"10.1016/j.cellimm.2025.104953","url":null,"abstract":"<div><div>Heterogeneity of monocyte-derived macrophages (MDMs) is gradually recognized in polyp tissue of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the contributions of MDM subsets for sustaining inflammation remain unclear. This study therefore aimed to characterize MDM subsets in polyp tissues and estimate their functions. We identified MDM subsets in polyp tissues by flow cytometry, and analyzed the correlation between the expression of these subsets and disease severity. We also explored the similarities and differences between tissue MDMs and classical <em>ex vivo</em> polarized MDMs. By using appropriate substitutes for tissue MDMs, we investigated the function of MDMs. MDM1 (lin<sup>−</sup>CD44<sup>+</sup>CD64<sup>+</sup>) and MDM3 (lin<sup>−</sup>CD44<sup>+</sup>CCR2<sup>+</sup>CD64<sup>−</sup>) were identified in polyp tissues by flow cytometry. Recurrent CRSwNP patients exhibited higher levels of MDM3 compared to non-recurrent patients. This increase in MDM3 was positively correlated with the Lund-Mackay score, the number of infiltrated tissue eosinophils, and IL-5 expression levels. <em>Ex vivo</em> polarized alternatively activated (M2a) macrophage preferentially expressed MDM3 marker genes, which can be used as the substitute for MDM3 within the polyp tissues. M2a macrophages engulfed more <em>Staphylococcus aureus</em> than classically activated (M1) macrophages. However, interferon lambda 1 (IFN-λ1) did not alter the bacterial killing efficiency of M2a macrophages, nor did it affect the activation of reactive oxidase substrate (ROS) and signal transducer and activator of transcription 1 (STAT1) pathway and viability. The increase in MDM3 within polyp tissues, similar to classical M2a macrophages, acted as bacterial reservoirs and contributed to persistent inflammation, offering insights into the underlying mechanisms of CRSwNP.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"411 ","pages":"Article 104953"},"PeriodicalIF":3.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-12DOI: 10.1016/j.cellimm.2025.104952
Chen Meng , Tatsuyuki Sato , Ryosuke Ueda , Jiwoo Kim , Maria Serena Longhi , Joji Fujisaki
Background
Adoptive transfer of regulatory T cells (Tregs) has been proposed as a next-generation treatment approach for the treatment of various inflammatory or autoimmune disorders(Amini et al., 2022; Bluestone et al., 2023, 2015; Dall'Era et al., 2019; Chandran et al., 2017; Laukova and Glatman Zaretsky, 2023; Voskens et al., 2023; Canavan et al., 20161–8), inclusive of inflammatory bowel diseases (IBD). Identification of the appropriate Treg populations as donor sources for effective cell therapy is of great importance. We have recently identified specialized Tregs that localize within the hematopoietic stem cell (HSC) microenvironments(Fujisaki et al., 2011; Hirata et al., 2018, 2019, 2015; Kakiuchi et al., 2021a, 2021b; Furuhashi et al., 20259–16) of bone marrow (BM), termed HSC niches. These BM niche Tregs exhibit robust anti-inflammatory and pro-regenerative effects and render HSCs immune privileged. The transfer of BM niche Tregs exhibits high therapeutic effects against BM transplantation and injury(Hirata et al., 2018; Kakiuchi et al., 2021b10, 14). Yet, the treatment effects of transferred BM niche Tregs in non-BM disease settings remain unknown.
Objectives
We investigated the therapeutic effects of transfer of BM niche Tregs for IBD using mouse models of experimental colitis. To identify the key effector molecule of niche Tregs, we further examined the roles of cell-surface ectoenzyme CD39 expressed at high levels by BM niche Tregs.
Study Design
Mouse colitis was induced by administering dextran sulfate sodium salt. Subsequently, the mice received intravenous injections of BM niche Tregs, BM non-niche Tregs, lymph node Tregs, or vehicle alone. We compared these treatment effects on clinical scores, histopathological features and profiles of immune cells. We also tested how targeted deletion of CD39 in the adoptively transferred Tregs impacted experimental outcomes.
Results
The transfer of as few as 1.5 × 104 BM niche Tregs per mouse ameliorated clinical and histopathological features of the mouse colitis far better than the transfer of other Tregs. The transfer of BM niche Tregs inhibited the generation of Th17 cells and promoted the regeneration and recovery of the colon tissue. Targeted deletion of CD39 in Tregs abrogated therapeutic effects of transferred BM niche Tregs.
Conclusion
We show robust therapeutic effects of the transfer of BM niche Tregs in the experimental model of colitis. Donor niche Tregs mediate anti-inflammatory and pro-regenerative effects via Treg CD39. Our work suggests the transfer of BM niche Tregs is a promising approach to treat colitic disorders and boost tissue regeneration.
调节性T细胞（Tregs）过继性转移已被提出作为治疗各种炎症或自身免疫性疾病的新一代治疗方法(Amini等人，2022；Bluestone等，2023,2015；Dall'Era等人，2019；Chandran et al., 2017；Laukova and Glatman Zaretsky, 2023；Voskens et al., 2023；Canavan等人，20161-8)，包括炎症性肠病（IBD）。鉴别合适的Treg群体作为有效细胞治疗的供体来源是非常重要的。我们最近发现了定位于造血干细胞（HSC）微环境中的特化treg (Fujisaki等人，2011；Hirata et al., 2018, 2019, 2015；Kakiuchi等，2021a, 2021b；Furuhashi等人，20259-16)的骨髓（BM），称为造血干细胞壁龛。这些BM小众Tregs表现出强大的抗炎和促再生作用，并使造血干细胞具有免疫特权。骨髓小生境Tregs的转移对骨髓移植和损伤具有很高的治疗效果(Hirata et al., 2018；Kakiuchi et al., 2021b10,14)。然而，转移的BM生态位Tregs在非BM疾病中的治疗效果仍然未知。目的利用实验性结肠炎小鼠模型，探讨BM生态位Tregs转移对IBD的治疗作用。为了确定生态位Tregs的关键效应分子，我们进一步研究了BM生态位Tregs高水平表达的细胞表面外酶CD39的作用。研究设计给药葡聚糖硫酸钠诱导小鼠结肠炎。随后，小鼠单独静脉注射BM生态位Tregs、BM非生态位Tregs、淋巴结Tregs或载体。我们比较了这些治疗对临床评分、组织病理学特征和免疫细胞谱的影响。我们还测试了在过继转移的treg中靶向删除CD39如何影响实验结果。结果每只小鼠移植1.5 × 104个BM小位treg对小鼠结肠炎临床和组织病理学特征的改善效果远优于其他treg。BM小生境Tregs的转移抑制了Th17细胞的产生，促进了结肠组织的再生和恢复。靶向删除treg中的CD39会使转移的BM生态位treg的治疗效果失效。结论BM生态位Tregs转移对结肠炎模型的治疗作用明显。供体小生境Treg通过Treg CD39介导抗炎和促再生作用。我们的研究表明，BM生态位Tregs的转移是治疗结肠炎和促进组织再生的一种有希望的方法。
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Pub Date : 2025-04-12DOI: 10.1016/j.cellimm.2025.104951
Himani Chinnapen , Laurent Boissel , Courtney Fleenor , Thomas Bickett , Zhimin Guo , Vidya Godbole , Manju Saxena , Patrick Soon-Shiong , Hans Klingemann
Lysates from human cells represent biofluids that are used in the biotechnology field for a number of reasons such as biomarker identification and antibody detection. Lysate from human blood platelets is widely used in the clinical setting to control bleeding. We hypothesized that the lysate from the cytotoxic natural killer cell line NK-92® should contain perforin and proteolytic enzymes in addition to immunomodulatory cytokines, all of which have biological relevance and could be used for local treatment of cancer lesions. Here lysate from NK-92 (aNK™) cells, and its erIL-2 engineered variant haNK™ was obtained by repeat freeze/thawing. Immunoblot, ELISA and cytokine immunoassay analysis confirmed the presence of perforin and the full spectrum of granzymes, as well as of various chemokines and cytokines known to be expressed in NK-92 cells. Lysate from haNK cells displayed cytotoxic and anti-proliferative activity against human and canine cancer cell lines after only a 15-min exposure in vitro. Importantly, under the same conditions the lysate did not affect primary cells. Intra-tumor injection of haNK lysate into intradermal tumors of immunocompetent C57BL/6 mice provided tumor control in 40 % of treated animals. When re-challenged with the same tumor line several weeks after primary tumor clearance, no growth occurred indicating that intra-tumor administration of haNK lysate can generate a vaccine-like effect.
{"title":"Characterization of lysate from NK-92 cells and its potential use as an immunotherapeutic modality","authors":"Himani Chinnapen , Laurent Boissel , Courtney Fleenor , Thomas Bickett , Zhimin Guo , Vidya Godbole , Manju Saxena , Patrick Soon-Shiong , Hans Klingemann","doi":"10.1016/j.cellimm.2025.104951","DOIUrl":"10.1016/j.cellimm.2025.104951","url":null,"abstract":"<div><div>Lysates from human cells represent biofluids that are used in the biotechnology field for a number of reasons such as biomarker identification and antibody detection. Lysate from human blood platelets is widely used in the clinical setting to control bleeding. We hypothesized that the lysate from the cytotoxic natural killer cell line NK-92® should contain perforin and proteolytic enzymes in addition to immunomodulatory cytokines, all of which have biological relevance and could be used for local treatment of cancer lesions. Here lysate from <em>NK-92 (aNK™)</em> cells, and its erIL-2 engineered variant <em>haNK™</em> was obtained by repeat freeze/thawing. Immunoblot, ELISA and cytokine immunoassay analysis confirmed the presence of perforin and the full spectrum of granzymes, as well as of various chemokines and cytokines known to be expressed in NK-92 cells. Lysate from haNK cells displayed cytotoxic and anti-proliferative activity against human and canine cancer cell lines after only a 15-min exposure in vitro. Importantly, under the same conditions the lysate did not affect primary cells. Intra-tumor injection of haNK lysate into intradermal tumors of immunocompetent C57BL/6 mice provided tumor control in 40 % of treated animals. When re-challenged with the same tumor line several weeks after primary tumor clearance, no growth occurred indicating that intra-tumor administration of haNK lysate can generate a vaccine-like effect.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"413 ","pages":"Article 104951"},"PeriodicalIF":3.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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