Pub Date : 2024-02-10DOI: 10.1038/s41435-024-00257-8
Dörte Symmank, Felix Clemens Richter, André F. Rendeiro
{"title":"Navigating the thymic landscape through development: from cellular atlas to tissue cartography","authors":"Dörte Symmank, Felix Clemens Richter, André F. Rendeiro","doi":"10.1038/s41435-024-00257-8","DOIUrl":"10.1038/s41435-024-00257-8","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00257-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716019","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}
Pub Date : 2024-01-24DOI: 10.1038/s41435-024-00255-w
A. Guffroy, L. Jacquel, Y. Seeleuthner, N. Paul, V. Poindron, F. Maurier, V. Delannoy, A. C. Voegeli, P. Zhang, B. Nespola, A. Molitor, M. J. Apithy, P. Soulas-Sprauel, T. Martin, R. E. Voll, S. Bahram, V. Gies, J. L. Casanova, A. Cobat, B. Boisson, R. Carapito, A. S. Korganow
Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti β2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.
原发性抗磷脂综合征的特征是血栓形成和针对磷脂或相关蛋白的自身抗体。原发性抗磷脂综合征的遗传病因尚不清楚。我们招募了21名血栓栓塞事件与狼疮抗凝物、抗心磷脂和抗β2糖蛋白1自身抗体相关的患者。我们进行了全外显子测序。我们将数据与公共数据库以及由873名非自身免疫患者组成的对照组进行了比较。我们对与血栓形成相关的基因、以前与APS或先天性免疫错误相关的候选基因进行了全外显子组测序和基于变异的系统分析。我们将这些数据与公共数据库以及由 873 名非自身免疫性患者组成的对照组进行了比较。采用最先进的方法对变异基因进行了鉴定。通过与对照组进行比较，进行了富集分析。我们发现这些患者不存在明显的 HLA 偏倚和遗传异质性，包括在检测涉及血栓形成的蛋白质编码基因中的罕见变异组合和与先天性免疫错误相关的基因中的变异组合时。这些结果提供了 PAPS 遗传异质性的证据，即使在同质的三阳性患者中也是如此。就个体而言，变异基因的组合可能会导致 B 细胞耐受性的破坏和血管损伤。
{"title":"An immunogenomic exome landscape of triple positive primary antiphospholipid patients","authors":"A. Guffroy, L. Jacquel, Y. Seeleuthner, N. Paul, V. Poindron, F. Maurier, V. Delannoy, A. C. Voegeli, P. Zhang, B. Nespola, A. Molitor, M. J. Apithy, P. Soulas-Sprauel, T. Martin, R. E. Voll, S. Bahram, V. Gies, J. L. Casanova, A. Cobat, B. Boisson, R. Carapito, A. S. Korganow","doi":"10.1038/s41435-024-00255-w","DOIUrl":"10.1038/s41435-024-00255-w","url":null,"abstract":"Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti β2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545707","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}
Pub Date : 2024-01-24DOI: 10.1038/s41435-024-00256-9
Peng Liu, Liwei Zhao, Guido Kroemer, Oliver Kepp
Recently we developed a dendritic cell (DC) genotype-phenotype screening platform that is based on CRISPR/Cas9-mediated gene editing of immortalized DC precursors. Whole genome screening for gain-of-function phenotypes led to the identification of BCL2 as a DC-specific immune checkpoint. Genetic or pharmacological inhibition of BCL2 similarly enhanced the antigen presentation capacity of conventional type-1 dendritic cells (cDC1) and mediated T cell-dependent anticancer immunity. The therapeutic anticancer efficacy of the BCL2 inhibitor venetoclax in mice was further increased when combined with a PD-1-targeted immune checkpoint inhibitor. In sum, we delineated a novel strategy of dual checkpoint blockade for cancer immunotherapy in which improvement of DC antigen presentation and avoidance of T cell exhaustion can be advantageously combined.
{"title":"BCL2 inhibition stimulates dendritic cell function for improved anticancer immunotherapy","authors":"Peng Liu, Liwei Zhao, Guido Kroemer, Oliver Kepp","doi":"10.1038/s41435-024-00256-9","DOIUrl":"10.1038/s41435-024-00256-9","url":null,"abstract":"Recently we developed a dendritic cell (DC) genotype-phenotype screening platform that is based on CRISPR/Cas9-mediated gene editing of immortalized DC precursors. Whole genome screening for gain-of-function phenotypes led to the identification of BCL2 as a DC-specific immune checkpoint. Genetic or pharmacological inhibition of BCL2 similarly enhanced the antigen presentation capacity of conventional type-1 dendritic cells (cDC1) and mediated T cell-dependent anticancer immunity. The therapeutic anticancer efficacy of the BCL2 inhibitor venetoclax in mice was further increased when combined with a PD-1-targeted immune checkpoint inhibitor. In sum, we delineated a novel strategy of dual checkpoint blockade for cancer immunotherapy in which improvement of DC antigen presentation and avoidance of T cell exhaustion can be advantageously combined.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545722","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}
Pub Date : 2024-01-22DOI: 10.1038/s41435-024-00254-x
Hao Zhang, Di Zhang, Yue Xu, He Zhang, Zijian Zhang, Xiaopeng Hu
Interferon-γ (IFN-γ) is an important cytokine in tissue homeostasis and immune response, while studies about it in antibody-mediated rejection (ABMR) are very limited. This study aims to comprehensively elucidate the role of IFN-γ in ABMR after renal transplantation. In six renal transplantation cohorts, the IFN-γ responses (IFNGR) biological process was consistently top up-regulated in ABMR compared to stable renal function or even T cell-mediated rejection in both allografts and peripheral blood. According to single-cell analysis, IFNGR levels were found to be broadly elevated in most cell types in allografts and peripheral blood with ABMR. In allografts with ABMR, M1 macrophages had the highest IFNGR levels and were heavily infiltrated, while kidney resident M2 macrophages were nearly absent. In peripheral blood, CD14+ monocytes had the top IFNGR level and were significantly increased in ABMR. Immunofluorescence assay showed that levels of IFN-γ and M1 macrophages were sharply elevated in allografts with ABMR than non-rejection. Importantly, the IFNGR level in allografts was identified as a strong risk factor for long-term renal graft survival. Together, this study systematically analyzed multi-omics from thirteen independent cohorts and identified IFN-γ and IFNGR as determinants of ABMR and clinical outcomes in patients after renal transplantation.
{"title":"Interferon-γ and its response are determinants of antibody-mediated rejection and clinical outcomes in patients after renal transplantation","authors":"Hao Zhang, Di Zhang, Yue Xu, He Zhang, Zijian Zhang, Xiaopeng Hu","doi":"10.1038/s41435-024-00254-x","DOIUrl":"10.1038/s41435-024-00254-x","url":null,"abstract":"Interferon-γ (IFN-γ) is an important cytokine in tissue homeostasis and immune response, while studies about it in antibody-mediated rejection (ABMR) are very limited. This study aims to comprehensively elucidate the role of IFN-γ in ABMR after renal transplantation. In six renal transplantation cohorts, the IFN-γ responses (IFNGR) biological process was consistently top up-regulated in ABMR compared to stable renal function or even T cell-mediated rejection in both allografts and peripheral blood. According to single-cell analysis, IFNGR levels were found to be broadly elevated in most cell types in allografts and peripheral blood with ABMR. In allografts with ABMR, M1 macrophages had the highest IFNGR levels and were heavily infiltrated, while kidney resident M2 macrophages were nearly absent. In peripheral blood, CD14+ monocytes had the top IFNGR level and were significantly increased in ABMR. Immunofluorescence assay showed that levels of IFN-γ and M1 macrophages were sharply elevated in allografts with ABMR than non-rejection. Importantly, the IFNGR level in allografts was identified as a strong risk factor for long-term renal graft survival. Together, this study systematically analyzed multi-omics from thirteen independent cohorts and identified IFN-γ and IFNGR as determinants of ABMR and clinical outcomes in patients after renal transplantation.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139511808","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}
Pub Date : 2024-01-22DOI: 10.1038/s41435-023-00233-8
Felix Clemens Richter, Mariia Saliutina, Ahmed N. Hegazy, Andreas Bergthaler
{"title":"Take my breath away—mitochondrial dysfunction drives CD8+ T cell exhaustion","authors":"Felix Clemens Richter, Mariia Saliutina, Ahmed N. Hegazy, Andreas Bergthaler","doi":"10.1038/s41435-023-00233-8","DOIUrl":"10.1038/s41435-023-00233-8","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-023-00233-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139520597","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}
Pub Date : 2024-01-20DOI: 10.1038/s41435-024-00253-y
Xiaohu Zhao, Dongmei Tong, Richard L. Ferrero
{"title":"Interleukin-18 produced by gastric epithelial cells protects against pre-neoplastic lesions in Helicobacter pylori infection in mice","authors":"Xiaohu Zhao, Dongmei Tong, Richard L. Ferrero","doi":"10.1038/s41435-024-00253-y","DOIUrl":"10.1038/s41435-024-00253-y","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139511887","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}
Pub Date : 2024-01-17DOI: 10.1038/s41435-024-00252-z
Yi Yao, KaiQing Yang, Qiang Wang, Zeming Zhu, Sheng Li, Bin Li, Bin Feng, Caixi Tang
This study aims to identify the cancer-associated fibroblasts (CAF)-related genes that can affect immunotherapy and drug sensitivity in hepatocellular carcinoma (HCC). Expression data and survival data associated with HCC were obtained in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted correlation network analysis (WGCNA) analysis was performed to obtain CAF-related genes. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for regression analysis and risk models. Subsequently, Gene Set Enrichment Analysis (GSEA) analysis, Gene Set Enrichment Analysis (ssGSEA) analysis, Tumor Immune Dysfunction and Exclusion (TIDE) analysis and drug sensitivity analysis were performed on the risk models. Survival analysis of CAF scores showed that the survival rate was lower in samples with high CAF scores than those with low scores. However, this difference was not significant, suggesting CAF may not directly influence the prognosis of HCC patients. Further screening of CAF-related genes yielded 33 CAF-related genes. Seven risk models constructed based on CDR2L, SPRED1, PFKP, ENG, KLF2, FSCN1 and VCAN, showed significant differences in immunotherapy and partial drug sensitivity in HCC. Seven CAF-related genes may have important roles in immunotherapy, drug sensitivity and prognostic survival in HCC patients.
本研究旨在确定可影响肝细胞癌（HCC）免疫疗法和药物敏感性的癌症相关成纤维细胞（CAF）相关基因。研究人员从癌症基因组图谱（TCGA）和基因表达总库（GEO）数据库中获得了与肝癌相关的表达数据和生存数据。通过加权相关网络分析（WGCNA）获得与CAF相关的基因。采用最小绝对收缩和选择操作器（LASSO）回归法进行回归分析和建立风险模型。随后，对风险模型进行了基因组富集分析（Gene Set Enrichment Analysis，GSEA）分析、基因组富集分析（Gene Set Enrichment Analysis，ssGSEA）分析、肿瘤免疫功能障碍和排斥（Tumor Immune Dysfunction and Exclusion，TIDE）分析以及药物敏感性分析。CAF 评分的生存率分析表明，CAF 评分高的样本生存率低于评分低的样本。然而，这一差异并不显著，表明CAF可能不会直接影响HCC患者的预后。对CAF相关基因的进一步筛选发现了33个CAF相关基因。根据CDR2L、SPRED1、PFKP、ENG、KLF2、FSCN1和VCAN构建的七个风险模型显示，这七个基因对HCC的免疫治疗和部分药物敏感性存在显著差异。七个CAF相关基因可能在HCC患者的免疫治疗、药物敏感性和预后生存中发挥重要作用。
{"title":"Prediction of CAF-related genes in immunotherapy and drug sensitivity in hepatocellular carcinoma: a multi-database analysis","authors":"Yi Yao, KaiQing Yang, Qiang Wang, Zeming Zhu, Sheng Li, Bin Li, Bin Feng, Caixi Tang","doi":"10.1038/s41435-024-00252-z","DOIUrl":"10.1038/s41435-024-00252-z","url":null,"abstract":"This study aims to identify the cancer-associated fibroblasts (CAF)-related genes that can affect immunotherapy and drug sensitivity in hepatocellular carcinoma (HCC). Expression data and survival data associated with HCC were obtained in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted correlation network analysis (WGCNA) analysis was performed to obtain CAF-related genes. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for regression analysis and risk models. Subsequently, Gene Set Enrichment Analysis (GSEA) analysis, Gene Set Enrichment Analysis (ssGSEA) analysis, Tumor Immune Dysfunction and Exclusion (TIDE) analysis and drug sensitivity analysis were performed on the risk models. Survival analysis of CAF scores showed that the survival rate was lower in samples with high CAF scores than those with low scores. However, this difference was not significant, suggesting CAF may not directly influence the prognosis of HCC patients. Further screening of CAF-related genes yielded 33 CAF-related genes. Seven risk models constructed based on CDR2L, SPRED1, PFKP, ENG, KLF2, FSCN1 and VCAN, showed significant differences in immunotherapy and partial drug sensitivity in HCC. Seven CAF-related genes may have important roles in immunotherapy, drug sensitivity and prognostic survival in HCC patients.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00252-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139484880","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}
Pub Date : 2024-01-12DOI: 10.1038/s41435-023-00251-6
Jonathan D. Worboys, Daniel M. Davis
{"title":"Do inhibitory receptors need to be proximal to stimulatory receptors to function?","authors":"Jonathan D. Worboys, Daniel M. Davis","doi":"10.1038/s41435-023-00251-6","DOIUrl":"10.1038/s41435-023-00251-6","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-023-00251-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139432443","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}
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