Pub Date : 2024-11-17DOI: 10.1016/j.imlet.2024.106946
Annemarie de Vreugd , Franz A. Zimmermann , Katja Steinbrücker , Maaike C. de Vries , Lonneke de Boer , Mirian CH Janssen , Martina Huemer , Saskia B. Wortmann
We here explore adverse events following immunization (AEFI) in children with mitochondrial disease (MD) recruited from two expertise centers in Austria (SALK) and The Netherlands (RUMC). Parents completed a questionnaire on the type of immunizations received and AEFI in a post-vaccination exposure period of seven days.
95 individuals were invited to this study, of whom 30 (median age 13.4 years) participated. Together these individuals had received 376 immunizations with a median of 12 vaccinations each. In 316 of 376 (84 %) vaccinations no AEFI occurred, 22 patients (73 %) never experienced any AEFI. Eight patients experienced 76 AEFI after 60 vaccinations, these were mild (redness (n = 9) /pain at injection site (n = 21), fever (n = 44), gastrointestinal complaints (n = 2)). None had a metabolic deterioration or seizures, no patient was admitted to the hospital.
Although our data is limited by the small sample size, this may aid in discussing responsible immunization decisions with parents.
{"title":"Vaccine safety in children with genetically confirmed mitochondrial disease","authors":"Annemarie de Vreugd , Franz A. Zimmermann , Katja Steinbrücker , Maaike C. de Vries , Lonneke de Boer , Mirian CH Janssen , Martina Huemer , Saskia B. Wortmann","doi":"10.1016/j.imlet.2024.106946","DOIUrl":"10.1016/j.imlet.2024.106946","url":null,"abstract":"<div><div>We here explore adverse events following immunization (AEFI) in children with mitochondrial disease (MD) recruited from two expertise centers in Austria (SALK) and The Netherlands (RUMC). Parents completed a questionnaire on the type of immunizations received and AEFI in a post-vaccination exposure period of seven days.</div><div>95 individuals were invited to this study, of whom 30 (median age 13.4 years) participated. Together these individuals had received 376 immunizations with a median of 12 vaccinations each. In 316 of 376 (84 %) vaccinations no AEFI occurred, 22 patients (73 %) never experienced any AEFI. Eight patients experienced 76 AEFI after 60 vaccinations, these were mild (redness (<em>n</em> = 9) /pain at injection site (<em>n</em> = 21), fever (<em>n</em> = 44), gastrointestinal complaints (<em>n</em> = 2)). None had a metabolic deterioration or seizures, no patient was admitted to the hospital.</div><div>Although our data is limited by the small sample size, this may aid in discussing responsible immunization decisions with parents.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"271 ","pages":"Article 106946"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667749","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 : 2024-11-13DOI: 10.1016/j.imlet.2024.106945
Fu Lv , Wuding Zhou , Ke Li
The collectins are soluble C-type lectins and a group of proteins characterized with common structural features: a collagen-like domain and a carbohydrate-binding domain. These proteins are essential components of the innate immune system, pivotal for recognizing and eliminating pathogens to protect against infections. Over recent decades, research has significantly advanced our understanding of collectins. Beyond their fundamental role in host defense, collectins have been emerged as multifunctional proteins involved in modulating inflammatory and immune responses, facilitating the clearance of cellular debris, and even stimulating cell proliferation. These diverse roles are critical for maintaining physiological balance and hold substantial implications in various disease processes, particularly in renal diseases and transplantation. Here, we review the roles of collectins in renal diseases and transplantation focusing on four prominent members of the collectin family: mannose-binding lectin (MBL), surfactant proteins (SP-A and SP-D), and collectin-11 (CL-11). These proteins have gained considerable attention in current research due to their roles in renal diseases and transplantation, shedding light on their impact beyond traditional immune defense mechanisms. Understanding their involvement in these contexts is crucial for exploring potential therapeutic avenues and interventions aimed at mitigating renal pathology and improving outcomes in transplantation settings.
采集蛋白是可溶性 C 型凝集素，是一组具有共同结构特征的蛋白质：一个胶原蛋白样结构域和一个碳水化合物结合结构域。这些蛋白质是先天性免疫系统的重要组成部分，在识别和消灭病原体以防止感染方面起着关键作用。近几十年来，研究极大地促进了我们对采集蛋白的了解。除了在宿主防御中的基本作用外，采集蛋白还被认为是一种多功能蛋白质，参与调节炎症和免疫反应，促进细胞碎片的清除，甚至刺激细胞增殖。这些不同的作用对于维持生理平衡至关重要，并在各种疾病过程中，尤其是在肾脏疾病和移植中具有重要意义。在此，我们回顾了采集蛋白在肾脏疾病和移植中的作用，重点是采集蛋白家族的四个主要成员：甘露糖结合凝集素（MBL）、表面活性蛋白（SP-A 和 SP-D）以及采集蛋白-11（CL-11）。由于这些蛋白在肾脏疾病和移植中的作用，它们在当前的研究中获得了相当大的关注，揭示了它们在传统免疫防御机制之外的影响。了解它们在这些情况下的参与对探索潜在的治疗途径和干预措施至关重要，这些途径和干预措施旨在减轻肾脏病理变化和改善移植手术的预后。
{"title":"The roles of collectins in renal diseases and transplantation","authors":"Fu Lv , Wuding Zhou , Ke Li","doi":"10.1016/j.imlet.2024.106945","DOIUrl":"10.1016/j.imlet.2024.106945","url":null,"abstract":"<div><div>The collectins are soluble C-type lectins and a group of proteins characterized with common structural features: a collagen-like domain and a carbohydrate-binding domain. These proteins are essential components of the innate immune system, pivotal for recognizing and eliminating pathogens to protect against infections. Over recent decades, research has significantly advanced our understanding of collectins. Beyond their fundamental role in host defense, collectins have been emerged as multifunctional proteins involved in modulating inflammatory and immune responses, facilitating the clearance of cellular debris, and even stimulating cell proliferation. These diverse roles are critical for maintaining physiological balance and hold substantial implications in various disease processes, particularly in renal diseases and transplantation. Here, we review the roles of collectins in renal diseases and transplantation focusing on four prominent members of the collectin family: mannose-binding lectin (MBL), surfactant proteins (SP-A and SP-D), and collectin-11 (CL-11). These proteins have gained considerable attention in current research due to their roles in renal diseases and transplantation, shedding light on their impact beyond traditional immune defense mechanisms. Understanding their involvement in these contexts is crucial for exploring potential therapeutic avenues and interventions aimed at mitigating renal pathology and improving outcomes in transplantation settings.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"271 ","pages":"Article 106945"},"PeriodicalIF":3.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619337","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 : 2024-11-12DOI: 10.1016/j.imlet.2024.106943
Yunmei Mu , Yusuke Ohno , Misa Mochizuki , Kenji Kawai , Motohito Goto , Tomoyuki Ogura , Riichi Takahashi , Mamoru Ito , Ryoji Ito
Human immune system-reconstituted humanized mice are useful animal models to study human immunology in vivo. Human hematopoietic stem cell-transferred NOG mice are well recognized as humanized immune system models with reconstitution of mature lymphoid lineage cells such as T and B cells. However, human myeloid lineage cells including dendritic cells (DCs) do not fully differentiate in conventional NOG mice. DCs play a crucial role in adaptive immunity through antigen presentation to T cells to acquire antigen specificity. In this study, we established a novel humanized mouse with human DC differentiation. To induce DCs, we generated human Fms-like tyrosine kinase 3 ligand (hFLT3L) transgenic NOG (hFLT3L-Tg) mice and transferred human CD34+ hematopoietic stem cells (HSC) into them. Unexpectedly, low frequency of human cell engraftment was observed in the hFLT3L-Tg mice after HPC reconstitution. In the Tg mice, mouse CD11b+Gr1− myeloid cells were markedly expanded in the bone marrow due to the cross-reaction between hFLT3L and mouse Flt3 receptor, and these myeloid leukemia-like cells interfered with the engraftment of human hematopoietic cells in hFLT3L-Tg mice. To avoid this cross-reaction, we further generated NOG FLT3 receptor KO (mFlt3 KO) mice by CRISPR/Cas9 technique, and the KO mice combined with hFLT3L Tg mice to create hFLT3L Tg/mFlt3 KO (FL Tg/KO) mice. Mouse CD11b+Gr1− leukemia-like cells did not proliferate in FL Tg/KO mice due to blockade of the FLT3 signals in mouse leukocytes. After human HSC transplantation, human CD45+ cells were successfully engrafted in FL Tg/KO mice. Furthermore, major subsets of human DC populations, cDC1, cDC2, and pDC, and skin Langerhans cells were significantly differentiated in FL Tg/KO mice. Therefore, these humanized mouse models are potentially valuable in the investigation of DC-mediated human adaptive immune responses in vivo.
重建人类免疫系统的人源化小鼠是研究体内人类免疫学的有用动物模型。人类造血干细胞转移 NOG 小鼠是公认的人源化免疫系统模型，可重建成熟的淋巴系细胞，如 T 细胞和 B 细胞。然而，包括树突状细胞（DC）在内的人类髓系细胞在传统的 NOG 小鼠中并没有完全分化。DCs通过向T细胞呈递抗原以获得抗原特异性，在适应性免疫中发挥着至关重要的作用。在这项研究中，我们建立了一种新型人源化小鼠，它具有人类 DC 分化功能。为了诱导DC，我们产生了人Fms样酪氨酸激酶3配体（hFLT3L）转基因NOG（hFLT3L-Tg）小鼠，并将人CD34+造血干细胞（HSC）转入其中。出乎意料的是，hFLT3L-Tg 小鼠在造血干细胞重组后，人体细胞移植的频率很低。在 Tg 小鼠中，由于 hFLT3L 和小鼠 Flt3 受体之间的交叉反应，小鼠 CD11b+Gr1- 髓系细胞在骨髓中明显增殖，这些髓系白血病样细胞干扰了人类造血细胞在 hFLT3L-Tg 小鼠中的移植。为了避免这种交叉反应，我们进一步通过CRISPR/Cas9技术产生了NOG FLT3受体KO（mFlt3 KO）小鼠，并将KO小鼠与hFLT3L Tg小鼠结合，产生了hFLT3L Tg/mFlt3 KO（FL Tg/KO）小鼠。由于小鼠白细胞中的FLT3信号被阻断，小鼠CD11b+Gr1-白血病样细胞在FL Tg/KO小鼠体内没有增殖。人类造血干细胞移植后，人类 CD45+ 细胞成功地移植到 FL Tg/KO 小鼠体内。此外，FL Tg/KO 小鼠体内的主要人 DC 亚群（cDC1、cDC2 和 pDC）和皮肤朗格汉斯细胞也显著分化。因此，这些人源化小鼠模型对研究 DC 介导的体内人类适应性免疫反应具有潜在价值。
{"title":"Human dendritic cell differentiation in hematopoietic stem cell-transplanted NOG hFLT3L Tg/mFlt3 KO humanized mice","authors":"Yunmei Mu , Yusuke Ohno , Misa Mochizuki , Kenji Kawai , Motohito Goto , Tomoyuki Ogura , Riichi Takahashi , Mamoru Ito , Ryoji Ito","doi":"10.1016/j.imlet.2024.106943","DOIUrl":"10.1016/j.imlet.2024.106943","url":null,"abstract":"<div><div>Human immune system-reconstituted humanized mice are useful animal models to study human immunology <em>in vivo</em>. Human hematopoietic stem cell-transferred NOG mice are well recognized as humanized immune system models with reconstitution of mature lymphoid lineage cells such as T and B cells. However, human myeloid lineage cells including dendritic cells (DCs) do not fully differentiate in conventional NOG mice. DCs play a crucial role in adaptive immunity through antigen presentation to T cells to acquire antigen specificity. In this study, we established a novel humanized mouse with human DC differentiation. To induce DCs, we generated human Fms-like tyrosine kinase 3 ligand (hFLT3L) transgenic NOG (hFLT3L-Tg) mice and transferred human CD34<sup>+</sup> hematopoietic stem cells (HSC) into them. Unexpectedly, low frequency of human cell engraftment was observed in the hFLT3L-Tg mice after HPC reconstitution. In the Tg mice, mouse CD11b<sup>+</sup>Gr1<sup>−</sup> myeloid cells were markedly expanded in the bone marrow due to the cross-reaction between hFLT3L and mouse Flt3 receptor, and these myeloid leukemia-like cells interfered with the engraftment of human hematopoietic cells in hFLT3L-Tg mice. To avoid this cross-reaction, we further generated NOG FLT3 receptor KO (mFlt3 KO) mice by CRISPR/Cas9 technique, and the KO mice combined with hFLT3L Tg mice to create hFLT3L Tg/mFlt3 KO (FL Tg/KO) mice. Mouse CD11b<sup>+</sup>Gr1<sup>−</sup> leukemia-like cells did not proliferate in FL Tg/KO mice due to blockade of the FLT3 signals in mouse leukocytes. After human HSC transplantation, human CD45<sup>+</sup> cells were successfully engrafted in FL Tg/KO mice. Furthermore, major subsets of human DC populations, cDC1, cDC2, and pDC, and skin Langerhans cells were significantly differentiated in FL Tg/KO mice. Therefore, these humanized mouse models are potentially valuable in the investigation of DC-mediated human adaptive immune responses <em>in vivo</em>.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"270 ","pages":"Article 106943"},"PeriodicalIF":3.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619333","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 : 2024-11-12DOI: 10.1016/j.imlet.2024.106944
Jacyelle Medeiros Silva , Renato Kaylan Alves de Oliveira França , Pedro Henrique Barros , Hitallo Guilherme Costa Fontinele , Simone Gonçalves Fonseca , Marcelo Macedo Brigido , Andrea Queiroz Maranhão
Immunological memory, a fundamental immune system mechanism, is instrumental in long-term protection. Successful vaccines can elicit and sustain immunological memory against pathogens for the long term. Memory B cells (MBC) are key players in secondary responses due to their longevity and rapid differentiation into high-affinity antibody-secreting cells upon second antigen exposure. However, the availability of circulating MBCs is limited. Here we describe a protocol, which presents a straightforward and practical method for activating and expanding Zika virus (ZIKV) specific MBC. PBMCs collected from individuals who had been infected with ZIKV two years prior were cultured by supplementing with IL-2 and R848, a TLR-7/8 agonist, and then pulsed with inactivated virus. After seven days, this stimulation led to a notable rise in virus-specific functional MBC, as evidenced by a significant increase in the production of anti-ZIKV IgG. Importantly, the ZIKV pulse did not induce changes in the PBMC culture of individuals without a history of ZIKV infection. These findings demonstrate that virus-specific MBC can be expanded in vitro, even using PBMC cultures from individuals infected years before. Therefore, our protocol is a practical and effective tool for studies that require a larger number of human MBCs from previously infected individuals that are functional and specific to the pathogen under investigation.
免疫记忆是免疫系统的一种基本机制，对长期保护至关重要。成功的疫苗可以激发并维持针对病原体的长期免疫记忆。记忆 B 细胞（MBC）寿命长，并且在第二次接触抗原时能迅速分化为高亲和性抗体分泌细胞，因此是次级反应的关键因素。然而，循环 MBC 的可用性有限。在此，我们介绍了一种激活和扩增寨卡病毒（ZIKV）特异性 MBC 的直接而实用的方法。通过补充 IL-2 和 TLR-7/8 激动剂 R848 来培养从两年前感染过 ZIKV 的人身上收集的 PBMC，然后用灭活病毒进行脉冲刺激。七天后，这种刺激导致病毒特异性功能性 MBC 明显增加，抗 ZIKV IgG 的产生显著增加就是证明。重要的是，ZIKV 脉冲不会诱导无 ZIKV 感染史的个体的 PBMC 培养发生变化。这些研究结果表明，病毒特异性 MBC 可以在体外扩增，即使使用的是多年前感染者的 PBMC 培养物。因此，我们的方案是一种实用而有效的工具，适用于需要从先前感染者那里获得更多具有功能性和对所研究病原体特异性的人类 MBC 的研究。
{"title":"Rescuing pathogen-specific memory B-cell from PBMC of prior Zika virus-infected individuals","authors":"Jacyelle Medeiros Silva , Renato Kaylan Alves de Oliveira França , Pedro Henrique Barros , Hitallo Guilherme Costa Fontinele , Simone Gonçalves Fonseca , Marcelo Macedo Brigido , Andrea Queiroz Maranhão","doi":"10.1016/j.imlet.2024.106944","DOIUrl":"10.1016/j.imlet.2024.106944","url":null,"abstract":"<div><div>Immunological memory, a fundamental immune system mechanism, is instrumental in long-term protection. Successful vaccines can elicit and sustain immunological memory against pathogens for the long term. Memory B cells (MBC) are key players in secondary responses due to their longevity and rapid differentiation into high-affinity antibody-secreting cells upon second antigen exposure. However, the availability of circulating MBCs is limited. Here we describe a protocol, which presents a straightforward and practical method for activating and expanding Zika virus (ZIKV) specific MBC. PBMCs collected from individuals who had been infected with ZIKV two years prior were cultured by supplementing with IL-2 and R848, a TLR-7/8 agonist, and then pulsed with inactivated virus. After seven days, this stimulation led to a notable rise in virus-specific functional MBC, as evidenced by a significant increase in the production of anti-ZIKV IgG. Importantly, the ZIKV pulse did not induce changes in the PBMC culture of individuals without a history of ZIKV infection. These findings demonstrate that virus-specific MBC can be expanded <em>in vitro</em>, even using PBMC cultures from individuals infected years before. Therefore, our protocol is a practical and effective tool for studies that require a larger number of human MBCs from previously infected individuals that are functional and specific to the pathogen under investigation.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"271 ","pages":"Article 106944"},"PeriodicalIF":3.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619335","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 : 2024-11-06DOI: 10.1016/j.imlet.2024.106939
Thomas C. Pelgrim , Bernard N. Jukema , Nienke Vrisekoop, Leo Koenderman
{"title":"Eosinophils are sparse in homeostatic rectal tissue which impedes studying resident eosinophils","authors":"Thomas C. Pelgrim , Bernard N. Jukema , Nienke Vrisekoop, Leo Koenderman","doi":"10.1016/j.imlet.2024.106939","DOIUrl":"10.1016/j.imlet.2024.106939","url":null,"abstract":"","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"270 ","pages":"Article 106939"},"PeriodicalIF":3.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604269","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 : 2024-11-01DOI: 10.1016/j.imlet.2024.106941
Wieteke Broeders , Julia van Tuijl , Harmke B. Duindam , Annemieke M. Peters van Ton , Marlies P. Noz , Peter Pickkers , Wilson F. Abdo , Mihai G. Netea , Siroon Bekkering , Niels P. Riksen
Major surgery such as coronary artery bypass grafting (CABG) is associated with an increased post-operative risk of atherosclerotic cardiovascular events. Cells of the innate immune system can adopt a long-lasting pro-inflammatory and atherogenic phenotype after brief exposure to exogenous or endogenous inflammatory stimuli, a process called “trained immunity”. We hypothesized that the surgery-induced inflammation leads to sustained alterations in monocyte function, which promote the subsequent occurrence of cardiovascular events. Blood from 13 patients undergoing elective CABG was obtained before, 3–7 days (median 4) after, and 6–8 weeks (median 6) weeks after surgery. At 3–7 days postoperatively, circulating C-reactive protein (CRP) concentration, leukocyte counts and ex vivo Peripheral Blood Mononuclear Cell (PBMC) IL-6, TNFα and IL-1Ra production after stimulation (with various inflammatory stimuli) were significantly increased. Simultaneously, there was a reduction in monocyte HLA-DR expression. 6–8 weeks after CABG there was an ongoing systemic pro-inflammatory state with higher CRP concentrations, increased stimulated ex vivo PBMC IL-6 production, changes in monocytes subsets, and a higher expression of CCR2 on monocytes compared to baseline. In conclusion, CABG induces a persistent systemic inflammatory reaction with a sustained activated monocyte phenotype. This might contribute to the increased atherosclerotic cardiovascular event risk observed in cardiac surgery patients.
{"title":"Long-term monocyte activation after coronary artery bypass grafting: An exploratory prospective observational study","authors":"Wieteke Broeders , Julia van Tuijl , Harmke B. Duindam , Annemieke M. Peters van Ton , Marlies P. Noz , Peter Pickkers , Wilson F. Abdo , Mihai G. Netea , Siroon Bekkering , Niels P. Riksen","doi":"10.1016/j.imlet.2024.106941","DOIUrl":"10.1016/j.imlet.2024.106941","url":null,"abstract":"<div><div>Major surgery such as coronary artery bypass grafting (CABG) is associated with an increased post-operative risk of atherosclerotic cardiovascular events. Cells of the innate immune system can adopt a long-lasting pro-inflammatory and atherogenic phenotype after brief exposure to exogenous or endogenous inflammatory stimuli, a process called “trained immunity”. We hypothesized that the surgery-induced inflammation leads to sustained alterations in monocyte function, which promote the subsequent occurrence of cardiovascular events. Blood from 13 patients undergoing elective CABG was obtained before, 3–7 days (median 4) after, and 6–8 weeks (median 6) weeks after surgery. At 3–7 days postoperatively, circulating C-reactive protein (CRP) concentration, leukocyte counts and <em>ex vivo</em> Peripheral Blood Mononuclear Cell (PBMC) IL-6, TNFα and IL-1Ra production after stimulation (with various inflammatory stimuli) were significantly increased. Simultaneously, there was a reduction in monocyte HLA-DR expression. 6–8 weeks after CABG there was an ongoing systemic pro-inflammatory state with higher CRP concentrations, increased stimulated <em>ex vivo</em> PBMC IL-6 production, changes in monocytes subsets, and a higher expression of CCR2 on monocytes compared to baseline. In conclusion, CABG induces a persistent systemic inflammatory reaction with a sustained activated monocyte phenotype. This might contribute to the increased atherosclerotic cardiovascular event risk observed in cardiac surgery patients.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"270 ","pages":"Article 106941"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.imlet.2024.106942
Enrico Maggi , Enrico Munari , Nadine Landolina , Francesca Romana Mariotti , Bruno Azzarone , Lorenzo Moretta
T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells.
In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.
T 细胞是参与抗肿瘤免疫的主要效应细胞，介导了大部分针对癌症的适应性反应。肿瘤抗原特异性的幼稚 T 淋巴细胞在淋巴结中启动后，会增殖并分化成效应 CD4+ 和 CD8+ T 细胞，它们会从外周迁移到肿瘤部位，目的是消灭癌细胞。然后，虽然大多数效应 T 细胞死亡，但仍有一小部分作为长效记忆 T 细胞存在并再循环，当再次遇到相同的抗原时，它们会产生更强的免疫反应。一些 T（和非 T）细胞亚群稳定地驻留在非淋巴外周组织中，可提供快速的免疫反应，而不依赖于从血液中招募的 T 细胞，以对抗癌细胞的再次出现。然而，当肿瘤生长时，肿瘤细胞会逃避效应细胞（NK 和 CTL 细胞）的免疫监视，而效应细胞已经耗竭，因此有利于 T（和非 T）调节细胞的局部扩增。在这篇综述中，我们将对成人和儿童实体瘤的肿瘤微环境（TME）中存在的 T 细胞的特征、上调免疫检查点分子的机制以及导致 T 效应细胞功能障碍和衰竭的转录和表观遗传景观进行综述。T 细胞与癌细胞或 TME 非肿瘤细胞的相互作用及其分泌的分子塑造了 T 细胞特征，损害了 T 细胞的内在可塑性，因此有利于免疫逃避。在这一阶段，调节性 T 细胞有助于维持高度免疫抑制的 TME，从而促进肿瘤细胞增殖和转移扩散。尽管癌症免疫疗法取得了进步，但许多肿瘤对免疫检查点抑制剂、治疗疫苗或基于 CAR T 细胞的领养疗法没有反应：最后提出了一些新策略来改进这些基于 T 细胞的疗法。
{"title":"T cell landscape in the microenvironment of human solid tumors","authors":"Enrico Maggi , Enrico Munari , Nadine Landolina , Francesca Romana Mariotti , Bruno Azzarone , Lorenzo Moretta","doi":"10.1016/j.imlet.2024.106942","DOIUrl":"10.1016/j.imlet.2024.106942","url":null,"abstract":"<div><div>T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells.</div><div>In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"270 ","pages":"Article 106942"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564380","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 : 2024-10-29DOI: 10.1016/j.imlet.2024.106940
Fangyuan Cong , Yang Zhang , Jun Xu , Xiaohui Fang , Xia Li , Qian Xue , Jingtong Wang , Yulan Liu
Immunosenescence is an age-associated change in immunological function. The intestinal mucosal immune system is considered the largest immune system in the human body, and its immunosenescence is closely related to the occurrence and development of many diseases. In recent years, studies have identified a crucial correlation between abnormal lipid metabolism induced by high-fat diet (HFD) and immunity, but the effect and mechanism of HFD on colonic mucosal immunosenescence are still unclear. In this study, we established an abnormal lipid metabolism model at different ages by feeding male wild-type mice HFD and compared the immunosenescence of the spleen, which reflects systemic immunity, and the colonic lamina propria (LP), which reflects local immunity. The results showed that HFD could lead to abnormal lipid metabolism at different ages, accelerate systemic and local immunosenescence, and increase the expression of inflammatory factors in colonic tissue. The levels of abnormal biochemical indicators induced by HFD were closely related to the proportions of T cell subsets associated with immunosenescence. Overall, the results showed that HFD had the most significant impact on aged mice. This study provides new ideas for further understanding the relationship between abnormal lipid metabolism and intestinal mucosal immunosenescence.
{"title":"The effect of abnormal lipid metabolism on immunosenescence of the colonic lamina propria in mice of different ages","authors":"Fangyuan Cong , Yang Zhang , Jun Xu , Xiaohui Fang , Xia Li , Qian Xue , Jingtong Wang , Yulan Liu","doi":"10.1016/j.imlet.2024.106940","DOIUrl":"10.1016/j.imlet.2024.106940","url":null,"abstract":"<div><div>Immunosenescence is an age-associated change in immunological function. The intestinal mucosal immune system is considered the largest immune system in the human body, and its immunosenescence is closely related to the occurrence and development of many diseases. In recent years, studies have identified a crucial correlation between abnormal lipid metabolism induced by high-fat diet (HFD) and immunity, but the effect and mechanism of HFD on colonic mucosal immunosenescence are still unclear. In this study, we established an abnormal lipid metabolism model at different ages by feeding male wild-type mice HFD and compared the immunosenescence of the spleen, which reflects systemic immunity, and the colonic lamina propria (LP), which reflects local immunity. The results showed that HFD could lead to abnormal lipid metabolism at different ages, accelerate systemic and local immunosenescence, and increase the expression of inflammatory factors in colonic tissue. The levels of abnormal biochemical indicators induced by HFD were closely related to the proportions of T cell subsets associated with immunosenescence. Overall, the results showed that HFD had the most significant impact on aged mice. This study provides new ideas for further understanding the relationship between abnormal lipid metabolism and intestinal mucosal immunosenescence.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"270 ","pages":"Article 106940"},"PeriodicalIF":3.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545263","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 : 2024-10-28DOI: 10.1016/j.imlet.2024.106937
Jo Spencer , Sahil Jain
The bacteria in the human colon outnumber the total number of nucleated cells in the human body by approximately 10:1. The DNA that the bacteria contain is enriched around 20-fold in immune stimulatory CpG motifs compared to the DNA of host cells. In addition, this DNA can have alternative more immunogeneic DNA structures and it may be presented to the immune system alongside other proinflammatory bacterial innate ligands such as LPS. To ensure that this immunostimulatory combination is not pathogenic, the luminal boundary of host tissues in the human gastrointestinal tract is protected by cells secreting bactericides together with the secreted enzyme DNASE1L3 that can break down bacterial DNA. Cells with RNA encoding DNASE1L3 are particularly abundant in the gut-associated lymphoid tissue where bacteria are specifically sampled into the body, alongside B cells noted for their T independent function. Importantly, individuals with loss of function mutations in DNASE1L3 develop anti-DNA antibodies and lupus symptoms.
In this review, we explore the possibility that a perfect storm might break tolerance to DNA: when bacterial DNA from microbiota that is not digested by DNASE1L3 directly encounters B cells that are not necessarily restricted by T cell dependence.
人体结肠中的细菌数量约为人体有核细胞总数的 10:1。与宿主细胞的 DNA 相比，细菌所含的 DNA 富含约 20 倍的免疫刺激 CpG 基序。此外，这种 DNA 可能具有替代性更强的免疫基因 DNA 结构，并可能与 LPS 等其他促炎性细菌先天配体一起呈现给免疫系统。为了确保这种免疫刺激组合不会致病，人类胃肠道中宿主组织的管腔边界受到了分泌杀菌剂的细胞以及能分解细菌 DNA 的分泌酶 DNASE1L3 的保护。具有编码 DNASE1L3 的 RNA 的细胞在肠道相关淋巴组织中特别多，细菌会在这些淋巴组织中被特异性地采集到体内。重要的是，DNASE1L3 功能缺失突变的个体会出现抗 DNA 抗体和狼疮症状。在这篇综述中，我们探讨了一场完美风暴可能会打破对 DNA 的耐受性的可能性：当微生物群中未被 DNASE1L3 消化的细菌 DNA 直接遇到不一定受 T 细胞依赖性限制的 B 细胞时。
{"title":"Could tolerance to DNA be broken in the gut in systemic lupus erythematosus?","authors":"Jo Spencer , Sahil Jain","doi":"10.1016/j.imlet.2024.106937","DOIUrl":"10.1016/j.imlet.2024.106937","url":null,"abstract":"<div><div>The bacteria in the human colon outnumber the total number of nucleated cells in the human body by approximately 10:1. The DNA that the bacteria contain is enriched around 20-fold in immune stimulatory CpG motifs compared to the DNA of host cells. In addition, this DNA can have alternative more immunogeneic DNA structures and it may be presented to the immune system alongside other proinflammatory bacterial innate ligands such as LPS. To ensure that this immunostimulatory combination is not pathogenic, the luminal boundary of host tissues in the human gastrointestinal tract is protected by cells secreting bactericides together with the secreted enzyme DNASE1L3 that can break down bacterial DNA. Cells with RNA encoding DNASE1L3 are particularly abundant in the gut-associated lymphoid tissue where bacteria are specifically sampled into the body, alongside B cells noted for their T independent function. Importantly, individuals with loss of function mutations in DNASE1L3 develop anti-DNA antibodies and lupus symptoms.</div><div>In this review, we explore the possibility that a perfect storm might break tolerance to DNA: when bacterial DNA from microbiota that is not digested by DNASE1L3 directly encounters B cells that are not necessarily restricted by T cell dependence.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"270 ","pages":"Article 106937"},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.imlet.2024.106938
Julia Busselaar , Merel Sijbranda , Jannie Borst
Both type I interferon (IFN-I) and CD4+ T-cell help are required to generate effective CD8+ T-cell responses to cancer. We here outline based on existing literature how IFN-I signaling and CD4+ T-cell help are connected. Both impact on the functional state of dendritic cells (DCs), particularly conventional (c)DC1. The cDC1s are critical for crosspresentation of cell-associated antigens and for delivery of CD4+ T-cell help for cytotoxic T-lymphocyte (CTL) effector and memory differentiation. In infection, production of IFN-I is prompted by pathogen-associated molecular patterns (PAMPs), while in cancer it relies on danger-associated molecular patterns (DAMPs). IFN-I production by tumor cells and pDCs in the tumor micro-environment (TME) is often limited. IFN-I signals increase the ability of migratory cDC1s and cDC2s to transport tumor antigens to tumor-draining lymph nodes (tdLNs). IFN-I also enables cDC1s to form and sustain the platform for help delivery by stimulating the production of chemokines that attract CD4+ and CD8+ T cells. IFN-I promotes delivery of help in concert with CD40 signals by additive and synergistic impact on cross-presentation and provision of critical costimulatory and cytokine signals for CTL effector and memory differentiation. The scenario of CD4+ T-cell help therefore depends on IFN-I signaling. This scenario can play out in tdLNs as well as in the TME, thereby contributing to the cancer immunity cycle. The collective observations may explain why both IFN-I and CD4+ T-cell help signatures in the TME correlate with good prognosis and response to PD-1 targeting immunotherapy in human cancer. They also may explain why a variety of tumor types in which IFN-I signaling is attenuated, remain devoid of functional CTLs.
I 型干扰素（IFN-I）和 CD4+ T 细胞的帮助对产生有效的 CD8+ T 细胞抗癌反应都是必需的。我们在此根据现有文献概述 IFN-I 信号传导与 CD4+ T 细胞帮助之间的联系。两者都会影响树突状细胞（DCs）的功能状态，尤其是常规（c）DC1。cDC1s对于细胞相关抗原的交叉呈递以及CD4+ T细胞对细胞毒性T淋巴细胞（CTL）效应器和记忆分化的帮助至关重要。在感染中，病原体相关分子模式（PAMPs）促使 IFN-I 的产生，而在癌症中，IFN-I 的产生则依赖于危险相关分子模式（DAMPs）。肿瘤微环境（TME）中的肿瘤细胞和 pDC 产生的 IFN-I 通常是有限的。IFN-I 信号能增强迁移性 cDC1s 和 cDC2s 将肿瘤抗原运送到肿瘤引流淋巴结（tdLNs）的能力。IFN-I 还能刺激趋化因子的产生，吸引 CD4+ 和 CD8+ T 细胞，从而使 cDC1s 形成并维持帮助递送平台。IFN-I 通过对交叉呈递和为 CTL 效应体和记忆分化提供关键性成本刺激和细胞因子信号产生相加和协同影响，从而与 CD40 信号共同促进帮助的传递。因此，CD4+ T 细胞的帮助取决于 IFN-I 信号。这种情况既可在tdLNs中发生，也可在TME中发生，从而促进癌症免疫循环。这些观察结果可以解释为什么在 TME 中 IFN-I 和 CD4+ T 细胞帮助特征与人类癌症的良好预后和对 PD-1 靶向免疫疗法的反应相关。它们还可以解释为什么 IFN-I 信号被削弱的各种肿瘤类型仍然缺乏功能性 CTL。
{"title":"The importance of type I interferon in orchestrating the cytotoxic T-cell response to cancer","authors":"Julia Busselaar , Merel Sijbranda , Jannie Borst","doi":"10.1016/j.imlet.2024.106938","DOIUrl":"10.1016/j.imlet.2024.106938","url":null,"abstract":"<div><div>Both type I interferon (IFN-I) and CD4<sup>+</sup> T-cell help are required to generate effective CD8<sup>+</sup> T-cell responses to cancer. We here outline based on existing literature how IFN-I signaling and CD4<sup>+</sup> T-cell help are connected. Both impact on the functional state of dendritic cells (DCs), particularly conventional (c)DC1. The cDC1s are critical for crosspresentation of cell-associated antigens and for delivery of CD4<sup>+</sup> T-cell help for cytotoxic T-lymphocyte (CTL) effector and memory differentiation. In infection, production of IFN-I is prompted by pathogen-associated molecular patterns (PAMPs), while in cancer it relies on danger-associated molecular patterns (DAMPs). IFN-I production by tumor cells and pDCs in the tumor micro-environment (TME) is often limited. IFN-I signals increase the ability of migratory cDC1s and cDC2s to transport tumor antigens to tumor-draining lymph nodes (tdLNs). IFN-I also enables cDC1s to form and sustain the platform for help delivery by stimulating the production of chemokines that attract CD4<sup>+</sup> and CD8<sup>+</sup> T cells. IFN-I promotes delivery of help in concert with CD40 signals by additive and synergistic impact on cross-presentation and provision of critical costimulatory and cytokine signals for CTL effector and memory differentiation. The scenario of CD4<sup>+</sup> T-cell help therefore depends on IFN-I signaling. This scenario can play out in tdLNs as well as in the TME, thereby contributing to the cancer immunity cycle. The collective observations may explain why both IFN-I and CD4<sup>+</sup> T-cell help signatures in the TME correlate with good prognosis and response to PD-1 targeting immunotherapy in human cancer. They also may explain why a variety of tumor types in which IFN-I signaling is attenuated, remain devoid of functional CTLs.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"270 ","pages":"Article 106938"},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560883","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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