Pub Date : 2024-06-06DOI: 10.1038/s41435-024-00279-2
Eric Engelbrecht, Oscar L. Rodriguez, Kaitlyn Shields, Steven Schultze, David Tieri, Uddalok Jana, Gur Yaari, William D. Lees, Melissa L. Smith, Corey T. Watson
Immunoglobulins (IGs), critical components of the human immune system, are composed of heavy and light protein chains encoded at three genomic loci. The IG Kappa (IGK) chain locus consists of two large, inverted segmental duplications. The complexity of the IG loci has hindered use of standard high-throughput methods for characterizing genetic variation within these regions. To overcome these limitations, we use long-read sequencing to create haplotype-resolved IGK assemblies in an ancestrally diverse cohort (n = 36), representing the first comprehensive description of IGK haplotype variation. We identify extensive locus polymorphism, including novel single nucleotide variants (SNVs) and novel structural variants harboring functional IGKV genes. Among 47 functional IGKV genes, we identify 145 alleles, 67 of which were not previously curated. We report inter-population differences in allele frequencies for 10 IGKV genes, including alleles unique to specific populations within this dataset. We identify haplotypes carrying signatures of gene conversion that associate with SNV enrichment in the IGK distal region, and a haplotype with an inversion spanning the proximal and distal regions. These data provide a critical resource of curated genomic reference information from diverse ancestries, laying a foundation for advancing our understanding of population-level genetic variation in the IGK locus.
{"title":"Resolving haplotype variation and complex genetic architecture in the human immunoglobulin kappa chain locus in individuals of diverse ancestry","authors":"Eric Engelbrecht, Oscar L. Rodriguez, Kaitlyn Shields, Steven Schultze, David Tieri, Uddalok Jana, Gur Yaari, William D. Lees, Melissa L. Smith, Corey T. Watson","doi":"10.1038/s41435-024-00279-2","DOIUrl":"10.1038/s41435-024-00279-2","url":null,"abstract":"Immunoglobulins (IGs), critical components of the human immune system, are composed of heavy and light protein chains encoded at three genomic loci. The IG Kappa (IGK) chain locus consists of two large, inverted segmental duplications. The complexity of the IG loci has hindered use of standard high-throughput methods for characterizing genetic variation within these regions. To overcome these limitations, we use long-read sequencing to create haplotype-resolved IGK assemblies in an ancestrally diverse cohort (n = 36), representing the first comprehensive description of IGK haplotype variation. We identify extensive locus polymorphism, including novel single nucleotide variants (SNVs) and novel structural variants harboring functional IGKV genes. Among 47 functional IGKV genes, we identify 145 alleles, 67 of which were not previously curated. We report inter-population differences in allele frequencies for 10 IGKV genes, including alleles unique to specific populations within this dataset. We identify haplotypes carrying signatures of gene conversion that associate with SNV enrichment in the IGK distal region, and a haplotype with an inversion spanning the proximal and distal regions. These data provide a critical resource of curated genomic reference information from diverse ancestries, laying a foundation for advancing our understanding of population-level genetic variation in the IGK locus.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 4","pages":"297-306"},"PeriodicalIF":5.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00279-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283487","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 : 2024-05-29DOI: 10.1038/s41435-024-00277-4
Alan Herbert
Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.
{"title":"Osteogenesis imperfecta type 10 and the cellular scaffolds underlying common immunological diseases","authors":"Alan Herbert","doi":"10.1038/s41435-024-00277-4","DOIUrl":"10.1038/s41435-024-00277-4","url":null,"abstract":"Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 4","pages":"265-276"},"PeriodicalIF":5.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174301","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 : 2024-05-29DOI: 10.1038/s41435-024-00278-3
Linyu Zhu, Lvya Zhang, Junhua Qi, Zhiyu Ye, Gang Nie, Shaolong Leng
The functions of immunosenescence are closely related to skin cutaneous melanoma (SKCM). The aim of this study is to uncover the characteristics of immunosenescence index (ISI) to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried out to identify risk prognostic genes, and their expression and prognostic value were evaluated. Then, we used the computational algorithm to estimate ISI. Finally, the distribution characteristics and clinical significance of ISI in SKCM by using multi-omics analysis. Patients with a lower ISI had a favorable survival rate, lower chromosomal instability, lower somatic copy-number alterations, lower somatic mutations, higher immune infiltration, and sensitive to immunotherapy. The ISI exhibited robust, which was validated in multiple datasets. Besides, the ISI is more effective than other published signatures in predicting survival outcomes for patients with SKCM. Single-cell analysis revealed higher ISI was specifically expressed in monocytes, and correlates with the differentiation fate of monocytes in SKCM. Besides, individuals exhibiting elevated ISI levels could potentially receive advantages from chemotherapy, and promising compounds with the potential to target high ISI were recognized. The ISI model is a valuable tool in categorizing SKCM patients based on their prognosis, gene mutation signatures, and response to immunotherapy.
{"title":"Machine learning-derived immunosenescence index for predicting outcome and drug sensitivity in patients with skin cutaneous melanoma","authors":"Linyu Zhu, Lvya Zhang, Junhua Qi, Zhiyu Ye, Gang Nie, Shaolong Leng","doi":"10.1038/s41435-024-00278-3","DOIUrl":"10.1038/s41435-024-00278-3","url":null,"abstract":"The functions of immunosenescence are closely related to skin cutaneous melanoma (SKCM). The aim of this study is to uncover the characteristics of immunosenescence index (ISI) to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried out to identify risk prognostic genes, and their expression and prognostic value were evaluated. Then, we used the computational algorithm to estimate ISI. Finally, the distribution characteristics and clinical significance of ISI in SKCM by using multi-omics analysis. Patients with a lower ISI had a favorable survival rate, lower chromosomal instability, lower somatic copy-number alterations, lower somatic mutations, higher immune infiltration, and sensitive to immunotherapy. The ISI exhibited robust, which was validated in multiple datasets. Besides, the ISI is more effective than other published signatures in predicting survival outcomes for patients with SKCM. Single-cell analysis revealed higher ISI was specifically expressed in monocytes, and correlates with the differentiation fate of monocytes in SKCM. Besides, individuals exhibiting elevated ISI levels could potentially receive advantages from chemotherapy, and promising compounds with the potential to target high ISI were recognized. The ISI model is a valuable tool in categorizing SKCM patients based on their prognosis, gene mutation signatures, and response to immunotherapy.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"219-231"},"PeriodicalIF":5.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174296","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}
The pathogenesis of Crohn’s disease (CD) involves abnormal immune cell infiltration and dysregulated immune response. Therefore, thorough research on immune cell abnormalities in CD is crucial for improved treatment of this disease. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data of CD were obtained from the Gene Expression Omnibus (GEO) database. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), weighted gene co-expression network analysis (WGCNA), protein–protein interaction (PPI) networks evaluated the proportion of immune infiltrating cells, constructed co-expression network and identified key genes, respectively. Based on the dataset (GSE134809), 15 cell clusters were defined and labeled as different cell types. Among the 11 modules, the yellow module had the closest relationship with plasma cells (cluster 5). Confirmed using RNA sequencing and IHC assay, the expression of COL5A2 in CD samples was higher than that in control samples. Furthermore, the COL5A2 protein expression remarkably decreased in the group of patients who responded to anti–tumor necrosis factor (TNF) treatments, compared to the non-response group. The comprehensive analyses described here provided novel insight into the landscape of CD-associated immune environment. In addition, COL5A2 were identified as potential diagnostic indicators for CD, as well as promising predictive markers for CD patients.
{"title":"Integrated analyses reveal the diagnostic and predictive values of COL5A2 and association with immune environment in Crohn’s disease","authors":"Tingting Zhong, Xiaoqing Cheng, Qianru Gu, Guoxiang Fu, Yihong Wang, Yujie Jiang, Jiaqi Xu, Zhinong Jiang","doi":"10.1038/s41435-024-00276-5","DOIUrl":"10.1038/s41435-024-00276-5","url":null,"abstract":"The pathogenesis of Crohn’s disease (CD) involves abnormal immune cell infiltration and dysregulated immune response. Therefore, thorough research on immune cell abnormalities in CD is crucial for improved treatment of this disease. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data of CD were obtained from the Gene Expression Omnibus (GEO) database. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), weighted gene co-expression network analysis (WGCNA), protein–protein interaction (PPI) networks evaluated the proportion of immune infiltrating cells, constructed co-expression network and identified key genes, respectively. Based on the dataset (GSE134809), 15 cell clusters were defined and labeled as different cell types. Among the 11 modules, the yellow module had the closest relationship with plasma cells (cluster 5). Confirmed using RNA sequencing and IHC assay, the expression of COL5A2 in CD samples was higher than that in control samples. Furthermore, the COL5A2 protein expression remarkably decreased in the group of patients who responded to anti–tumor necrosis factor (TNF) treatments, compared to the non-response group. The comprehensive analyses described here provided novel insight into the landscape of CD-associated immune environment. In addition, COL5A2 were identified as potential diagnostic indicators for CD, as well as promising predictive markers for CD patients.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"209-218"},"PeriodicalIF":5.0,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00276-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093362","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 : 2024-05-22DOI: 10.1038/s41435-024-00274-7
Miriam Langguth, Eleftheria Maranou, Saara A. Koskela, Oskar Elenius, Roosa E. Kallionpää, Eva-Maria Birkman, Otto I. Pulkkinen, Maria Sundvall, Marko Salmi, Carlos R. Figueiredo
Immune checkpoint therapies (ICT) for advanced solid tumors mark a new milestone in cancer therapy. Yet their efficacy is often limited by poor immunogenicity, attributed to inadequate priming and generation of antitumor T cells by dendritic cells (DCs). Identifying biomarkers to enhance DC functions in such tumors is thus crucial. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), recognized for its influence on immune cells, has an underexplored relationship with DCs. Our research reveals a correlation between high TIMP1 levels in metastatic melanoma and increased CD8 + T cell infiltration and survival. Network studies indicate a functional connection with HLA genes. Spatial transcriptomic analysis of a national melanoma cohort revealed that TIMP1 expression in immune compartments associates with an HLA-A/MHC-I peptide loading signature in lymph nodes. Primary human and bone-marrow-derived DCs secrete TIMP-1, which notably increases MHC-I expression in classical type 1 dendritic cells (cDC1), especially under melanoma antigen exposure. TIMP-1 affects the immunoproteasome/TAP complex, as seen by upregulated PSMB8 and TAP-1 levels of myeloid DCs. This study uncovers the role of TIMP-1 in DC-mediated immunogenicity with insights into CD8 + T cell activation, providing a foundation for mechanistic exploration and highlighting its potential as a new target for combinatorial immunotherapy to enhance ICT effectiveness.
治疗晚期实体瘤的免疫检查点疗法（ICT）标志着癌症治疗的一个新里程碑。然而，由于树突状细胞（DC）对抗肿瘤 T 细胞的启动和生成不足，它们的疗效往往受到免疫原性差的限制。因此，确定生物标志物以增强树突状细胞在此类肿瘤中的功能至关重要。组织金属蛋白酶抑制剂-1（TIMP-1）因其对免疫细胞的影响而被公认，但它与直流电细胞的关系却未得到充分探索。我们的研究揭示了转移性黑色素瘤中高 TIMP1 水平与 CD8 + T 细胞浸润和存活率增加之间的相关性。网络研究表明了与 HLA 基因的功能性联系。对全国黑色素瘤队列进行的空间转录组学分析表明，TIMP1在免疫分区中的表达与淋巴结中的HLA-A/MHC-I肽负载特征有关。原代人类和骨髓源性 DCs 会分泌 TIMP-1，它能显著增加经典 1 型树突状细胞（cDC1）的 MHC-I 表达，尤其是在黑色素瘤抗原暴露的情况下。TIMP-1会影响免疫保护体/TAP复合体，这一点从髓源性DC的PSMB8和TAP-1水平上调可以看出。这项研究揭示了TIMP-1在DC介导的免疫原性中的作用，并深入了解了CD8 + T细胞的活化，为机理探索奠定了基础，并凸显了其作为组合免疫疗法新靶点的潜力，以提高ICT的有效性。
{"title":"TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity","authors":"Miriam Langguth, Eleftheria Maranou, Saara A. Koskela, Oskar Elenius, Roosa E. Kallionpää, Eva-Maria Birkman, Otto I. Pulkkinen, Maria Sundvall, Marko Salmi, Carlos R. Figueiredo","doi":"10.1038/s41435-024-00274-7","DOIUrl":"10.1038/s41435-024-00274-7","url":null,"abstract":"Immune checkpoint therapies (ICT) for advanced solid tumors mark a new milestone in cancer therapy. Yet their efficacy is often limited by poor immunogenicity, attributed to inadequate priming and generation of antitumor T cells by dendritic cells (DCs). Identifying biomarkers to enhance DC functions in such tumors is thus crucial. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), recognized for its influence on immune cells, has an underexplored relationship with DCs. Our research reveals a correlation between high TIMP1 levels in metastatic melanoma and increased CD8 + T cell infiltration and survival. Network studies indicate a functional connection with HLA genes. Spatial transcriptomic analysis of a national melanoma cohort revealed that TIMP1 expression in immune compartments associates with an HLA-A/MHC-I peptide loading signature in lymph nodes. Primary human and bone-marrow-derived DCs secrete TIMP-1, which notably increases MHC-I expression in classical type 1 dendritic cells (cDC1), especially under melanoma antigen exposure. TIMP-1 affects the immunoproteasome/TAP complex, as seen by upregulated PSMB8 and TAP-1 levels of myeloid DCs. This study uncovers the role of TIMP-1 in DC-mediated immunogenicity with insights into CD8 + T cell activation, providing a foundation for mechanistic exploration and highlighting its potential as a new target for combinatorial immunotherapy to enhance ICT effectiveness.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"188-200"},"PeriodicalIF":5.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00274-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081226","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}
Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options for GBM include surgical resection, radiation, and chemotherapy, which predominantly slow cancer growth and reduce symptoms, resulting in a 5-year survival rate of no more than 10%. Chimeric antigen receptor (CAR) T-cell therapy is a new class of cellular immunotherapy that has made great progress in treating malignant tumors. Human epidermal growth factor receptor 2 (HER2) is overexpressed in GBM and may provide a potential therapeutic target for GBM treatment. In this study, we constructed third-generation CAR-T cells targeting the HER2 antigen in GBM. HER2-CAR-T cells showed effective anti-tumor activity both in vitro and in vivo. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting abilities against GBM cells in vitro. Anti-HER2 CAR-T cells also exhibited increased cytotoxicity with increasing effector-to-target ratios. Anti-HER2 CAR-T cells delivered via peritumoral injection successfully stunted tumor progression in vivo. Moreover, peritumoral intravenous administration of anti-HER2 CAR-T cells resulted in therapeutic improvement against GBM cells compared with intravenous administration. In conclusion, our study shows that HER2 CAR-T cells represent an emerging immunotherapy for treating GBM.
{"title":"HER2-targeting CAR-T cells show highly efficient anti-tumor activity against glioblastoma both in vitro and in vivo","authors":"Xueying Li, Lifen Zhao, Wenzhe Li, Peng Gao, Nianzhu Zhang","doi":"10.1038/s41435-024-00275-6","DOIUrl":"10.1038/s41435-024-00275-6","url":null,"abstract":"Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options for GBM include surgical resection, radiation, and chemotherapy, which predominantly slow cancer growth and reduce symptoms, resulting in a 5-year survival rate of no more than 10%. Chimeric antigen receptor (CAR) T-cell therapy is a new class of cellular immunotherapy that has made great progress in treating malignant tumors. Human epidermal growth factor receptor 2 (HER2) is overexpressed in GBM and may provide a potential therapeutic target for GBM treatment. In this study, we constructed third-generation CAR-T cells targeting the HER2 antigen in GBM. HER2-CAR-T cells showed effective anti-tumor activity both in vitro and in vivo. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting abilities against GBM cells in vitro. Anti-HER2 CAR-T cells also exhibited increased cytotoxicity with increasing effector-to-target ratios. Anti-HER2 CAR-T cells delivered via peritumoral injection successfully stunted tumor progression in vivo. Moreover, peritumoral intravenous administration of anti-HER2 CAR-T cells resulted in therapeutic improvement against GBM cells compared with intravenous administration. In conclusion, our study shows that HER2 CAR-T cells represent an emerging immunotherapy for treating GBM.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"201-208"},"PeriodicalIF":5.0,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00275-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140851071","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 : 2024-04-22DOI: 10.1038/s41435-024-00273-8
Henrique G. Colaço, Kelsey Voss
{"title":"Oxidized phospholipids during microbial challenge: friend or foe?","authors":"Henrique G. Colaço, Kelsey Voss","doi":"10.1038/s41435-024-00273-8","DOIUrl":"10.1038/s41435-024-00273-8","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"177-178"},"PeriodicalIF":5.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00273-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140672781","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 : 2024-04-11DOI: 10.1038/s41435-024-00272-9
Mahmoud Mohammad Yaseen, Nizar Mohammad Abuharfeil, Homa Darmani
Myeloid-derived suppressor cells (MDSCs) become expanded in different pathological conditions including human immunodeficiency virus (HIV) infection and this may worsen the disease status and accelerate disease progression. In HIV infection, MDSCs suppress anti-HIV immune responses and hamper immune reconstitution. Understanding the factors and mechanisms of MDSC expansion during HIV infection is central to understanding the pathophysiology of HIV infection. This may pave the way to developing new therapeutic targets or strategies. In this work we addressed (i) the mechanisms that regulate MDSC expansion, (ii) the impact of antiretroviral therapy (ART) on the frequency of MDSCs during HIV infection; (iii) the impact of MDSCs on immune reconstitution during successful ART; and (iv) the potential of MDSCs as a therapeutic target.
在包括人类免疫缺陷病毒（HIV）感染在内的不同病理情况下，髓源性抑制细胞（MDSCs）会发生扩增，这可能会恶化疾病状况并加速疾病进展。在 HIV 感染中，MDSCs 会抑制抗 HIV 免疫反应，阻碍免疫重建。了解 HIV 感染期间 MDSC 扩增的因素和机制对于理解 HIV 感染的病理生理学至关重要。这可能为开发新的治疗靶点或策略铺平道路。在这项工作中，我们探讨了（i）调节 MDSC 扩增的机制；（ii）抗逆转录病毒疗法（ART）对 HIV 感染期间 MDSCs 频率的影响；（iii）成功抗逆转录病毒疗法期间 MDSCs 对免疫重建的影响；以及（iv）MDSCs 作为治疗靶点的潜力。
{"title":"MDSC expansion during HIV infection: regulators, ART and immune reconstitution","authors":"Mahmoud Mohammad Yaseen, Nizar Mohammad Abuharfeil, Homa Darmani","doi":"10.1038/s41435-024-00272-9","DOIUrl":"10.1038/s41435-024-00272-9","url":null,"abstract":"Myeloid-derived suppressor cells (MDSCs) become expanded in different pathological conditions including human immunodeficiency virus (HIV) infection and this may worsen the disease status and accelerate disease progression. In HIV infection, MDSCs suppress anti-HIV immune responses and hamper immune reconstitution. Understanding the factors and mechanisms of MDSC expansion during HIV infection is central to understanding the pathophysiology of HIV infection. This may pave the way to developing new therapeutic targets or strategies. In this work we addressed (i) the mechanisms that regulate MDSC expansion, (ii) the impact of antiretroviral therapy (ART) on the frequency of MDSCs during HIV infection; (iii) the impact of MDSCs on immune reconstitution during successful ART; and (iv) the potential of MDSCs as a therapeutic target.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"242-253"},"PeriodicalIF":5.0,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140566212","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 : 2024-04-09DOI: 10.1038/s41435-024-00269-4
Lisabeth Pimenov, Azuah Lucrecia Gonzalez, Amanda C. Doran, Sylvia Knapp
{"title":"Correction: Same name, different game?—How ontogeny shapes classical monocyte phenotypes","authors":"Lisabeth Pimenov, Azuah Lucrecia Gonzalez, Amanda C. Doran, Sylvia Knapp","doi":"10.1038/s41435-024-00269-4","DOIUrl":"10.1038/s41435-024-00269-4","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"264-264"},"PeriodicalIF":5.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00269-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140723829","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 : 2024-04-05DOI: 10.1038/s41435-024-00271-w
Charalabos Antonatos, Georgios K. Georgakilas, Evangelos Evangelou, Yiannis Vasilopoulos
Despite the abundance of epidemiological evidence for the high comorbid rate between psoriasis and obesity, systematic approaches to common inflammatory mechanisms have not been adequately explored. We performed a meta-analysis of publicly available RNA-sequencing datasets to unveil putative mechanisms that are postulated to exacerbate both diseases, utilizing both late-stage, disease-specific meta-analyses and consensus gene co-expression network (cWGCNA). Single-gene meta-analyses reported several common inflammatory mechanisms fostered by the perturbed expression profile of inflammatory cells. Assessment of gene overlaps between both diseases revealed significant overlaps between up- (n = 170, P value = 6.07 × 10−65) and down-regulated (n = 49, P value = 7.1 × 10−7) genes, associated with increased T cell response and activated transcription factors. Our cWGCNA approach disentangled 48 consensus modules, associated with either the differentiation of leukocytes or metabolic pathways with similar correlation signals in both diseases. Notably, all our analyses confirmed the association of the perturbed T helper (Th)17 differentiation pathway in both diseases. Our novel findings through whole transcriptomic analyses characterize the inflammatory commonalities between psoriasis and obesity implying the assessment of several expression profiles that could serve as putative comorbid disease progression biomarkers and therapeutic interventions.
{"title":"Transcriptomic meta-analysis characterizes molecular commonalities between psoriasis and obesity","authors":"Charalabos Antonatos, Georgios K. Georgakilas, Evangelos Evangelou, Yiannis Vasilopoulos","doi":"10.1038/s41435-024-00271-w","DOIUrl":"10.1038/s41435-024-00271-w","url":null,"abstract":"Despite the abundance of epidemiological evidence for the high comorbid rate between psoriasis and obesity, systematic approaches to common inflammatory mechanisms have not been adequately explored. We performed a meta-analysis of publicly available RNA-sequencing datasets to unveil putative mechanisms that are postulated to exacerbate both diseases, utilizing both late-stage, disease-specific meta-analyses and consensus gene co-expression network (cWGCNA). Single-gene meta-analyses reported several common inflammatory mechanisms fostered by the perturbed expression profile of inflammatory cells. Assessment of gene overlaps between both diseases revealed significant overlaps between up- (n = 170, P value = 6.07 × 10−65) and down-regulated (n = 49, P value = 7.1 × 10−7) genes, associated with increased T cell response and activated transcription factors. Our cWGCNA approach disentangled 48 consensus modules, associated with either the differentiation of leukocytes or metabolic pathways with similar correlation signals in both diseases. Notably, all our analyses confirmed the association of the perturbed T helper (Th)17 differentiation pathway in both diseases. Our novel findings through whole transcriptomic analyses characterize the inflammatory commonalities between psoriasis and obesity implying the assessment of several expression profiles that could serve as putative comorbid disease progression biomarkers and therapeutic interventions.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 3","pages":"179-187"},"PeriodicalIF":5.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140737220","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}
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