Pub Date : 2024-09-12DOI: 10.3389/fimmu.2024.1450173
Meng Su, Luoquan Chen, Li Xie, Aurore Fleurie, Renaud Jonquieres, Qing Cao, Benshang Li, Ji Liang, Yanjing Tang
CAR-T cell therapy is a revolutionary new treatment for hematological malignancies, but it can also result in significant adverse effects, with cytokine release syndrome (CRS) being the most common and potentially life-threatening. The identification of biomarkers to predict the severity of CRS is crucial to ensure the safety and efficacy of CAR-T therapy. To achieve this goal, we characterized the expression profiles of seven cytokines, four conventional biochemical markers, and five hematological markers prior to and following CAR-T cell infusion. Our results revealed that IL-2, IFN-γ, IL-6, and IL-10 are the key cytokines for predicting severe CRS (sCRS). Notably, IL-2 levels rise at an earlier stage of sCRS and have the potential to serve as the most effective cytokine for promptly detecting the condition’s onset. Furthermore, combining these cytokine biomarkers with hematological factors such as lymphocyte counts can further enhance their predictive performance. Finally, a predictive tree model including lymphocyte counts, IL-2, and IL-6 achieved an accuracy of 85.11% (95% CI = 0.763–0.916) for early prediction of sCRS. The model was validated in an independent cohort and achieved an accuracy of 74.47% (95% CI = 0.597–0.861). This new prediction model has the potential to become an effective tool for assessing the risk of CRS in clinical practice.
{"title":"Identification of early predictive biomarkers for severe cytokine release syndrome in pediatric patients with chimeric antigen receptor T-cell therapy","authors":"Meng Su, Luoquan Chen, Li Xie, Aurore Fleurie, Renaud Jonquieres, Qing Cao, Benshang Li, Ji Liang, Yanjing Tang","doi":"10.3389/fimmu.2024.1450173","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1450173","url":null,"abstract":"CAR-T cell therapy is a revolutionary new treatment for hematological malignancies, but it can also result in significant adverse effects, with cytokine release syndrome (CRS) being the most common and potentially life-threatening. The identification of biomarkers to predict the severity of CRS is crucial to ensure the safety and efficacy of CAR-T therapy. To achieve this goal, we characterized the expression profiles of seven cytokines, four conventional biochemical markers, and five hematological markers prior to and following CAR-T cell infusion. Our results revealed that IL-2, IFN-γ, IL-6, and IL-10 are the key cytokines for predicting severe CRS (sCRS). Notably, IL-2 levels rise at an earlier stage of sCRS and have the potential to serve as the most effective cytokine for promptly detecting the condition’s onset. Furthermore, combining these cytokine biomarkers with hematological factors such as lymphocyte counts can further enhance their predictive performance. Finally, a predictive tree model including lymphocyte counts, IL-2, and IL-6 achieved an accuracy of 85.11% (95% CI = 0.763–0.916) for early prediction of sCRS. The model was validated in an independent cohort and achieved an accuracy of 74.47% (95% CI = 0.597–0.861). This new prediction model has the potential to become an effective tool for assessing the risk of CRS in clinical practice.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and contributes to high morbidity and mortality. However, our current understanding of the development and progression of aGVHD after allo-HSCT remains limited. To identify the potential biomarkers for the prevention and treatment of aGVHD during the early hematopoietic reconstruction after transplantation, we meticulously performed a comparative analysis of single-cell RNA sequencing data from post-transplant patients with or without aGVHD. Prior to the onset of aGVHD, monocytes in the peripheral blood of patients with aGVHD experienced a dramatic rise and activation on day 21 post-transplantation. This phenomenon is closely aligned with clinical cohort results obtained from blood routine examinations. Furthermore, in vitro co-culture experiments showed that peripheral blood monocytes extracted from patients with aGVHD approximately 21 days post-transplantation induced a significantly higher proliferation rate of allogeneic T cells compared to those from patients without aGVHD. Our study indicates that monocytes could be a crucial early clinical risk factor for the development of aGVHD, and this insight could potentially guide the timing of monitoring efforts, recommending assessments at the pivotal juncture of approximately day 21 post-transplantation, shedding fresh light on the significance of early hematopoietic regeneration in relation to the onset of aGVHD.
{"title":"Monocytes as an early risk factor for acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation","authors":"Huimin Sun, Linjie Wu, Xueying Zhao, Yingying Huo, Peiyuan Dong, Aiming Pang, Yawei Zheng, Yiwen Han, Shihui Ma, Erlie Jiang, Fang Dong, Tao Cheng, Sha Hao","doi":"10.3389/fimmu.2024.1433091","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1433091","url":null,"abstract":"Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and contributes to high morbidity and mortality. However, our current understanding of the development and progression of aGVHD after allo-HSCT remains limited. To identify the potential biomarkers for the prevention and treatment of aGVHD during the early hematopoietic reconstruction after transplantation, we meticulously performed a comparative analysis of single-cell RNA sequencing data from post-transplant patients with or without aGVHD. Prior to the onset of aGVHD, monocytes in the peripheral blood of patients with aGVHD experienced a dramatic rise and activation on day 21 post-transplantation. This phenomenon is closely aligned with clinical cohort results obtained from blood routine examinations. Furthermore, <jats:italic>in vitro</jats:italic> co-culture experiments showed that peripheral blood monocytes extracted from patients with aGVHD approximately 21 days post-transplantation induced a significantly higher proliferation rate of allogeneic T cells compared to those from patients without aGVHD. Our study indicates that monocytes could be a crucial early clinical risk factor for the development of aGVHD, and this insight could potentially guide the timing of monitoring efforts, recommending assessments at the pivotal juncture of approximately day 21 post-transplantation, shedding fresh light on the significance of early hematopoietic regeneration in relation to the onset of aGVHD.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundHigh altitude pulmonary edema (HAPE) is an idiopathic, noncardiogenic form of pulmonary edema that occurs at high altitudes. It is characterized by a severe clinical course and carries a significant mortality risk. Despite its clinical relevance, the molecular mechanisms underlying HAPE are not well understood.MethodsWe conducted whole-transcriptome RNA sequencing on blood samples from 6 pairs of HAPE patients and healthy controls to identify differentially expressed (DE) mRNAs, miRNAs, circRNAs, lncRNAs, along with alternative splicing (AS) events, gene fusions, and novel transcripts. To explore the regulatory dynamics, we constructed ceRNA networks and analyzed immune cell infiltration patterns, further annotating the biological functions of these transcripts. For empirical validation, we selected five circRNAs from the ceRNA network and conducted RT-qPCR on 50 paired samples. Additionally, we assessed the correlations between circRNA expression levels and clinical data to evaluate their diagnostic potential.ResultsWe observed 2,023 differentially expressed mRNAs (DEmRNAs), 84 DEmiRNAs, 200 DEcircRNAs, and 3,573 DElncRNAs. A total of 139 ‘A3SS’ events, 103 ‘A5SS’ events, 545 ‘MXE’ events, 14 ‘RI’ events, and 1,482 ‘SE’ events were identified in the AS events analysis between the two groups. Two ceRNA networks were constructed. T cells, follicular helper, and Macrophages M1 cells exhibited the strongest positive correlation (R=0.82), while naive B cells and memory B cells demonstrated the strongest negative correlation (R=-0.62). In total, the expression of three circRNAs was significantly different in a larger cohort. Hsa_circ_0058497, hsa_circ_0081006, and hsa_circ_0083220 demonstrated consistent with the RNA sequencing results. These three circRNAs strongly correlate with clinical indicators and exhibit potential as diagnostic biomarkers. Finally, we verified five genes (CXCR4, HSD17B2, ANGPTL4, TIMP3, N4BP3) that were differentially expressed in endothelial cells under normoxia and hypoxia through bioinformatics and RT-qPCR analyses.ConclusionThis study elucidates the differential expression of coding and non-coding RNAs (ncRNAs) in HAPE, identifies new transcripts and genes, and enhances our understanding of the transcriptional characteristics of HAPE. Moreover, it highlights the potential role of circRNAs in advancing the diagnosis and treatment of HAPE.
{"title":"Whole transcriptome landscape in HAPE under the stress of environment at high altitudes: new insights into the mechanisms of hypobaric hypoxia tolerance","authors":"Qiong Li, Fujin Fang, Chuanli Yang, Dong Yu, Qianhui Gong, Xiaobing Shen","doi":"10.3389/fimmu.2024.1444666","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1444666","url":null,"abstract":"BackgroundHigh altitude pulmonary edema (HAPE) is an idiopathic, noncardiogenic form of pulmonary edema that occurs at high altitudes. It is characterized by a severe clinical course and carries a significant mortality risk. Despite its clinical relevance, the molecular mechanisms underlying HAPE are not well understood.MethodsWe conducted whole-transcriptome RNA sequencing on blood samples from 6 pairs of HAPE patients and healthy controls to identify differentially expressed (DE) mRNAs, miRNAs, circRNAs, lncRNAs, along with alternative splicing (AS) events, gene fusions, and novel transcripts. To explore the regulatory dynamics, we constructed ceRNA networks and analyzed immune cell infiltration patterns, further annotating the biological functions of these transcripts. For empirical validation, we selected five circRNAs from the ceRNA network and conducted RT-qPCR on 50 paired samples. Additionally, we assessed the correlations between circRNA expression levels and clinical data to evaluate their diagnostic potential.ResultsWe observed 2,023 differentially expressed mRNAs (DEmRNAs), 84 DEmiRNAs, 200 DEcircRNAs, and 3,573 DElncRNAs. A total of 139 ‘A3SS’ events, 103 ‘A5SS’ events, 545 ‘MXE’ events, 14 ‘RI’ events, and 1,482 ‘SE’ events were identified in the AS events analysis between the two groups. Two ceRNA networks were constructed. T cells, follicular helper, and Macrophages M1 cells exhibited the strongest positive correlation (R=0.82), while naive B cells and memory B cells demonstrated the strongest negative correlation (R=-0.62). In total, the expression of three circRNAs was significantly different in a larger cohort. Hsa_circ_0058497, hsa_circ_0081006, and hsa_circ_0083220 demonstrated consistent with the RNA sequencing results. These three circRNAs strongly correlate with clinical indicators and exhibit potential as diagnostic biomarkers. Finally, we verified five genes (CXCR4, HSD17B2, ANGPTL4, TIMP3, N4BP3) that were differentially expressed in endothelial cells under normoxia and hypoxia through bioinformatics and RT-qPCR analyses.ConclusionThis study elucidates the differential expression of coding and non-coding RNAs (ncRNAs) in HAPE, identifies new transcripts and genes, and enhances our understanding of the transcriptional characteristics of HAPE. Moreover, it highlights the potential role of circRNAs in advancing the diagnosis and treatment of HAPE.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fimmu.2024.1425363
Yichuan Xv, Yiyi Feng, Jiang Lin
ObjectivesThere is already substantial evidence indicating that neutrophil extracellular trap (NET) formation contributes to the inflammatory cascade in ulcerative colitis (UC). However, the precise regulatory mechanisms governing this process remain elusive. This study aimed to determine the role of NET-related genes in UC and reveal possible mechanisms.MethodsEmploying a two-sample MR methodology, we investigated the correlations between NET-associated genes (NRGs) and UC with summary data derived from a genome-wide association study (12,366 cases vs. 33,609 controls) and FinnGen (8,279 cases vs. 261,098 controls). The main analysis employed the inverse variance weighted method, supplemented by the MR-Egger method and weighted median method. Sensitivity analysis was conducted to rule out the interference of heterogeneity and pleiotropy among utilized instrument variables. The colocalization analysis was used to determine whether the identified NRGs and UC shared casual variants. Cross-tissue expression analysis was performed to characterize the expression patterns of target NRGs, while multi-gene correlation analysis and GSEA analysis were conducted to explore the mechanisms by which target NRGs promote UC and NET formation. Immunohistochemistry was used to validate the protein expression of target NRGs in the colon tissue of UC patients.ResultsAfter the validation of two datasets, seven NRGs were associated with the risk of UC. The higher expression of ITGB2 was associated with increased UC risk, while the expression of CXCR1, CXCR2, IRAK4, MAPK3, SIGLEC14, and SLC22A4 were inversely associated with UC risk. Colocalization analysis supported the correlation between CXCR1/2 and UC risk. Expression analysis indicated that CXCR1/2 were down-regulated in peripheral blood, but up-regulated in colon tissue. GSEA analysis and correlation analysis indicated that CXCR1/2 promoted UC and NET formation through neutrophil chemotaxis and PAD4-mediated pathways, separately. Immunohistochemical results confirmed the high expression of CXCR1/2 in colon tissues of UC patients.ConclusionsOur study identified CXCR1/2 as candidate targets in UC among all NRGs through multi-method argumentation, providing new insights of the regulation mechanisms of NET formation in the pathogenesis of UC.
{"title":"CXCR1 and CXCR2 are potential neutrophil extracellular trap-related treatment targets in ulcerative colitis: insights from Mendelian randomization, colocalization and transcriptomic analysis","authors":"Yichuan Xv, Yiyi Feng, Jiang Lin","doi":"10.3389/fimmu.2024.1425363","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1425363","url":null,"abstract":"ObjectivesThere is already substantial evidence indicating that neutrophil extracellular trap (NET) formation contributes to the inflammatory cascade in ulcerative colitis (UC). However, the precise regulatory mechanisms governing this process remain elusive. This study aimed to determine the role of NET-related genes in UC and reveal possible mechanisms.MethodsEmploying a two-sample MR methodology, we investigated the correlations between NET-associated genes (NRGs) and UC with summary data derived from a genome-wide association study (12,366 cases vs. 33,609 controls) and FinnGen (8,279 cases vs. 261,098 controls). The main analysis employed the inverse variance weighted method, supplemented by the MR-Egger method and weighted median method. Sensitivity analysis was conducted to rule out the interference of heterogeneity and pleiotropy among utilized instrument variables. The colocalization analysis was used to determine whether the identified NRGs and UC shared casual variants. Cross-tissue expression analysis was performed to characterize the expression patterns of target NRGs, while multi-gene correlation analysis and GSEA analysis were conducted to explore the mechanisms by which target NRGs promote UC and NET formation. Immunohistochemistry was used to validate the protein expression of target NRGs in the colon tissue of UC patients.ResultsAfter the validation of two datasets, seven NRGs were associated with the risk of UC. The higher expression of ITGB2 was associated with increased UC risk, while the expression of CXCR1, CXCR2, IRAK4, MAPK3, SIGLEC14, and SLC22A4 were inversely associated with UC risk. Colocalization analysis supported the correlation between CXCR1/2 and UC risk. Expression analysis indicated that CXCR1/2 were down-regulated in peripheral blood, but up-regulated in colon tissue. GSEA analysis and correlation analysis indicated that CXCR1/2 promoted UC and NET formation through neutrophil chemotaxis and PAD4-mediated pathways, separately. Immunohistochemical results confirmed the high expression of CXCR1/2 in colon tissues of UC patients.ConclusionsOur study identified CXCR1/2 as candidate targets in UC among all NRGs through multi-method argumentation, providing new insights of the regulation mechanisms of NET formation in the pathogenesis of UC.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fimmu.2024.1427519
Mohamed A Selim, Reda A. Suef, Ebrahim Saied, Mostafa A. Abdel-Maksoud, Saeedah Musaed Almutairi, Mohammed Aufy, Adel A. Mousa, Mohamed T. M. Mansour, Mohamed M. S. Farag
BackgroundThe relationship between chronic hepatitis B (CHB) infection and natural killer (NK) cell dysfunction is well-established, but the specific role of HBV viral antigens in driving NK cell impairment in patients with CHB remains unclear. This study investigates the modulatory effects of hepatitis B virus subviral particles (HBVsvp, a representative model for HBsAg) on the phenotypic regulation (activating and inhibitory receptors), cytokine production and cytotoxic potential of peripheral blood mononuclear cell-derived natural killer cells (PBMCs-derived NK cell), which contributes to NK cell dysfunction in CHB infection, potentially serving as an effective HBV immune evasion strategy by the virus.MethodsNK cells were isolated from peripheral blood of patients with CHB (n=5) and healthy individuals (n=5), stimulated with HBVsvp. Subsequent flow cytometric characterization involved assessing changes in activating (NKp46 and NKG2D) and inhibitory (CD94) receptors expression, quantifying TNF-α and IFN- γ cytokine secretion, and evaluating the cytotoxic response against HepG2.2.15 cells with subsequent HBVsvp quantification.ResultsIn CHB patients, in vitro exposure of PBMCs-derived NK cell with HBVsvp (represent HBsAg model) significantly reduced NK cell-activating receptors expression (P = 0.022), increased expression of CD94 + NK cells (p = 0.029), accompanied with a reduced TNF-α - IFN-γ cytokine levels, and impaired cytotoxic capacity (evidenced by increased cell proliferation and elevated HBVsvp levels in co-cultures with HepG2.2.15 cells in a time-dependent), relative to healthy donors.ConclusionThese findings suggest that HBVsvp may induce dysfunctional NK cell responses characterized by phenotypic imbalance with subsequent reduction in cytokine and cytotoxic levels, indicating HBVsvp immunosuppressive effect that compromises antiviral defense in CHB patients. These data enhance our understanding of NK cell interactions with HBsAg and highlight the potential for targeting CD94 inhibitory receptors to restore NK cell function as an immunotherapeutic approach. Further clinical research is needed to validate these observations and establish their utility as reliable biomarkers.
背景慢性乙型肝炎（CHB）感染与自然杀伤细胞（NK）功能障碍之间的关系已得到证实，但 HBV 病毒抗原在慢性乙型肝炎患者 NK 细胞功能障碍中的具体作用仍不清楚。本研究探讨了乙型肝炎病毒亚病毒颗粒（HBVsvp，HBsAg的代表模型）对外周血单核细胞源性自然杀伤细胞（PBMCs-derived NK cell）的表型调节（激活和抑制受体）、细胞因子产生和细胞毒性潜能的调节作用。方法从 CHB 患者（5 人）和健康人（5 人）的外周血中分离出 NK 细胞，并用 HBVsvp 进行刺激。随后的流式细胞鉴定包括评估活化受体（NKp46 和 NKG2D）和抑制受体（CD94）表达的变化，量化 TNF-α 和 IFN- γ 细胞因子的分泌，以及评估对 HepG2.2 的细胞毒性反应。结果在 CHB 患者中，体外暴露于 HBVsvp（代表 HBsAg 模型）的 PBMCs 衍生 NK 细胞显著降低了 NK 细胞激活受体的表达（P = 0.022），增加了 CD94 + NK 细胞的表达（P = 0.029），与健康供体相比，TNF-α - IFN-γ 细胞因子水平降低，细胞毒性能力受损（表现为与 HepG2.2.15 细胞共培养时细胞增殖增加和 HBVsvp 水平升高，且呈时间依赖性）。结论这些研究结果表明，HBVsvp 可能会诱导 NK 细胞功能失调，表现为表型失衡，细胞因子和细胞毒性水平随之降低，这表明 HBVsvp 具有免疫抑制作用，会损害 CHB 患者的抗病毒防御能力。这些数据加深了我们对 NK 细胞与 HBsAg 相互作用的理解，并强调了靶向 CD94 抑制受体恢复 NK 细胞功能作为一种免疫治疗方法的潜力。要验证这些观察结果并将其作为可靠的生物标记物，还需要进一步的临床研究。
{"title":"Peripheral NK cell phenotypic alteration and dysfunctional state post hepatitis B subviral particles stimulation in CHB patients: evading immune surveillance","authors":"Mohamed A Selim, Reda A. Suef, Ebrahim Saied, Mostafa A. Abdel-Maksoud, Saeedah Musaed Almutairi, Mohammed Aufy, Adel A. Mousa, Mohamed T. M. Mansour, Mohamed M. S. Farag","doi":"10.3389/fimmu.2024.1427519","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1427519","url":null,"abstract":"BackgroundThe relationship between chronic hepatitis B (CHB) infection and natural killer (NK) cell dysfunction is well-established, but the specific role of HBV viral antigens in driving NK cell impairment in patients with CHB remains unclear. This study investigates the modulatory effects of hepatitis B virus subviral particles (HBVsvp, a representative model for HBsAg) on the phenotypic regulation (activating and inhibitory receptors), cytokine production and cytotoxic potential of peripheral blood mononuclear cell-derived natural killer cells (PBMCs-derived NK cell), which contributes to NK cell dysfunction in CHB infection, potentially serving as an effective HBV immune evasion strategy by the virus.MethodsNK cells were isolated from peripheral blood of patients with CHB (n=5) and healthy individuals (n=5), stimulated with HBVsvp. Subsequent flow cytometric characterization involved assessing changes in activating (NKp46 and NKG2D) and inhibitory (CD94) receptors expression, quantifying TNF-α and IFN- γ cytokine secretion, and evaluating the cytotoxic response against HepG2.2.15 cells with subsequent HBVsvp quantification.ResultsIn CHB patients, <jats:italic>in vitro</jats:italic> exposure of PBMCs-derived NK cell with HBVsvp (represent HBsAg model) significantly reduced NK cell-activating receptors expression (P = 0.022), increased expression of CD94 <jats:sup>+</jats:sup> NK cells (p = 0.029), accompanied with a reduced TNF-α - IFN-γ cytokine levels, and impaired cytotoxic capacity (evidenced by increased cell proliferation and elevated HBVsvp levels in co-cultures with HepG2.2.15 cells in a time-dependent), relative to healthy donors.ConclusionThese findings suggest that HBVsvp may induce dysfunctional NK cell responses characterized by phenotypic imbalance with subsequent reduction in cytokine and cytotoxic levels, indicating HBVsvp immunosuppressive effect that compromises antiviral defense in CHB patients. These data enhance our understanding of NK cell interactions with HBsAg and highlight the potential for targeting CD94 inhibitory receptors to restore NK cell function as an immunotherapeutic approach. Further clinical research is needed to validate these observations and establish their utility as reliable biomarkers.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundIntervertebral disc degeneration (IDD) progression involves multiple factors, including loss of nucleus pulposus cells and extracellular matrix as the basic pathological mechanism of degeneration, and is closely related to cellular senescence and immune cell infiltration. The aim of study was to identify critical cellular senescence-related genes and immune cell infiltration characteristics in IDD.MethodsFour datasets, including GSE70362, GSE112216, GSE114169, and GSE150408, were downloaded from the Gene Expression Omnibus database. The senescence-related genes were acquired from the CellAge Database and intersected with differentially expressed genes (DEGs) between IDD and control samples for senescence-related DEGs (SRDEGs). Protein-protein interaction (PPI) network analysis was performed to obtain ten hub SRDEGs. A consensus cluster analysis based on these hub genes was performed to divide the patients into clusters. The functional enrichment, and immune infiltration statuses of the clusters were compared. Weighted gene co-expression network analysis was used to identified key gene modules. The overlapping genes from key modules, DEGs of clusters and hub SRDEGs were intersected to obtain potential biomarkers. To verify the expression of potential biomarkers, quantitative polymerase chain reaction (qPCR) and immunohistochemistry were performed by using human intervertebral disc tissues.ResultsIn the GSE70362 dataset, a total of 364 DEGs were identified, of which 150 were upregulated and 214 were downregulated, and 35 genes were selected as SRDEGs. PPI analysis revealed ten hub SRDEGs and consensus cluster analysis divided the patients into two clusters. Compared to Cluster 2, Cluster 1 was highly enriched in extracellular matrix organization and various metabolic process. The level of Follicular T helper cells in the Cluster 1 was significantly higher than that in the Cluster 2. IGFBP3 and NQO1 were identified as potential biomarkers. The remaining 3 datasets, and the result of qPCR and immunohistochemistry showed that the expression levels of NQO1 and IGFBP3 in the degenerated group were higher than those in the control or treatment groups.ConclusionSenescence-related genes play a key role in the development and occurrence of IDD. IGFBP3 and NQO1 are strongly correlated with immune infiltration in the IDD and could become novel therapeutic targets that prevent the progression of IDD.
{"title":"Identification of cellular senescence-related genes and immune cell infiltration characteristics in intervertebral disc degeneration","authors":"Muyi Wang, Hao Wang, Xin Wang, Yifei Shen, Dong Zhou, Yuqing Jiang","doi":"10.3389/fimmu.2024.1439976","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1439976","url":null,"abstract":"BackgroundIntervertebral disc degeneration (IDD) progression involves multiple factors, including loss of nucleus pulposus cells and extracellular matrix as the basic pathological mechanism of degeneration, and is closely related to cellular senescence and immune cell infiltration. The aim of study was to identify critical cellular senescence-related genes and immune cell infiltration characteristics in IDD.MethodsFour datasets, including GSE70362, GSE112216, GSE114169, and GSE150408, were downloaded from the Gene Expression Omnibus database. The senescence-related genes were acquired from the CellAge Database and intersected with differentially expressed genes (DEGs) between IDD and control samples for senescence-related DEGs (SRDEGs). Protein-protein interaction (PPI) network analysis was performed to obtain ten hub SRDEGs. A consensus cluster analysis based on these hub genes was performed to divide the patients into clusters. The functional enrichment, and immune infiltration statuses of the clusters were compared. Weighted gene co-expression network analysis was used to identified key gene modules. The overlapping genes from key modules, DEGs of clusters and hub SRDEGs were intersected to obtain potential biomarkers. To verify the expression of potential biomarkers, quantitative polymerase chain reaction (qPCR) and immunohistochemistry were performed by using human intervertebral disc tissues.ResultsIn the GSE70362 dataset, a total of 364 DEGs were identified, of which 150 were upregulated and 214 were downregulated, and 35 genes were selected as SRDEGs. PPI analysis revealed ten hub SRDEGs and consensus cluster analysis divided the patients into two clusters. Compared to Cluster 2, Cluster 1 was highly enriched in extracellular matrix organization and various metabolic process. The level of Follicular T helper cells in the Cluster 1 was significantly higher than that in the Cluster 2. IGFBP3 and NQO1 were identified as potential biomarkers. The remaining 3 datasets, and the result of qPCR and immunohistochemistry showed that the expression levels of NQO1 and IGFBP3 in the degenerated group were higher than those in the control or treatment groups.ConclusionSenescence-related genes play a key role in the development and occurrence of IDD. IGFBP3 and NQO1 are strongly correlated with immune infiltration in the IDD and could become novel therapeutic targets that prevent the progression of IDD.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fimmu.2024.1457213
Janelle A. Noble
More than 50 years have elapsed since the association of human leukocyte antigens (HLA) with type 1 diabetes (T1D) was first reported. Since then, methods for identification of HLA have progressed from cell based to DNA based, and the number of recognized HLA variants has grown from a few to tens of thousands. Current genotyping methodology allows for exact identification of all HLA-encoding genes in an individual’s genome, with statistical analysis methods evolving to digest the enormous amount of data that can be produced at an astonishing rate. The HLA region of the genome has been repeatedly shown to be the most important genetic risk factor for T1D, and the original reported associations have been replicated, refined, and expanded. Even with the remarkable progress through 50 years and over 5,000 reports, a comprehensive understanding of all effects of HLA on T1D remains elusive. This report represents a summary of the field as it evolved and as it stands now, enumerating many past and present challenges, and suggests possible paradigm shifts for moving forward with future studies in hopes of finally understanding all the ways in which HLA influences the pathophysiology of T1D.
{"title":"Fifty years of HLA-associated type 1 diabetes risk: history, current knowledge, and future directions","authors":"Janelle A. Noble","doi":"10.3389/fimmu.2024.1457213","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1457213","url":null,"abstract":"More than 50 years have elapsed since the association of human leukocyte antigens (HLA) with type 1 diabetes (T1D) was first reported. Since then, methods for identification of HLA have progressed from cell based to DNA based, and the number of recognized HLA variants has grown from a few to tens of thousands. Current genotyping methodology allows for exact identification of all HLA-encoding genes in an individual’s genome, with statistical analysis methods evolving to digest the enormous amount of data that can be produced at an astonishing rate. The HLA region of the genome has been repeatedly shown to be the most important genetic risk factor for T1D, and the original reported associations have been replicated, refined, and expanded. Even with the remarkable progress through 50 years and over 5,000 reports, a comprehensive understanding of all effects of HLA on T1D remains elusive. This report represents a summary of the field as it evolved and as it stands now, enumerating many past and present challenges, and suggests possible paradigm shifts for moving forward with future studies in hopes of finally understanding all the ways in which HLA influences the pathophysiology of T1D.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fimmu.2024.1452879
Pauline Krupa, Hannah Wein, Lea Sophie Zemmrich, Marek Zygmunt, Damián Oscar Muzzio
A well-balanced maternal immune system is crucial to maintain fetal tolerance in case of infections during pregnancy. Immune adaptations include an increased secretion of soluble mediators to protect the semi-allogeneic fetus from excessive pro-inflammatory response. B lymphocytes acquire a higher capacity to express CD83 and secrete soluble CD83 (sCD83) upon exposure to bacteria-derived components such as LPS. CD83 possesses immune modulatory functions and shows a promising therapeutic potential against inflammatory conditions. The administration of sCD83 to pregnant mice reduces LPS-induced abortion rates. The increased CD83 expression by endometrial B cells as compared to peripheral blood B cells suggests its modulatory role in the fetal tolerance, especially in the context of infection. We postulate that in pregnancy, CD83 expression and release is controlled by pregnancy-related hormones. The intra- and extracellular expression of CD83 in leukocytes from peripheral blood or decidua basalis and parietalis at term were analyzed by flow cytometry. After treatment with pregnancy-related hormones and LPS, ELISA and qPCR were performed to study sCD83 release and CD83 gene expression, respectively. Cleavage prediction analysis was used to find potential proteases targeting CD83. Expression of selected proteases was analyzed by ELISA. Higher levels of CD83 were found in CD11c+ dendritic cells, CD3+ T cells and CD19+ B cells from decidua basalis and decidua parietalis after LPS-stimulation in vitro. An increase of intracellular expression of CD83 was also detected in CD19+ B cells from both compartments. Stimulated B cells displayed significantly higher percentages of CD83+ cells than dendritic cells and T cells from decidua basalis and peripheral blood. Treatment of B lymphocytes with pregnancy-related molecules (E2, P4, TGF-β1 and hCG) enhanced the LPS-mediated increase of CD83 expression, while dexamethasone led to a reduction. Similarly, the release of sCD83 was increased under TGF-β1 treatment but decreased upon dexamethasone stimulation. Finally, we found that the hormonal regulation of CD83 expression is likely a result from a balance between gene transcription from CD83 and the modulation of the metalloproteinase MMP-7. Thus, data supports and complements our previous murine studies on hormonal regulation of CD83 expression, reinforcing its immunomodulatory relevance in anti-bacterial responses during pregnancy.
母体免疫系统的平衡对于在孕期感染时维持胎儿的耐受性至关重要。免疫适应包括增加可溶性介质的分泌，以保护半异体胎儿免受过度的促炎症反应。B 淋巴细胞在暴露于细菌衍生成分（如 LPS）时，会获得更高的表达 CD83 和分泌可溶性 CD83（sCD83）的能力。CD83 具有免疫调节功能，对炎症有很好的治疗潜力。给怀孕小鼠注射 sCD83 可降低 LPS 诱导的流产率。与外周血 B 细胞相比，子宫内膜 B 细胞的 CD83 表达量增加，这表明 CD83 对胎儿的耐受性有调节作用，尤其是在感染的情况下。我们推测，在妊娠期，CD83的表达和释放受妊娠相关激素的控制。我们用流式细胞术分析了足月时外周血或蜕膜基底层和顶浆层白细胞中 CD83 的细胞内和细胞外表达。用妊娠相关激素和 LPS 处理后，分别用 ELISA 和 qPCR 研究 sCD83 的释放和 CD83 基因的表达。裂解预测分析用于寻找以 CD83 为靶标的潜在蛋白酶。通过 ELISA 分析了所选蛋白酶的表达。体外 LPS 刺激后，在基底蜕膜和顶叶蜕膜的 CD11c+ 树突状细胞、CD3+ T 细胞和 CD19+ B 细胞中发现了较高水平的 CD83。在这两个分区的 CD19+ B 细胞中还检测到细胞内 CD83 表达的增加。受刺激的 B 细胞显示的 CD83+ 细胞百分比明显高于树突状细胞和来自蜕膜基底层和外周血的 T 细胞。用妊娠相关分子（E2、P4、TGF-β1 和 hCG）处理 B 淋巴细胞会增强 LPS 介导的 CD83 表达增加，而地塞米松则会使其减少。同样，在 TGF-β1 处理下，sCD83 的释放增加，但在地塞米松刺激下则减少。最后，我们发现激素对 CD83 表达的调节可能是 CD83 基因转录与金属蛋白酶 MMP-7 调节之间平衡的结果。因此，这些数据支持并补充了我们之前关于激素调节 CD83 表达的小鼠研究，加强了其在妊娠期抗细菌反应中的免疫调节作用。
{"title":"Pregnancy-related factors induce immune tolerance through regulation of sCD83 release","authors":"Pauline Krupa, Hannah Wein, Lea Sophie Zemmrich, Marek Zygmunt, Damián Oscar Muzzio","doi":"10.3389/fimmu.2024.1452879","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1452879","url":null,"abstract":"A well-balanced maternal immune system is crucial to maintain fetal tolerance in case of infections during pregnancy. Immune adaptations include an increased secretion of soluble mediators to protect the semi-allogeneic fetus from excessive pro-inflammatory response. B lymphocytes acquire a higher capacity to express CD83 and secrete soluble CD83 (sCD83) upon exposure to bacteria-derived components such as LPS. CD83 possesses immune modulatory functions and shows a promising therapeutic potential against inflammatory conditions. The administration of sCD83 to pregnant mice reduces LPS-induced abortion rates. The increased CD83 expression by endometrial B cells as compared to peripheral blood B cells suggests its modulatory role in the fetal tolerance, especially in the context of infection. We postulate that in pregnancy, CD83 expression and release is controlled by pregnancy-related hormones. The intra- and extracellular expression of CD83 in leukocytes from peripheral blood or <jats:italic>decidua basalis</jats:italic> and <jats:italic>parietalis</jats:italic> at term were analyzed by flow cytometry. After treatment with pregnancy-related hormones and LPS, ELISA and qPCR were performed to study sCD83 release and <jats:italic>CD83</jats:italic> gene expression, respectively. Cleavage prediction analysis was used to find potential proteases targeting CD83. Expression of selected proteases was analyzed by ELISA. Higher levels of CD83 were found in CD11c<jats:sup>+</jats:sup> dendritic cells, CD3<jats:sup>+</jats:sup> T cells and CD19<jats:sup>+</jats:sup> B cells from <jats:italic>decidua basalis</jats:italic> and <jats:italic>decidua parietalis</jats:italic> after LPS-stimulation <jats:italic>in vitro</jats:italic>. An increase of intracellular expression of CD83 was also detected in CD19<jats:sup>+</jats:sup> B cells from both compartments. Stimulated B cells displayed significantly higher percentages of CD83<jats:sup>+</jats:sup> cells than dendritic cells and T cells from <jats:italic>decidua basalis</jats:italic> and peripheral blood. Treatment of B lymphocytes with pregnancy-related molecules (E2, P4, TGF-β1 and hCG) enhanced the LPS-mediated increase of CD83 expression, while dexamethasone led to a reduction. Similarly, the release of sCD83 was increased under TGF-β1 treatment but decreased upon dexamethasone stimulation. Finally, we found that the hormonal regulation of CD83 expression is likely a result from a balance between gene transcription from <jats:italic>CD83</jats:italic> and the modulation of the metalloproteinase MMP-7. Thus, data supports and complements our previous murine studies on hormonal regulation of CD83 expression, reinforcing its immunomodulatory relevance in anti-bacterial responses during pregnancy.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fimmu.2024.1465124
Zheng Shen, Landon G. vom Steeg, Mickey V. Patel, Marta Rodriguez-Garcia, Charles R. Wira
Since CD4+ T cells are essential for regulating adaptive immune responses and for long lasting mucosal protection, changes in CD4+ T cell numbers and function are likely to affect protective immunity. What remains unclear is whether CD4+ T cell composition and function in the female reproductive tract (FRT) changes as women age. Here we investigated the changes in the composition and function of CD4+ T cells in the endometrium (EM), endocervix (CX), and ectocervix (ECX) with aging. We observed a significant decrease in both the total number and percentage of CD4+ T cells in the EM with increasing age, particularly in the years following menopause. CD4+ T cells within the FRT predominantly expressed CD69. The proportion of CD69+CD4+ T cells increased significantly with increasing age in the EM, CX and ECX. The composition of T helper cell subsets within the EM CD4+ T cell population also showed age-related changes. Specifically, there was a significant increase in the proportion of Th1 cells and a significant decrease in Th17 and Treg cells with increasing age. Furthermore, the production of IFNγ by CD4+ T cells in the EM, CX, and ECX significantly decreased with increasing age upon activation. Our findings highlight the complex changes occurring in CD4+ T cell frequency, phenotype, and function within the FRT as women age. Understanding these age-related immune changes in the FRT is crucial for enhancing our knowledge of reproductive health and immune responses in women.
由于 CD4+ T 细胞对调节适应性免疫反应和持久的粘膜保护至关重要，因此 CD4+ T 细胞数量和功能的变化很可能会影响保护性免疫。目前仍不清楚的是，女性生殖道（FRT）中 CD4+ T 细胞的组成和功能是否会随着女性年龄的增长而发生变化。在这里，我们研究了子宫内膜（EM）、宫颈内口（CX）和宫颈外口（ECX）中 CD4+ T 细胞的组成和功能随年龄增长而发生的变化。我们观察到，随着年龄的增长，特别是在绝经后的几年里，子宫内膜中 CD4+ T 细胞的总数和百分比都明显下降。FRT 中的 CD4+ T 细胞主要表达 CD69。在 EM、CX 和 ECX 中，CD69+CD4+ T 细胞的比例随着年龄的增长而显著增加。EM CD4+ T细胞群中T辅助细胞亚群的组成也出现了与年龄相关的变化。具体来说，随着年龄的增长，Th1 细胞的比例明显增加，而 Th17 和 Treg 细胞则明显减少。此外，随着年龄的增加，EM、CX 和 ECX 中的 CD4+ T 细胞在激活后产生的 IFNγ 明显减少。我们的研究结果突显了随着女性年龄的增长，FRT 中 CD4+ T 细胞的频率、表型和功能会发生复杂的变化。了解 FRT 中这些与年龄相关的免疫变化对于增进我们对女性生殖健康和免疫反应的了解至关重要。
{"title":"Impact of aging on the frequency, phenotype, and function of CD4+ T cells in the human female reproductive tract","authors":"Zheng Shen, Landon G. vom Steeg, Mickey V. Patel, Marta Rodriguez-Garcia, Charles R. Wira","doi":"10.3389/fimmu.2024.1465124","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1465124","url":null,"abstract":"Since CD4+ T cells are essential for regulating adaptive immune responses and for long lasting mucosal protection, changes in CD4+ T cell numbers and function are likely to affect protective immunity. What remains unclear is whether CD4+ T cell composition and function in the female reproductive tract (FRT) changes as women age. Here we investigated the changes in the composition and function of CD4+ T cells in the endometrium (EM), endocervix (CX), and ectocervix (ECX) with aging. We observed a significant decrease in both the total number and percentage of CD4+ T cells in the EM with increasing age, particularly in the years following menopause. CD4+ T cells within the FRT predominantly expressed CD69. The proportion of CD69+CD4+ T cells increased significantly with increasing age in the EM, CX and ECX. The composition of T helper cell subsets within the EM CD4+ T cell population also showed age-related changes. Specifically, there was a significant increase in the proportion of Th1 cells and a significant decrease in Th17 and Treg cells with increasing age. Furthermore, the production of IFNγ by CD4+ T cells in the EM, CX, and ECX significantly decreased with increasing age upon activation. Our findings highlight the complex changes occurring in CD4+ T cell frequency, phenotype, and function within the FRT as women age. Understanding these age-related immune changes in the FRT is crucial for enhancing our knowledge of reproductive health and immune responses in women.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fimmu.2024.1408109
Zeyi Li, Peng Jin, Rufang Xiang, Xiaoyang Li, Jie Shen, Mengke He, Xiaxin Liu, Hongming Zhu, Shishuang Wu, Fangyi Dong, Huijin Zhao, Han Liu, Zhen Jin, Junmin Li
Although advancements in genomic and epigenetic research have deepened our understanding of acute myeloid leukemia (AML), only one-third of patients can achieve durable remission. Growing evidence suggests that the immune microenvironment in bone marrow influences prognosis and survival in AML. There is a specific association between CD8+ T cells and the prognosis of AML patients. To develop a CD8+ T cell-related immune risk score for AML, we first evaluated the accuracy of CIBERSORTx in predicting the abundance of CD8+ T cells in bulk RNA-seq and found it significantly correlated with observed single-cell RNA sequencing data and the proportions of CD8+ T cells derived from flow cytometry. Next, we constructed the CTCG15, a 15-gene prognostic signature, using univariate and LASSO regression on the differentially expressed genes between CD8+ THigh and CD8+ TLow groups. The CTCG15 was further validated across six datasets in different platforms. The CTCG15 has been shown to be independent of established prognostic markers, and can distill transcriptomic consequences of several genetic abnormalities closely related to prognosis in AML patients. Finally, integrating this model into the 2022 European LeukemiaNet contributed to a higher predictive power for prognosis prediction. Collectively, our study demonstrates that CD8+ T cell-related signature could improve the comprehensive risk stratification and prognosis prediction in AML.
尽管基因组学和表观遗传学研究的进展加深了我们对急性髓性白血病（AML）的了解，但只有三分之一的患者能获得持久缓解。越来越多的证据表明，骨髓中的免疫微环境影响着急性髓细胞白血病的预后和存活。CD8+ T细胞与急性髓细胞性白血病患者的预后有特定的联系。为了开发与 CD8+ T 细胞相关的急性髓细胞白血病免疫风险评分，我们首先评估了 CIBERSORTx 预测大量 RNA-seq 中 CD8+ T 细胞丰度的准确性，发现它与观察到的单细胞 RNA 测序数据和流式细胞术得出的 CD8+ T 细胞比例显著相关。接下来，我们通过对 CD8+ THigh 组和 CD8+ TLow 组的差异表达基因进行单变量和 LASSO 回归，构建了 15 个基因的预后特征 CTCG15。CTCG15 在不同平台的六个数据集上得到了进一步验证。结果表明，CTCG15 独立于已有的预后标志物，并能提炼出与急性髓细胞性白血病患者预后密切相关的几种基因异常的转录组后果。最后，将该模型纳入 2022 年欧洲白血病网络有助于提高预后预测能力。总之，我们的研究表明，CD8+ T 细胞相关特征可以改善急性髓细胞白血病的综合风险分层和预后预测。
{"title":"A CD8+ T cell related immune score predicts survival and refines the risk assessment in acute myeloid leukemia","authors":"Zeyi Li, Peng Jin, Rufang Xiang, Xiaoyang Li, Jie Shen, Mengke He, Xiaxin Liu, Hongming Zhu, Shishuang Wu, Fangyi Dong, Huijin Zhao, Han Liu, Zhen Jin, Junmin Li","doi":"10.3389/fimmu.2024.1408109","DOIUrl":"https://doi.org/10.3389/fimmu.2024.1408109","url":null,"abstract":"Although advancements in genomic and epigenetic research have deepened our understanding of acute myeloid leukemia (AML), only one-third of patients can achieve durable remission. Growing evidence suggests that the immune microenvironment in bone marrow influences prognosis and survival in AML. There is a specific association between CD8<jats:sup>+</jats:sup> T cells and the prognosis of AML patients. To develop a CD8<jats:sup>+</jats:sup> T cell-related immune risk score for AML, we first evaluated the accuracy of CIBERSORTx in predicting the abundance of CD8<jats:sup>+</jats:sup> T cells in bulk RNA-seq and found it significantly correlated with observed single-cell RNA sequencing data and the proportions of CD8<jats:sup>+</jats:sup> T cells derived from flow cytometry. Next, we constructed the CTCG15, a 15-gene prognostic signature, using univariate and LASSO regression on the differentially expressed genes between CD8<jats:sup>+</jats:sup> T<jats:sup>High</jats:sup> and CD8<jats:sup>+</jats:sup> T<jats:sup>Low</jats:sup> groups. The CTCG15 was further validated across six datasets in different platforms. The CTCG15 has been shown to be independent of established prognostic markers, and can distill transcriptomic consequences of several genetic abnormalities closely related to prognosis in AML patients. Finally, integrating this model into the 2022 European LeukemiaNet contributed to a higher predictive power for prognosis prediction. Collectively, our study demonstrates that CD8<jats:sup>+</jats:sup> T cell-related signature could improve the comprehensive risk stratification and prognosis prediction in AML.","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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