European Journal of Immunology最新文献_第8页

Immune signature of patients with cardiovascular disease predicts increased risk for a severe course of COVID-19 心血管疾病患者的免疫特征可预测 COVID-19 严重病程的风险增加。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-08-02 DOI: 10.1002/eji.202451145

Manina Günter, Karin Anne Lydia Mueller, Mathew J. Salazar, Sarah Gekeler, Carolin Prang, Tobias Harm, Meinrad Paul Gawaz, Stella E. Autenrieth

{"title":"Immune signature of patients with cardiovascular disease predicts increased risk for a severe course of COVID-19","authors":"Manina Günter, Karin Anne Lydia Mueller, Mathew J. Salazar, Sarah Gekeler, Carolin Prang, Tobias Harm, Meinrad Paul Gawaz, Stella E. Autenrieth","doi":"10.1002/eji.202451145","DOIUrl":"10.1002/eji.202451145","url":null,"abstract":"Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can lead to life-threatening clinical manifestations. Patients with cardiovascular disease (CVD) are at higher risk for severe courses of COVID-19. So far, however, there are hardly any strategies for predicting the course of SARS-CoV-2 infection in CVD patients at hospital admission. Thus, we investigated whether this prediction is achievable by prospectively analysing the blood immunophenotype of 94 nonvaccinated participants, including uninfected and acutely SARS-CoV-2-infected CVD patients and healthy donors, using a 36-colour spectral flow cytometry panel. Unsupervised data analysis revealed little differences between healthy donors and CVD patients, whereas the distribution of the cell populations changed dramatically in SARS-CoV-2-infected CVD patients. The latter had more mature NK cells, activated monocyte subsets, central memory CD4+ T cells, and plasmablasts but fewer dendritic cells, CD16+ monocytes, innate lymphoid cells, and CD8+ T-cell subsets. Moreover, we identified an immune signature characterised by CD161+ T cells, intermediate effector CD8+ T cells, and natural killer T (NKT) cells that is predictive for CVD patients with a severe course of COVID-19. Thus, intensified immunophenotype analyses can help identify patients at risk of severe COVID-19 at hospital admission, improving clinical outcomes through specific treatment.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 11","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diversity of regulatory B cells: Markers and functions 调节性 B 细胞的多样性：标记和功能。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-31 DOI: 10.1002/eji.202350496

Hannah F. Bradford, Claudia Mauri

引用次数: 0

Vaccinia virus F1L blocks the ribotoxic stress response to subvert ZAKα-dependent NLRP1 inflammasome activation 疫苗病毒 F1L 阻止核糖毒性应激反应，从而颠覆 ZAKα 依赖性 NLRP1 炎症小体的激活。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-31 DOI: 10.1002/eji.202451135

Inga Szymanska, Stefan Bauernfried, Tobias Komar, Veit Hornung

{"title":"Vaccinia virus F1L blocks the ribotoxic stress response to subvert ZAKα-dependent NLRP1 inflammasome activation","authors":"Inga Szymanska, Stefan Bauernfried, Tobias Komar, Veit Hornung","doi":"10.1002/eji.202451135","DOIUrl":"10.1002/eji.202451135","url":null,"abstract":"Inflammasomes are essential for host defense, recognizing foreign or stress signals to trigger immune responses, including maturation of IL-1 family cytokines and pyroptosis. Here, NLRP1 is emerging as an important sensor of viral infection in barrier tissues. NLRP1 is activated by various stimuli, including viral double-stranded (ds) RNA, ribotoxic stress, and inhibition of dipeptidyl peptidases 8 and 9 (DPP8/9). However, certain viruses, most notably the vaccinia virus, have evolved strategies to subvert inflammasome activation or effector functions. Using the modified vaccinia virus Ankara (MVA) as a model, we investigated how the vaccinia virus inhibits inflammasome activation. We confirmed that the early gene F1L plays a critical role in inhibiting NLRP1 inflammasome activation. Interestingly, it blocks dsRNA and ribotoxic stress-dependent NLRP1 activation without affecting its DPP9-inhibition-mediated activation. Complementation and loss-of-function experiments demonstrated the sufficiency and necessity of F1L in blocking NLRP1 activation. Furthermore, we found that F1L-deficient, but not wild-type MVA, induced ZAKα activation. Indeed, an F1L-deficient virus was found to disrupt protein translation more prominently than an unmodified virus, suggesting that F1L acts in part upstream of ZAKα. These findings underscore the inhibitory role of F1L on NLRP1 inflammasome activation and provide insight into viral evasion of host defenses and the intricate mechanisms of inflammasome activation.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 10","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451135","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Illuminating the impact of γδ T cells in man and mice in spondylarthritides 阐明γδ T 细胞对人类和小鼠脊柱关节炎的影响。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-30 DOI: 10.1002/eji.202451071

Anja Meyer

{"title":"Illuminating the impact of γδ T cells in man and mice in spondylarthritides","authors":"Anja Meyer","doi":"10.1002/eji.202451071","DOIUrl":"10.1002/eji.202451071","url":null,"abstract":"Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 10","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sepsis shapes the human γδ TCR repertoire in an age- and pathogen-dependent manner 败血症以年龄和病原体依赖的方式塑造人类γδ TCR 复合物。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-29 DOI: 10.1002/eji.202451190

Eric Giannoni, Guillem Sanchez Sanchez, Isoline Verdebout, Maria Papadopoulou, Moosa Rezwani, Raya Ahmed, Kristin Ladell, Kelly L. Miners, James E. McLaren, Donald J. Fraser, David A. Price, Matthias Eberl, Swiss Pediatric Sepsis Study, Philipp K.A. Agyeman, Luregn J Schlapbach, David Vermijlen

{"title":"Sepsis shapes the human γδ TCR repertoire in an age- and pathogen-dependent manner","authors":"Eric Giannoni, Guillem Sanchez Sanchez, Isoline Verdebout, Maria Papadopoulou, Moosa Rezwani, Raya Ahmed, Kristin Ladell, Kelly L. Miners, James E. McLaren, Donald J. Fraser, David A. Price, Matthias Eberl, Swiss Pediatric Sepsis Study, Philipp K.A. Agyeman, Luregn J Schlapbach, David Vermijlen","doi":"10.1002/eji.202451190","DOIUrl":"10.1002/eji.202451190","url":null,"abstract":"Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0–16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 10","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451190","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Innate immune mechanisms promote human response to Acinetobacter baumannii infection 先天免疫机制促进人类对鲍曼不动杆菌感染的反应。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-28 DOI: 10.1002/eji.202451170

Andrea Sabatini, Massimiliano Lucidi, Serena Ciolfi, Claudia Vuotto, Marco De Bardi, Paolo Visca, Luca Battistini, Daniela Visaggio, Elisabetta Volpe

{"title":"Innate immune mechanisms promote human response to Acinetobacter baumannii infection","authors":"Andrea Sabatini, Massimiliano Lucidi, Serena Ciolfi, Claudia Vuotto, Marco De Bardi, Paolo Visca, Luca Battistini, Daniela Visaggio, Elisabetta Volpe","doi":"10.1002/eji.202451170","DOIUrl":"10.1002/eji.202451170","url":null,"abstract":"Acinetobacter baumannii is an opportunistic Gram-negative bacterium representing one of the leading causes of ventilator-associated pneumonia. The development of pneumonia results from a complex interplay between pathogens and pulmonary innate mucosal immunity. Therefore, the knowledge of the host immune responses is pivotal for the development of effective therapeutics to treat A. baumannii infections. Previous studies were conducted using cell lines and animal models, but a comprehensive understanding of the interaction between A. baumannii and primary human immune cells is still lacking. To bridge this gap, we investigated the response of primary monocytes, macrophages, and dendritic cells to the A. baumannii-type strain and an epidemic clinical isolate. We found that all immune cells trigger different responses when interacting with A. baumannii. In particular, macrophages and monocytes mediate bacterial clearance, whereas monocytes and dendritic cells activate a late response through the production of cytokines, chemokines, and the expression of co-stimulatory molecules. The epidemic strain induces lower expression of interleukin-10 and CD80 compared with the type strain, potentially constituting two immune evasion strategies.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 11","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PP2A catalytic subunit alpha is critically required for CD8+ T-cell homeostasis and antibacterial responses PP2A 催化亚基α是 CD8+ T 细胞平衡和抗菌反应的关键所在。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-28 DOI: 10.1002/eji.202451080

Xian Zhou, Meilu Li, Minji Ai, Yanfeng Li, Xingxing Zhu, Michael J. Hansen, Jun Zhong, Kenneth L. Johnson, Roman Zenka, Akhilesh Pandey, Larry R. Pease, Hu Zeng

{"title":"PP2A catalytic subunit alpha is critically required for CD8+ T-cell homeostasis and antibacterial responses","authors":"Xian Zhou, Meilu Li, Minji Ai, Yanfeng Li, Xingxing Zhu, Michael J. Hansen, Jun Zhong, Kenneth L. Johnson, Roman Zenka, Akhilesh Pandey, Larry R. Pease, Hu Zeng","doi":"10.1002/eji.202451080","DOIUrl":"10.1002/eji.202451080","url":null,"abstract":"Although the functions of tyrosine phosphatases in T-cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4+ T-cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8+ T-cell homeostasis and effector functions. Our results demonstrate that T-cell intrinsic PP2A Cα is critically required for CD8+ T-cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα–deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T-cell antibacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8+ T-cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8+ T-cell homeostasis and effector functions.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 10","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Release of IL-1β and IL-18 in human primary bronchial epithelial cells exposed to cigarette smoke is independent of NLRP3 暴露于香烟烟雾的人原代支气管上皮细胞中 IL-1β 和 IL-18 的释放与 NLRP3 无关。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-27 DOI: 10.1002/eji.202451053

Paola Dino, Maria Rita Giuffrè, Marco Buscetta, Serena Di Vincenzo, Agnese La Mensa, Marta Cristaldi, Fabio Bucchieri, Giovanna Lo Iacono, Alessandro Bertani, Elisabetta Pace, Chiara Cipollina

{"title":"Release of IL-1β and IL-18 in human primary bronchial epithelial cells exposed to cigarette smoke is independent of NLRP3","authors":"Paola Dino, Maria Rita Giuffrè, Marco Buscetta, Serena Di Vincenzo, Agnese La Mensa, Marta Cristaldi, Fabio Bucchieri, Giovanna Lo Iacono, Alessandro Bertani, Elisabetta Pace, Chiara Cipollina","doi":"10.1002/eji.202451053","DOIUrl":"10.1002/eji.202451053","url":null,"abstract":"Cigarette smoke (CS) is a major risk factor for chronic lung diseases and promotes activation of pattern recognition receptors in the bronchial epithelium. NOD-like receptor family, pyrin domain-containing 3 (NLRP3) is a pattern recognition receptor whose activation leads to caspase-1 cleavage, maturation/release of IL-1β and IL-18, and eventually pyroptosis. Whether the NLRP3 inflammasome participates in CS-induced inflammation in bronchial epithelial cells is still unclear. Herein, we evaluated the involvement of NLRP3 in CS-induced inflammatory responses in human primary bronchial epithelial cells. To this purpose, human primary bronchial epithelial cells were stimulated with CS extracts (CSE) and lytic cell death, caspase activation (-1, -8, -3/7), cytokine release (IL-1β, IL-18, and IL-8), NLRP3, pro-IL-1β/pro-IL-18 mRNA, and protein expression were measured. The impact of inhibitors of NLRP3 (MCC950), caspases, and the effect of the antioxidant N-acetyl cysteine were evaluated. We found that CSE increased pro-IL-1β expression and induced activation of caspase-1 and release of IL-1β and IL-18. These events were independent of NLRP3 and we found that NLRP3 was not expressed. N-acetyl cysteine reverted CSE-induced caspase-1 activation. Overall, our findings support that the bronchial epithelium may play a central role in the release of IL-1 family cytokines independently of NLRP3 in the lungs of smokers.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 10","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Med1 controls thymic T-cell migration into lymph node through enhancer-based Foxo1-Klf2 transcription program Med1 通过基于增强子的 Foxo1-Klf2 转录程序控制胸腺 T 细胞向淋巴结迁移。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-27 DOI: 10.1002/eji.202350887

Ning Yuan, Yanhong Su, Yang Gao, Biao Yang, Tianzhe Zhang, Qianhao Wang, Dan Zhang, Lin Shi, Anjun Jiao, Lei Lei, Lina Sun, Baojun Zhang

{"title":"Med1 controls thymic T-cell migration into lymph node through enhancer-based Foxo1-Klf2 transcription program","authors":"Ning Yuan, Yanhong Su, Yang Gao, Biao Yang, Tianzhe Zhang, Qianhao Wang, Dan Zhang, Lin Shi, Anjun Jiao, Lei Lei, Lina Sun, Baojun Zhang","doi":"10.1002/eji.202350887","DOIUrl":"10.1002/eji.202350887","url":null,"abstract":"The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter-based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T-cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4+ and CD8+ T cells in LNs, as well as a decrease of CD8+ T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αβT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αβT-cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer-based Foxo1-Klf2 transcriptional program and the migration of αβT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 10","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RAG1/2 induces double-stranded DNA breaks at non-Ig loci in the proximity of single sequence repeats in developing B cells 在发育中的 B 细胞中，RAG1/2 在单序列重复序列附近的非 Ig 基因座上诱导双链 DNA 断裂。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-07-24 DOI: 10.1002/eji.202350958

Katarina Ochodnicka-Mackovicova, Michal Mokry, Martin Haagmans, Ted E. Bradley, Carel J.M. van Noesel, Jeroen E.J. Guikema

{"title":"RAG1/2 induces double-stranded DNA breaks at non-Ig loci in the proximity of single sequence repeats in developing B cells","authors":"Katarina Ochodnicka-Mackovicova, Michal Mokry, Martin Haagmans, Ted E. Bradley, Carel J.M. van Noesel, Jeroen E.J. Guikema","doi":"10.1002/eji.202350958","DOIUrl":"10.1002/eji.202350958","url":null,"abstract":"In developing B cells, V(D)J gene recombination is initiated by the RAG1/2 endonuclease complex, introducing double-stranded DNA breaks (DSBs) in V, D, and J genes and resulting in the formation of the hypervariable parts of immunoglobulins (Ig). Persistent or aberrant RAG1/2 targeting is a potential threat to genome integrity. While RAG1 and RAG2 have been shown to bind various regions genome-wide, the in vivo off-target DNA damage instigated by RAG1/2 endonuclease remains less well understood. In the current study, we identified regions containing RAG1/2-induced DNA breaks in mouse pre-B cells on a genome-wide scale using a global DNA DSB detection strategy. We detected 1489 putative RAG1/2-dependent DSBs, most of which were located outside the Ig loci. DNA sequence motif analysis showed a specific enrichment of RAG1/2-induced DNA DSBs at GA- and CA-repeats and GC-rich motifs. These findings provide further insights into RAG1/2 off-target activity. The ability of RAG1/2 to introduce DSBs on the non-Ig loci during the endogenous V(D)J recombination emphasizes its genotoxic potential in developing lymphocytes.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"54 10","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202350958","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0