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Background: Childhood acute myeloid leukemia (cAML) is the second most common pediatric blood cancer, with high heterogeneity and poor prognosis. Recent studies have highlighted cuproptosis, a newly discovered form of programmed cell death triggered by the accumulation of intracellular copper ions, as a critical mechanism influencing cancer survival and resistance. Given its emerging role in cancer biology, we investigated cuproptosis-related genes (CRGs) in cAML to explore their potential in prognostic prediction and therapeutic targeting. Methods: Gene expression data from publicly available sources were analyzed to identify differentially expressed CRGs. Samples were categorized based on their expression profiles, followed by the development of a prognostic risk model using multivariable Cox regression, LASSO, and univariable analyses. The model's performance was evaluated through Kaplan-Meier survival analysis and ROC analysis. Immune infiltration in the tumor microenvironment was assessed using ssGSEA, validated by CIBERSORT. Drug sensitivity correlations were analyzed, and functional validation experiments were conducted on THP-1 and MOLM13 cell lines to assess the role of CNN3. Results: A set of 12 differential CRGs was used to build a robust prognostic risk model, with high accuracy in predicting patient outcomes (P < 0.001). Significant differences in immune cell composition were identified between risk groups, particularly in T cells, B cells, monocytes, and dendritic cells. Drug sensitivity analysis revealed altered IC50 values for drugs like 5-fluorouracil and bortezomib. Knockdown of CNN3 in leukemia cell lines led to reduced cell proliferation. Conclusion: Our CRGs-based prognostic model shows potential for guiding personalized treatment strategies in cAML. The differences in immune cell infiltration between risk groups suggest that immune modulation is key in cAML progression. CNN3 and LGR4 were identified as modulators of cAML progression, making them potential therapeutic targets. Future studies with larger cohorts are essential to validate these findings and further explore CRGs-targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke (IS) is a global health issue linked to lipid metabolism and immune cell responses. This study uses Mendelian randomization (MR) to identify genetic risk factors for IS subtypes using comprehensive genetic data from lipidomic and immune cell profiles. Methods: We assessed genetic susceptibility to IS across 179 lipids and 731 immune cell phenotypes using instrumental variables (IVs) from recent genome-wide association studies. A two-sample MR approach evaluated correlations, and a two-step MR mediation analysis explored the role of immune cell phenotypes in the lipid-IS pathway. Sensitivity analyses, including MR-Egger and Cochran Q tests, ensured robust results. Results: Genetic IVs for 162 lipids and 614 immune cell phenotypes were identified. Significant genetic causality was found between 35 lipids and large artery stroke (LAS), with 12 as risk factors (sterol esters, phosphatidylcholines, phosphatidylethanolamines) and 23 as protective factors (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols). For small vessel stroke (SVS), 8 as risk factors (sterol esters, phosphatidylcholines), and 2 as protective factors (phosphatidylinositol, sphingomyelin). For cardioembolic stroke (CS), 2 as risk factors, and 4 as protective factors. Mediation analysis revealed that CCR2 on granulocytes, CD11c on CD62L+ myeloid dendritic cells, and FSC-A on granulocytes mediated the lipid-immune cell-LAS pathway, while CD4 on activated CD4 regulatory T cells and CD4 on activated & secreting CD4 regulatory T cells mediated the lipid-immune cell-SVS pathway. Conclusion: This study identifies genetic links between specific lipids and IS subtypes, highlights immune cells' role in IS risk and mediation, suggests new therapeutic targets, and uncovers IS genetic drivers. [ABSTRACT FROM AUTHOR]

Introduction: The intricate roles of immune cells and inflammatory factors in cancer, particularly their association with the risk of bladder cancer, are not well understood. Methods: This study aimed to clarify potential causal relationships between these elements and the development of bladder cancer using genome-wide association study (GWAS) summary statistics for 731 immune cell phenotypes and 91 circulating inflammatory factors (cases=2,053; controls=287,137). The primary analytical approach was Inverse Variance Weighting (IVW), supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses included Cochran Q test, MR-Egger intercept test, and Leave-one-out test. Results: The findings indicated that monocytes are positively correlated with an increased risk of bladder cancer. On the contrary, double-negative (DN) T cells, HLA DR+CD8br, and CD28 on CD28+CD45RA+CD8br T cells exhibited an inverse correlation, suggesting a possible protective effect. Furthermore, inflammatory factors IL-20, IL-22RA1, and Eotaxin were significantly associated with an increased risk of bladder cancer. Discussion: These results suggest that certain immune cell phenotypes and inflammatory factors may play a role in the development of bladder cancer and could serve as potential biomarkers for assessing tumor risk. The findings also offer new insights into the pathogenesis of bladder cancer, indicating a need for further investigation. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke (IS) is a global health issue linked to lipid metabolism and immune cell responses. This study uses Mendelian randomization (MR) to identify genetic risk factors for IS subtypes using comprehensive genetic data from lipidomic and immune cell profiles. Methods: We assessed genetic susceptibility to IS across 179 lipids and 731 immune cell phenotypes using instrumental variables (IVs) from recent genome- wide association studies. A two-sample MR approach evaluated correlations, and a two-step MR mediation analysis explored the role of immune cell phenotypes in the lipid-IS pathway. Sensitivity analyses, including MR-Egger and Cochran Q tests, ensured robust results. Results: Genetic IVs for 162 lipids and 614 immune cell phenotypes were identified. Significant genetic causality was found between 35 lipids and large artery stroke (LAS), with 12 as risk factors (sterol esters, phosphatidylcholines, phosphatidylethanolamines) and 23 as protective factors (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols). For small vessel stroke (SVS), 8 as risk factors (sterol esters, phosphatidylcholines), and 2 as protective factors (phosphatidylinositol, sphingomyelin). For cardioembolic stroke (CS), 2 as risk factors, and 4 as protective factors. Mediation analysis revealed that CCR2 on granulocytes, CD11c on CD62L+ myeloid dendritic cells, and FSC-A on granulocytes mediated the lipid-immune cell-LAS pathway, while CD4 on activated CD4 regulatory T cells and CD4 on activated & secreting CD4 regulatory T cells mediated the lipid-immune cell-SVS pathway. Conclusion: This study identifies genetic links between specific lipids and IS subtypes, highlights immune cells’ role in IS risk and mediation, suggests new therapeutic targets, and uncovers IS genetic drivers. [ABSTRACT FROM AUTHOR]

Background: Inflammaging, an immune status characterized by a sustained increase in pro-inflammatory markers and a decline in anti-inflammatory mechanisms, is a critical risk factor in the development of sarcopenia. Landscapes of the causal relationships between immunity and sarcopenia are needed to understand the mechanism of sarcopenia and provide novel treatments comprehensively. Methods: We used Mendelian Randomization (MR) as the basic method in this study. By setting immune proteins, immune cells, and sarcopenia as exposures and outcomes alternatively, and then combining them in different directions, we potentially estimated their causal relationships and directions and subsequently mapped the comprehensive causal landscape based on this information efficiently. To further understand the network, we developed a method based on rank-sums to integrate multiple algorithms and identify the key immune cells and proteins. Results: More than 1,000 causal relationships were identified between immune cell phenotypes, proteins, and sarcopenia traits (p < 0.05), and the causal maps of these linkages were established. In the threshold of FDR < 0.05, hundreds of causal linkages were still significant. The final comprehensive map included 13 immune cell phenotypes and 8 immune proteins. The star factors in the final map included EM CD8br %CD8br, EM DN (CD4- CD8-) %DN, SIRT2, and so on. Conclusion: By reading the landscapes in this study, we may not only find the factors and the pathways that have been reported and proven but also identify multiple novel immunity cell phenotypes and proteins with enriched upstream and downstream pathways. [ABSTRACT FROM AUTHOR]

Background: Biliary tract cancer stands as a prevalent illness, posing significant risks to human health, where immune cells are pivotal in both its development and recovery processes. Due to the diverse functionalities exhibited by different immune cell phenotypes within the organism, and the relatively limited research on their relationship with biliary tract cancer, this study employed Mendelian randomization (MR) to explore their potential association, thereby aiding in a better understanding of the causal link between immune cell phenotypes and biliary tract cancer. Methods: In this study, the causative association of 731 immunophenotype with biliary tract cancer was established using publicly accessible genome-wide association study (GWAS) genetic data through two-sample MR analysis. Sensitivity analyses assess horizontal pleiotropy and heterogeneity of the study findings. Results: Among the 731 immunophenotypes examined, a total of 26 immune cell phenotypes were found to exhibit positive results, indicating a significant association with the risk of biliary tract cancer. We confirmed that among these 26 types of immune cells, there are primarily 13 types of B cells; three types of classical dendritic cells (CDCs), including CD80 on myeloid DC, HLA DR on myeloid DC, and Myeloid DC %DC; one type of mature stage T cell, CD4RA on TD CD4+; six types of regulatory T cells; and three types of myeloid cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most common and lethal malignancies, and various factors have been confirmed to contribute to its occurrence. However, the causal role of immune cell-specific changes in the development of colorectal cancer has not been investigated. The bidirectional two-sample Mendelian randomization analysis was performed to explore the association between 731 types of immune cell phenotypes-specific changes and colorectal cancer. The inverse variance weighting results indicated that a total of 31 and 28 immune cell phenotypes significantly associated with colorectal cancer in two different datasets, respectively. The primary results of inverse variance weighting Mendelian randomization suggested that the immune cell phenotypes BAFF-R on IgD+ CD38dim (OR = 1.033, 95%CI: 1.005–1.062) and SSC-A on monocyte (OR = 1.055, 95%CI: 1.016–1.096) served as risk factor for colorectal cancer. In addition, the meta-analysis further supports the causal link of BAFF-R on IgD+ CD38dim (pooled OR = 1.035, 95%CI: 1.013–1.059) and SSC-A on monocyte (pooled OR = 1.060, 95%CI: 1.026–1.095) with colorectal cancer. Finally, the inverse variance weighting Mendelian randomization result suggested that genetic determinants of colorectal cancer may decrease the level of HLA DR++ monocyte absolute count (OR = 0.686, 95%CI: 0.508–0.925). Our results indicated that the potential causal association of BAFF-R on IgD+ CD38dim and SSC-A on monocyte with colorectal cancer. The identified immune cells may be appealing drug targets for colorectal cancer, but lack confirmation from real clinical evidence. Further studies are needed to investigate the roles of these immune cells in colorectal cancer.

BackgroundChildhood acute myeloid leukemia (cAML) is the second most common pediatric blood cancer, with high heterogeneity and poor prognosis. Recent studies have highlighted cuproptosis, a newly discovered form of programmed cell death triggered by the accumulation of intracellular copper ions, as a critical mechanism influencing cancer survival and resistance. Given its emerging role in cancer biology, we investigated cuproptosis-related genes (CRGs) in cAML to explore their potential in prognostic prediction and therapeutic targeting.MethodsGene expression data from publicly available sources were analyzed to identify differentially expressed CRGs. Samples were categorized based on their expression profiles, followed by the development of a prognostic risk model using multivariable Cox regression, LASSO, and univariable analyses. The model’s performance was evaluated through Kaplan-Meier survival analysis and ROC analysis. Immune infiltration in the tumor microenvironment was assessed using ssGSEA, validated by CIBERSORT. Drug sensitivity correlations were analyzed, and functional validation experiments were conducted on THP-1 and MOLM13 cell lines to assess the role of CNN3.ResultsA set of 12 differential CRGs was used to build a robust prognostic risk model, with high accuracy in predicting patient outcomes (P < 0.001). Significant differences in immune cell composition were identified between risk groups, particularly in T cells, B cells, monocytes, and dendritic cells. Drug sensitivity analysis revealed altered IC50 values for drugs like 5-fluorouracil and bortezomib. Knockdown of CNN3 in leukemia cell lines led to reduced cell proliferation.ConclusionOur CRGs-based prognostic model shows potential for guiding personalized treatment strategies in cAML. The differences in immune cell infiltration between risk groups suggest that immune modulation is key in cAML progression. CNN3 and LGR4 were identified as modulators of cAML progression, making them potential therapeutic targets. Future studies with larger cohorts are essential to validate these findings and further explore CRGs-targeted therapies.

Objectives: Preeclampsia/eclampsia (PE), a critical complication during pregnancy, has been suggested to correlate with immune cell phenotypes and levels of circulating inflammatory proteins. Our study aimed to employ a twosample mendelian randomization (MR) analysis to assess the potential causal effects of immune cell phenotypes and circulating inflammatory proteins on the onset of PE. Methods: We utilized summary-level data from genome-wide association studies (GWAS). This included statistics for 371 immune cell phenotypes from 3,757 individuals in the Sardinian founder population, and data on 91 circulating inflammatory proteins from 14,824 European ancestry participants. Additionally, genetic associations related to PE were extracted from the FinnGen consortium, involving 1,413 cases and 287,137 controls. We applied inverse variance weighting (IVW) and supplementary methods like MR-Egger, weighted median, and weighted mode to comprehensively assess potential causal links. Results: Our analysis revealed significant causal associations of several immune cells type and inflammatory proteins with PE. Out of the immune cell phenotypes analyzed, six immune phenotypes emerged as significant risk factors (p <0.01), mainly include CD4 on activated and secreting CD4 regulatory T cells, CD28 on CD39+ CD4+ T cells, CD127- CD8+ T cell absolute cell (AC) counts, HLA DR on HLA DR+ CD8+ T cell, CD66b on CD66b++ myeloid cells, and HLA DR on dendritic cells. And ten were identified as protective factors (p <0.01). Such as CD45 on CD33br HLA DR+ CD14-, CD33+ HLA DR+ AC, CD33+ HLA DR+ CD14- AC, CD33+ HLA DR+ CD14dim AC, CD27 on CD24+ CD27+ B cell, CD20- CD38- %B cell, IgD- CD24- %B cell CD80 on plasmacytoid DC, CD25 on CD4+ T cell, and CD25 on activated & secreting CD4 regulatory T cell. Furthermore, among the inflammatory proteins studied, five showed a significant association with PE, with three offering protective effects mainly include that C-X-C motif chemokine 1, tumor necrosis factor ligand superfamily member 14, and C-C motif chemokine 19 and two exacerbating PE risk such as STAM-binding domain and Interleukin-6 (p <0.05). Conclusions: Our study highlights the pivotal roles played by diverse immune cell phenotypes and circulating inflammatory proteins in the pathophysiology of PE. These findings illuminate the underlying genetic mechanisms, emphasizing the criticality of immune regulation during pregnancy. Such insights could pave the way for novel intervention strategies in managing PE, potentially enhancing maternal and neonatal health outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Numerous observational studies have indicated that smoking is a substantial risk factor for esophageal cancer. However, there is a shortage of research that delves into the specific causal relationship and potential mediators between the two. Our study aims to validate the correlation between smokingrelated traits and esophageal cancer while exploring the possible mediating effects of immune factors. Methods: Initially, we conducted bidirectional univariate Mendelian Randomization (MR) analyses to forecast the causal effects linking smokingrelated traits and esophageal cancer. Subsequently, we employed a two-step MR analysis to scrutinize immune cell phenotypes that could mediate these effects. Finally, the coefficient product method was employed to determine the precise mediating impact. Additionally, we have refined our sensitivity analysis to ensure the reliability of the outcomes. Results: After analysis, Smoking status: Never had a significant negative association with the incidence of esophageal cancer (inverse-variance weighted (IVW) method, p=1.82e-05, OR=0.10, 95%CI=0.04~0.29). Ever smoked (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) and Current tobacco smoking (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) showed the promoting effect on the pathogenesis of esophageal cancer. Through further examination, researchers discovered 21 immune cell phenotypes that have a causal relationship with esophageal cancer. After careful screening, two immune cell phenotypes were found to have potential mediating effects. In particular, it was observed that in the case of the preventive effect of Smoking status: Never on esophageal cancer, the absolute count of CD62L plasmacytoid dendritic cells mediated a reduction of 4.21%, while the mediating effect of CD27 in CD20-CD38-B cells was -4.12%. In addition, sensitivity analyses did not reveal significant heterogeneity or level pleiotropy. Conclusion: The study provides new evidence for the causal relationship between smoking-related features and esophageal cancer and proposes immune factors with potential mediating effects. However, this finding needs to be further demonstrated by more extensive clinical studies. [ABSTRACT FROM AUTHOR]

Problem: Preeclampsia, a multifaceted condition during pregnancy characterized by hypertension and organ dysfunction, poses significant risks to both maternal and fetal health. This study aims to investigate the bidirectional causal relationship between peripheral immune cell phenotypes and preeclampsia using a two-sample Mendelian randomization (MR) approach. Method of study: Genetic data from two sizable cohorts were utilized: 3757 individuals from Sardinia, providing information on 731 immune traits, and 200 929 Finnish adult females, encompassing 6663 preeclampsia cases. Single-nucleotide polymorphisms served as instrumental variables. The MR analyses employed the inverse variance-weighted (IVW) method as the primary tool, supplemented by MR-Egger, weighted median, and weighted mode methods to enhance reliability and address potential heterogeneity and horizontal pleiotropy. Results: Among the 731 immune cell phenotypes studied, 18 displayed a suggestive positive association (IVW p < .05) with heightened preeclampsia risk, while 20 exhibited a suggestive negative association linked to reduced risk. Following false discovery rate (FDR) adjustment, four immune phenotypes showed significant associations with decreased preeclampsia risk: CD27 on CD24+CD27+B cells (B-cell panel) (odds ratio [OR] = 0.927, PFDR = 0.061), CD33+ HLA DR+ CD14- absolute count (OR = 0.963, PFDR = 0.061), CD80 on plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061); and CD80 on CD62L+ plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061). In the reverse-directionMR analysis, no significant causal effects of preeclampsia on immune cell phenotypes were observed. Conclusions: This study provides quantifiable evidence linking specific immune cell phenotypes to the risk of developing preeclampsia. This novel understanding of the immunological aspects underlying preeclampsia's pathogenesis could lead to innovative therapeutic strategies centered on immune modulation. [ABSTRACT FROM AUTHOR]

Background: Cerebral aneurysms (CAs) are a significant cerebrovascular ailment with a multifaceted etiology influenced by various factors including heredity and environment. This study aimed to explore the possible link between different types of immune cells and the occurrence of CAs. Methods: We analyzed the connection between 731 immune cell signatures and the risk of CAs by using publicly available genetic data. The analysis included four immune features, specifically median brightness levels (MBL), proportionate cell (PC), definite cell (DC), and morphological attributes (MA). Mendelian randomization (MR) analysis was conducted using the instrumental variables (IVs) derived from the genetic variation linked to CAs. Results: After multiple test adjustment based on the FDR method, the inverse variance weighted (IVW) method revealed that 3 immune cell phenotypes were linked to the risk of CAs. These included CD45 on HLA DR+NK (odds ratio (OR), 1.116; 95% confidence interval (CI), 1.001-1.244; p = 0.0489), CX3CR1 on CD14-CD16- (OR, 0.973; 95% CI, 0.948-0.999; p = 0.0447). An immune cell phenotype CD16- CD56 on NK was found to have a significant association with the risk of CAs in reverse MR study (OR, 0.950; 95% CI, 0.911-0.990; p = 0.0156). Conclusion: Our investigation has yielded findings that support a substantial genetic link between immune cells and CAs, thereby suggesting possible implications for future clinical interventions. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most common and lethal malignancies, and various factors have been confirmed to contribute to its occurrence. However, the causal role of immune cell-specific changes in the development of colorectal cancer has not been investigated. The bidirectional two-sample Mendelian randomization analysis was performed to explore the association between 731 types of immune cell phenotypes-specific changes and colorectal cancer. The inverse variance weighting results indicated that a total of 31 and 28 immune cell phenotypes significantly associated with colorectal cancer in two different datasets, respectively. The primary results of inverse variance weighting Mendelian randomization suggested that the immune cell phenotypes BAFF-R on IgD+ CD38dim (OR = 1.033, 95%CI: 1.005-1.062) and SSC-A on monocyte (OR = 1.055, 95%CI: 1.016-1.096) served as risk factor for colorectal cancer. In addition, the meta-analysis further supports the causal link of BAFF-R on IgD+ CD38dim (pooled OR = 1.035, 95%CI: 1.013-1.059) and SSC-A on monocyte (pooled OR = 1.060, 95%CI: 1.026-1.095) with colorectal cancer. Finally, the inverse variance weighting Mendelian randomization result suggested that genetic determinants of colorectal cancer may decrease the level of HLA DR++ monocyte absolute count (OR = 0.686, 95%CI: 0.508-0.925). Our results indicated that the potential causal association of BAFF-R on IgD+ CD38dim and SSC-A on monocyte with colorectal cancer. The identified immune cells may be appealing drug targets for colorectal cancer, but lack confirmation from real clinical evidence. Further studies are needed to investigate the roles of these immune cells in colorectal cancer.

Background: Increasing evidence suggests that immunophenotypes play a crucial role in Metabolic dysfunction-associated fatty liver disease (MAFLD), but the specific immunophenotypes contributing to its pathogenesis remain unclear., Objectives: This study aimed to elucidate the causal associations between immunophenotypes and MAFLD and identify the underlying mediation pathways involved., Design: Mendelian randomization (MR) study., Methods: This study is a quasi-causal inference analysis using univariable and multivariable MR (UVMR and MVMR). Five MAFLD genome-wide association studies (GWASs) and the largest immunophenotype GWAS were analyzed to assess their causal associations. Two-step MR identified potential mediators and quantified their mediation proportions. Comprehensive MR methods, multiple sensitivity analyses, meta-analyses, and false discovery rate (FDR) further enhanced the robustness of our findings., Results: Pooled inverse-variance weighted (IVW) estimates in UVMR identified 47 immunophenotypes having a suggestive causal association with MAFLD. After adjusting for FDR, three lymphocyte phenotypes remained significant: CD20 on IgD - CD24 - B cells (OR: 1.035, p fdr : 0.006), terminally differentiated CD8 + T cells %T cells (OR: 1.052, p fdr : 0.006), and CD4 on CD39 + secreting CD4 + regulatory T cells (OR: 1.036, p fdr : 0.046). Meta-analysis of IVW MVMR estimates with confounders adjustment confirmed that CD20 on IgD - CD24 - B cells and terminally differentiated CD8 + T cells %T cells had significant direct causal associations on MAFLD ( p fdr  < 0.05). Additionally, two-step MR analysis identified the waist-to-hip ratio as a mediator, accounting for 42.64% of the causal association between CD20 on IgD - CD24 - B cells and MAFLD., Conclusion: The causal associations of three lymphocyte phenotypes with increased MAFLD risk were identified in this study. CD20 on IgD - CD24 - B cells may both directly and indirectly elevate MAFLD risk, while terminally differentiated CD8 + T cells have a direct causal relationship with MAFLD. These findings suggest new possibilities for targeted therapies and underscore the potential for personalized immunotherapy in managing MAFLD., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Introduction: The intricate roles of immune cells and inflammatory factors in cancer, particularly their association with the risk of bladder cancer, are not well understood., Methods: This study aimed to clarify potential causal relationships between these elements and the development of bladder cancer using genome-wide association study (GWAS) summary statistics for 731 immune cell phenotypes and 91 circulating inflammatory factors (cases=2,053; controls=287,137). The primary analytical approach was Inverse Variance Weighting (IVW), supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses included Cochran Q test, MR-Egger intercept test, and Leave-one-out test., Results: The findings indicated that monocytes are positively correlated with an increased risk of bladder cancer. On the contrary, double-negative (DN) T cells, HLA DR+CD8br, and CD28 on CD28+CD45RA+CD8br T cells exhibited an inverse correlation, suggesting a possible protective effect. Furthermore, inflammatory factors IL-20, IL-22RA1, and Eotaxin were significantly associated with an increased risk of bladder cancer., Discussion: These results suggest that certain immune cell phenotypes and inflammatory factors may play a role in the development of bladder cancer and could serve as potential biomarkers for assessing tumor risk. The findings also offer new insights into the pathogenesis of bladder cancer, indicating a need for further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer XD declared a shared parent affiliation, with no collaboration, with the authors to the handling editor at the time of the review., (Copyright © 2024 Un, Wusimanjiang, Zhan, Zhang, Li, Lei, Lin, Zhang, Chen and Wang.)

Background: Inflammaging, an immune status characterized by a sustained increase in pro-inflammatory markers and a decline in anti-inflammatory mechanisms, is a critical risk factor in the development of sarcopenia. Landscapes of the causal relationships between immunity and sarcopenia are needed to understand the mechanism of sarcopenia and provide novel treatments comprehensively., Methods: We used Mendelian Randomization (MR) as the basic method in this study. By setting immune proteins, immune cells, and sarcopenia as exposures and outcomes alternatively, and then combining them in different directions, we potentially estimated their causal relationships and directions and subsequently mapped the comprehensive causal landscape based on this information efficiently. To further understand the network, we developed a method based on rank-sums to integrate multiple algorithms and identify the key immune cells and proteins., Results: More than 1,000 causal relationships were identified between immune cell phenotypes, proteins, and sarcopenia traits (p < 0.05), and the causal maps of these linkages were established. In the threshold of FDR < 0.05, hundreds of causal linkages were still significant. The final comprehensive map included 13 immune cell phenotypes and 8 immune proteins. The star factors in the final map included EM CD8br %CD8br, EM DN (CD4- CD8-) %DN, SIRT2, and so on., Conclusion: By reading the landscapes in this study, we may not only find the factors and the pathways that have been reported and proven but also identify multiple novel immunity cell phenotypes and proteins with enriched upstream and downstream pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Wang, Han, Fu, Pan, Yang and Sun.)

Background: Biliary tract cancer stands as a prevalent illness, posing significant risks to human health, where immune cells are pivotal in both its development and recovery processes. Due to the diverse functionalities exhibited by different immune cell phenotypes within the organism, and the relatively limited research on their relationship with biliary tract cancer, this study employed Mendelian randomization (MR) to explore their potential association, thereby aiding in a better understanding of the causal link between immune cell phenotypes and biliary tract cancer., Methods: In this study, the causative association of 731 immunophenotype with biliary tract cancer was established using publicly accessible genome-wide association study (GWAS) genetic data through two-sample MR analysis. Sensitivity analyses assess horizontal pleiotropy and heterogeneity of the study findings., Results: Among the 731 immunophenotypes examined, a total of 26 immune cell phenotypes were found to exhibit positive results, indicating a significant association with the risk of biliary tract cancer. We confirmed that among these 26 types of immune cells, there are primarily 13 types of B cells; three types of classical dendritic cells (CDCs), including CD80 on myeloid DC, HLA DR on myeloid DC, and Myeloid DC %DC; one type of mature stage T cell,CD4RA on TD CD4+; six types of regulatory T cells; and three types of myeloid cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Wang, Chen, Jin, Guo and Tang.)

Objectives: Preeclampsia/eclampsia (PE), a critical complication during pregnancy, has been suggested to correlate with immune cell phenotypes and levels of circulating inflammatory proteins. Our study aimed to employ a two-sample mendelian randomization (MR) analysis to assess the potential causal effects of immune cell phenotypes and circulating inflammatory proteins on the onset of PE., Methods: We utilized summary-level data from genome-wide association studies (GWAS). This included statistics for 371 immune cell phenotypes from 3,757 individuals in the Sardinian founder population, and data on 91 circulating inflammatory proteins from 14,824 European ancestry participants. Additionally, genetic associations related to PE were extracted from the FinnGen consortium, involving 1,413 cases and 287,137 controls. We applied inverse variance weighting (IVW) and supplementary methods like MR-Egger, weighted median, and weighted mode to comprehensively assess potential causal links., Results: Our analysis revealed significant causal associations of several immune cells type and inflammatory proteins with PE. Out of the immune cell phenotypes analyzed, six immune phenotypes emerged as significant risk factors ( p < 0.01), mainly include CD4 on activated and secreting CD4 regulatory T cells, CD28 on CD39+ CD4+ T cells, CD127- CD8+ T cell absolute cell (AC) counts, HLA DR on HLA DR+ CD8+ T cell, CD66b on CD66b++ myeloid cells, and HLA DR on dendritic cells. And ten were identified as protective factors ( p < 0.01). Such as CD45 on CD33br HLA DR+ CD14-, CD33+ HLA DR+ AC, CD33+ HLA DR+ CD14- AC, CD33+ HLA DR+ CD14dim AC, CD27 on CD24+ CD27+ B cell, CD20- CD38- %B cell, IgD- CD24- %B cell CD80 on plasmacytoid DC, CD25 on CD4+ T cell, and CD25 on activated & secreting CD4 regulatory T cell. Furthermore, among the inflammatory proteins studied, five showed a significant association with PE, with three offering protective effects mainly include that C-X-C motif chemokine 1, tumor necrosis factor ligand superfamily member 14, and C-C motif chemokine 19 and two exacerbating PE risk such as STAM-binding domain and Interleukin-6 (p <0.05)., Conclusions: Our study highlights the pivotal roles played by diverse immune cell phenotypes and circulating inflammatory proteins in the pathophysiology of PE. These findings illuminate the underlying genetic mechanisms, emphasizing the criticality of immune regulation during pregnancy. Such insights could pave the way for novel intervention strategies in managing PE, potentially enhancing maternal and neonatal health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Zhang, Du and Chen.)

Problem: Preeclampsia, a multifaceted condition during pregnancy characterized by hypertension and organ dysfunction, poses significant risks to both maternal and fetal health. This study aims to investigate the bidirectional causal relationship between peripheral immune cell phenotypes and preeclampsia using a two-sample Mendelian randomization (MR) approach., Method of Study: Genetic data from two sizable cohorts were utilized: 3757 individuals from Sardinia, providing information on 731 immune traits, and 200 929 Finnish adult females, encompassing 6663 preeclampsia cases. Single-nucleotide polymorphisms served as instrumental variables. The MR analyses employed the inverse variance-weighted (IVW) method as the primary tool, supplemented by MR-Egger, weighted median, and weighted mode methods to enhance reliability and address potential heterogeneity and horizontal pleiotropy., Results: Among the 731 immune cell phenotypes studied, 18 displayed a suggestive positive association (IVW p < .05) with heightened preeclampsia risk, while 20 exhibited a suggestive negative association linked to reduced risk. Following false discovery rate (FDR) adjustment, four immune phenotypes showed significant associations with decreased preeclampsia risk: CD27 on CD24+ CD27+ B cells (B-cell panel) (odds ratio [OR] = 0.927, P FDR  = 0.061), CD33+ HLA DR+ CD14- absolute count (OR = 0.963, P FDR  = 0.061), CD80 on plasmacytoid dendritic cells (OR = 0.923, P FDR  = 0.061); and CD80 on CD62L+ plasmacytoid dendritic cells (OR = 0.923, P FDR  = 0.061). In the reverse-direction MR analysis, no significant causal effects of preeclampsia on immune cell phenotypes were observed., Conclusions: This study provides quantifiable evidence linking specific immune cell phenotypes to the risk of developing preeclampsia. This novel understanding of the immunological aspects underlying preeclampsia's pathogenesis could lead to innovative therapeutic strategies centered on immune modulation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Numerous observational studies have indicated that smoking is a substantial risk factor for esophageal cancer. However, there is a shortage of research that delves into the specific causal relationship and potential mediators between the two. Our study aims to validate the correlation between smoking-related traits and esophageal cancer while exploring the possible mediating effects of immune factors., Methods: Initially, we conducted bidirectional univariate Mendelian Randomization (MR) analyses to forecast the causal effects linking smoking-related traits and esophageal cancer. Subsequently, we employed a two-step MR analysis to scrutinize immune cell phenotypes that could mediate these effects. Finally, the coefficient product method was employed to determine the precise mediating impact. Additionally, we have refined our sensitivity analysis to ensure the reliability of the outcomes., Results: After analysis, Smoking status: Never had a significant negative association with the incidence of esophageal cancer (inverse-variance weighted (IVW) method, p=1.82e-05, OR=0.10, 95%CI=0.04~0.29). Ever smoked (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) and Current tobacco smoking (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) showed the promoting effect on the pathogenesis of esophageal cancer. Through further examination, researchers discovered 21 immune cell phenotypes that have a causal relationship with esophageal cancer. After careful screening, two immune cell phenotypes were found to have potential mediating effects. In particular, it was observed that in the case of the preventive effect of Smoking status: Never on esophageal cancer, the absolute count of CD62L plasmacytoid dendritic cells mediated a reduction of 4.21%, while the mediating effect of CD27 in CD20-CD38-B cells was -4.12%. In addition, sensitivity analyses did not reveal significant heterogeneity or level pleiotropy., Conclusion: The study provides new evidence for the causal relationship between smoking-related features and esophageal cancer and proposes immune factors with potential mediating effects. However, this finding needs to be further demonstrated by more extensive clinical studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Li, Ding, Meng, Zhang and Sun.)

Background: Cerebral aneurysms (CAs) are a significant cerebrovascular ailment with a multifaceted etiology influenced by various factors including heredity and environment. This study aimed to explore the possible link between different types of immune cells and the occurrence of CAs. Methods: We analyzed the connection between 731 immune cell signatures and the risk of CAs by using publicly available genetic data. The analysis included four immune features, specifically median brightness levels (MBL), proportionate cell (PC), definite cell (DC), and morphological attributes (MA). Mendelian randomization (MR) analysis was conducted using the instrumental variables (IVs) derived from the genetic variation linked to CAs. Results: After multiple test adjustment based on the FDR method, the inverse variance weighted (IVW) method revealed that 3 immune cell phenotypes were linked to the risk of CAs. These included CD45 on HLA DR+NK (odds ratio (OR), 1.116; 95% confidence interval (CI), 1.001-1.244; p = 0.0489), CX3CR1 on CD14 - CD16 - (OR, 0.973; 95% CI, 0.948-0.999; p = 0.0447). An immune cell phenotype CD16 - CD56 on NK was found to have a significant association with the risk of CAs in reverse MR study (OR, 0.950; 95% CI, 0.911-0.990; p = 0.0156). Conclusion: Our investigation has yielded findings that support a substantial genetic link between immune cells and CAs, thereby suggesting possible implications for future clinical interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shi, Wang, Teng, Hou and Lin.)

An immune cell's phenotype expresses through its high-dimensional marker signature. Cluster analyses of data from high-throughput mass and flow cytometry marker panels permit discovery of previously undescribed immune cell phenotypes. Impactful reporting of new phenotypes demands low-dimensional visualization tools that preserve with integrity phenotypes' original high-dimensional structure. For this purpose, we introduce penalized supervised star plots. As designed and as we demonstrate, penalized supervised star plots are two-dimensional projections that tend to preserve separation of clusters as well as information on the relative contributions of various markers in differentiating phenotypes. The new method is robust to markers that do not differentiate phenotypes at all, as shown in a challenge data set. Results include comparison with other popular procedures. Penalized supervised star plots incorporate cross-validation to permit portability of estimated optimal projections to new samples. Supervised star plots are further illustrated with a featured influenza-specific T cell data set as well as a peripheral blood mononuclear cell phenotyping data set. [ABSTRACT FROM AUTHOR]

Background & Aims: Chronic inflammatory liver diseases are frequently associated with neuropsychiatric and cognitive dysfunctions. We hypothesized that symptomatic patients may show altered levels of soluble inflammatory mediators (SIMs) as well as changes in immune cell phenotypes. Methods: A comprehensive immune‐phenotyping including investigation of 50 SIMs as well as ex‐vivo phenotypes of NK‐cells, CD3+, CD4+, CD8+ and regulatory T cells in 40 patients with viral and autoimmune chronic liver diseases was performed. The patients' cognitive functions were assessed using an extensive battery of neuropsychological testing. Results and Conclusion: Overall, our data indicate that while SIMs are significantly up‐regulated, NK‐ and T‐cells are less‐activated in patients with neuropsychiatric symptoms accompanying chronic inflammatory liver diseases compared to patients without these symptoms. Moreover, HCV patients showed a unique pattern of immune alterations as compared to patients with HBV, autoimmune hepatitis and primary biliary cirrhosis. These findings hint towards potential mechanisms explaining these symptoms in patients with chronic liver diseases. [ABSTRACT FROM AUTHOR]

Background Previous studies on Natalizumab ( NAT) have shown increased circulation of most white blood cells ( WBC) in multiple sclerosis ( MS) patients shortly after its introduction. Aim To describe peripheral immune cell phenotypes after more than 2 years of continuous NAT therapy and test for associations with clinical response to therapy. Methods Peripheral immune cell subsets were analyzed in 44 NAT- MS patients receiving NAT for over 24 months, and in 22 NAT-free control- MS patients. Results NAT- MS patients displayed significantly higher numbers of all WBC when compared with controls. B lymphocytes exhibited a more pronounced increase when compared with CD4+, CD8+ and NK T-cells ( P = 0.011). CD4/ CD8 ratio was significantly decreased in NAT- MS patients ( P = 0.018) and showed no correlation with the number of NAT doses. The reduced CD4/ CD8 ratio was attributable to the ' EDSS improvement' group only, irrespective of age, sex and disease severity. Conclusions The study suggests that there is no desensitization effect after prolonged NAT exposure. A reduced CD4/ CD8 ratio was associated with long-term response to therapy; thus, those patients who most benefitted from the drug might be at greater risk for opportunistic infections like progressive multifocal leucoencephalopathy ( PML). We provide implications for future research for the CD4/ CD8 ratio as a possible contributor to the recently developed risk stratification scheme for PML. [ABSTRACT FROM AUTHOR]

Simple Summary: Classic Hodgkin lymphoma (cHL) is one of the most enigmatic study models of the tumor microenvironment (TME), in which the Hodgkin–Reed Sternberg (HRS) cells are distributed throughout an abundant but ineffective immune ecosystem. The hyperactivation of HRS cells due to somatic mutations leads to complex interactions with the different subsets of immune cell populations, modeling the pathophysiology of the disease. There are remaining loose ends regarding the identification of the immune functional states in the cHL microenvironment and their influence on tumor cell survival. Here, we review the most relevant immune populations identified in the cHL context, focusing on integrative functional signatures. The classic Hodgkin lymphoma (cHL) tumor microenvironment (TME) is by far the most abundant component of tumors and is responsible for most of their biological and clinical characteristics. Recent advances in our knowledge of these networks in cellular interactions allow us to understand that the neoplastic Hodgkin and Reed Sternberg (HRS) cells, although they are in the minority, are the main architects of this dysregulated immune milieu. Here, we review the major changes that have happened in recent years: from TME as a helpless bystander, reflecting an ineffective immune response, to a dynamic tumor-promoting and immunosuppressive element. The HRS cells promote survival through interconnected intrinsic and extrinsic alterations, boosting pro-tumoral signaling pathways through genetic aberrations and autocrine growth signals, in parallel with abnormal cytokine secretion for the recruitment and selection of the best cell partners for this immunosuppressive TME. In turn, cHL is already proving to be the perfect model with which to address an immune checkpoint blockade. Preliminary data demonstrate the utility of druggable key signaling pathways in this ensemble, such as JAK-STAT, NF-κB, and others. In addition, myriad biomarkers predicting a response await validation by new in situ multiplex analytical methods, single-cell gene expression, and other techniques. Together, these components will define the functional phenotypes with which we will elucidate the molecular pathogenesis of the disease and improve the survival of patients who are refractory to conventional therapies. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To examine immune cell phenotypes in viable tubal pregnancies (VTP) and in tubal abortions (TA). Methods: Paraffin-embedded specimens of VTP (n =7) and ongoing TA (n =6) were double-stained for cytokeratin for trophoblast as well as for CD45, CD3, CD8, CD68 and CD20 for immune cell phenotypes. In all cases, the amniotic sac was detected by ultrasound. Histological examination showed no evidence of necrosis within the tissues included in this study. Quantification of the subpopulations was performed in each slide by two independent examiners in five areas (0.085mm2 each) of the invasion zone as marked by cytokeratin-positive stromal extravillous trophoblast (EVT) cells. For statistical analysis, the non-parametric two-tailed t-test was used (p <0.05). Results: The differences in the number of CD45+, CD68+ and CD20+ cells was significant (p =0.0423, p =0.0469 and p =0.0494, respectively); however, the number of CD3+, and among those the number of CD8+ cells, was approximately eight-fold higher in TA than in VTP (p <0.0001 and p =0.0012, respectively). Conclusion: The unequal distribution of CD8+ cells in VTP and TA suggests a significant role of this immune cell phenotype in the further outcome of a tubal pregnancy either to an abortive or a viable, potentially life-threatening, entity. [Copyright &y& Elsevier]

The role of endogenously produced cytokines and growth factors in the impaired healing of chronic leg ulcers remains uncertain. The aim of this study was to determine the functional capacity of skin cells in ulcer bed tissue compared to those in the edge of ulcers and skin distal to ulcers. Biopsies from leg ulcers of ten randomly selected patients were examined immunohistochemically for cytokines and growth factors produced by keratinocytes (KC) and vascular endothelial cells (EC). The phenotype of leukocytes infiltrating venous ulcers and the expression of vascular adhesion molecules responsible for extravasation were also studied. The expression of cytokines and growth factors by KC was similar in areas adjacent and remote from an ulcer. In the dermis adjacent to an ulcer, the expression of IL-1a, IL-1ß, IL-1Ra, EGF and PDGFa by EC was higher than the levels of expression in EC from the distant dermis. The expression of IL-6, TNFa and GM-CSF was comparable to that in cells from intact dermis. For all these factors staining was cytoplasmic, suggesting production in these areas. Ulcer bed tissue contained few fibroblasts and blood capillaries showing a high staining intensity for CD62E and CD106 EC adhesion molecules but no FGF2 expression (P<0.05). The intensity of staining for scavenging CD15+elastase+ granulocytes and CD35+ (C3bR) activated macrophages in the ulcer bed was comparable to that in the margin but higher than that in the distant dermis (P<0.05), whereas staining for CD68+, HLA DR+, TGFß+ and CD54+ dermal macrophages was similar in all areas. There was reduced staining for CD4+ and CD8+ cells in the ulcer bed (P<0.05). There were no CD1a+ Langerhans cells in the epidermis encroaching upon the granulation tissue and there was reduced CD1a staining in the adjacent epidermis (P<0.05). In conclusion, there is chronic accumulation of scavenging cells with lack of remodeling of the granulation tissue and, at the same time, preserved cytokine and growth factor secretory potential of KC and dermal EC in non-healing venous leg ulcers. [ABSTRACT FROM AUTHOR]