Recent breakthroughs in discovering novel immune signaling pathways have revolutionized different disease treatments. SERPINB9 (Sb9), also known as Proteinase Inhibitor 9 (PI-9), is a well-known endogenous inhibitor of Granzyme B (GzmB). GzmB is a potent cytotoxic molecule secreted by cytotoxic T lymphocytes and natural killer cells, which plays a crucial role in inducing apoptosis in target cells during immune responses. Sb9 acts as a protective mechanism against the potentially harmful effects of GzmB within the cells of the immune system itself. On the other hand, overexpression of Sb9 is an important mechanism of immune evasion in diseases like cancers and viral infections. The intricate functions of Sb9 in different cell types represent a fine-tuned regulatory mechanism for preventing immunopathology, protection against autoimmune diseases, and the regulation of cell death, all of which are essential for maintaining health and responding effectively to disease challenges. Dysregulation of the Sb9 will disrupt human normal physiological condition, potentially leading to a range of diseases, including cancers, inflammatory conditions, viral infections or other pathological disorders. Deepening our understanding of the role of Sb9 will aid in the discovery of innovative and effective treatments for various medical conditions. Therefore, the objective of this review is to consolidate current knowledge regarding the biological role of Sb9. It aims to offer insights into its discovery, structure, functions, distribution, its association with various diseases, and the potential of nanoparticle-based therapies targeting Sb9.

UNASSIGNED: Heart failure (HF) is a disease with numerous genetic and environmental factors that affect it. The results of previous studies indicated that immune phenotypes are associated with HF, but there have been inconclusive studies regarding a causal relationship. Therefore, Mendelian randomization (MR) analyses were undertaken to confirm the causal connections between immune phenotypes and HF, providing genetic evidence supporting the association of immune cell factors with HF risk.
UNASSIGNED: We selected instrumental variables that met the criteria based on data from the results of genome-wide association studies (GWAS) of immune phenotype and all-cause HF. An evaluation of the causal association between 731 immune cell factors and HF risk was carried out using the inverse variance weighted (IVW), MR-Egger regression (MR-Egger), and weighted median (WM) analysis methods. To determine the horizontal pleiotropy, heterogeneity, and stability of the genetic variants, the MR-Egger intercept test, Cochran\'s Q test, MR-PRESSO, and leave-one-out sensitivity analysis were performed.
UNASSIGNED: MR principal method (IVW) analysis showed that a total of 38 immune cell-related factors were significantly causally associated with HF. Further analyses combining three methods (IVW, MR-Egger and WME) showed that six exposure factors significantly associated with heart failure, as shown below. The effect of Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell on heart failure was positive. Whereas, a reverse effect was observed for CD14+ CD16+ monocyte% monocyte.
UNASSIGNED: We investigated the causal relationship between immune phenotypes and all-cause HF. According to the results, Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell aggravate HF, and the risk of HF is decreased by CD14+ CD16+ monocyte% monocyte. These phenotypes may serve as new biomarkers, providing new therapeutic insights for the prevention and treatment of all-cause HF.

Tissue fibrosis represents a complex pathological condition characterized by the excessive accumulation of collagenous extracellular matrix (ECM) components, resulting in impaired organ function. Fibroblasts are central to the fibrotic process and crucially involved in producing and depositing collagen-rich ECM. Apart from their primary function in ECM synthesis, fibroblasts engage in diverse activities such as inflammation and shaping the tissue microenvironment, which significantly influence cellular and tissue functions. This review explores the role of Yes-associated protein (Yap) and Transcriptional co-activator with PDZ-binding motif (Taz) in fibroblast signaling and their impact on tissue fibrosis. Gaining a comprehensive understanding of the intricate molecular mechanisms of Yap/Taz signaling in fibroblasts may reveal novel therapeutic targets for fibrotic diseases.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of malignant tumor with high morbidity. Aberrant levels of N7-methylguanosine (m7G) are closely associated with tumor progression. However, the characteristics of the tumor microenvironment (TME) in NPC associated with m7G modification remain unclear.
METHODS: A total of 68,795 single cells from single-cell RNA sequencing data derived from 11 NPC tumor samples and 3 nasopharyngeal lymphatic hyperplasia (NLH) samples were clustered using a nonnegative matrix factorization algorithm according to 61 m7G RNA modification regulators.
RESULTS: The m7G regulators were found differential expression in the TME cells of NPC, and most m7G-related immune cell clusters in NPC tissues had a higher abundance compared to non-NPC tissues. Specifically, m7G scores in the CD4+ and CD8+ T cell clusters were significantly lower in NPC than in NLH. T cell clusters differentially expressed immune co-stimulators and co-inhibitors. Macrophage clusters differentially expressed EIF4A1, and high EIF4A1 expression was associated with poor survival in patients with head and neck squamous carcinoma. EIF4A1 was upregulated in NPC tissues compared to the non-NPC tissues and mainly expressed in CD86+ macrophages. Moreover, B cell clusters exhibited tumor biological characteristics under the regulation of m7G-related genes in NPC. The fibroblast clusters interacted with the above immune cell clusters and enriched tumor biological pathways, such as FGER2 signaling pathway. Importantly, there were correlations and interactions through various ligand-receptor links among epithelial cells and m7G-related TME cell clusters.
CONCLUSIONS: Our study revealed tumor-associated characteristics and immune dysregulation in the NPC microenvironment under the regulation of m7G-related TME cells. These results demonstrated the underlying regulatory roles of m7G in NPC.

Background: As we delve into the intricate world of mitochondrial inner membrane proteins, particularly Optic Atrophy types 1 and 3 (OPA1/3), we uncover their pivotal role in maintaining mitochondrial dynamic equilibrium and fusion, crucial for cellular energy production and synthesis. Despite extensive scrutiny, the significance of OPA1/3 in breast cancer (BRCA) and its interplay with the immune microenvironment remain elusive. Materials and Methods: We meticulously sourced BRCA data from renowned repositories such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA), leveraging cutting-edge techniques including single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and pharmacogenomics. Through multifaceted data analysis, we endeavored to unravel the intricate role and potential value of OPA1/3 in BRCA tumorigenesis and progression. Results: Our investigation reveals a conspicuous upregulation of OPA1/3 expression in BRCA, correlating with dismal prognoses. Kaplan-Meier plot analysis underscores that heightened OPA1/3 levels are associated with poor survival rates. Both clinical specimens and biobank biopsies corroborate the elevated expression of OPA1/3 in breast cancer patients. Moreover, scRNA-seq unveils a strong correlation between OPA1/3 and macrophage infiltration in the BRCA immune milieu, alongside its association with the cellular communication network involving CXCL, TGFb, VEGF, and IL16. Conclusion: In light of these findings, OPA1/3 emerges as a promising contender for therapeutic targeting and as a potential diagnostic, prognostic, and survival biomarker in BRCA. The implications of our study underscore the pressing need to explore these novel biomarkers to enhance patient outcomes.

UNASSIGNED: Investigating the relationship between gut microbiota and Rheumatic Valve Disease (RVD) is crucial for understanding the disease\'s etiology and developing effective interventions. Our study adopts a novel approach to examine the potential causal connections between these factors.
UNASSIGNED: Utilizing a two-sample Mendelian Randomization (MR) framework, we incorporated a multi-variable MR (MVMR) strategy to assess the mediatory mechanisms involved. This approach involved analyzing data from the MiBioGen consortium for gut microbiota and the FinnGen for RVD, among other sources. Instrumental variables (IVs) were carefully selected based on rigorous MR principles, and statistical analysis was conducted using bidirectional two-sample MR, such as inverse variance-weighted (IVW), weighted median, MR-Egger regression and MR Steiger Test methods. The MR-PRESSO strategy was employed for outlier detection, and MVMR was used to untangle the complex relationships between multiple microbiota and RVD.
UNASSIGNED: Our analysis highlighted several gut microbiota classes and families with potential protective effects against RVD, including Lentisphaerae, Alphaproteobacteria, and Streptococcaceae. In contrast, certain genera, such as Eubacterium eligens and Odoribacter, were identified as potential risk factors. The MVMR analysis revealed significant mediation effects of various immune cell traits and biomarkers, such as CD4-CD8- T cells, CD3 on Terminally Differentiated CD8+ T cell and Pentraxin-related protein PTX, elucidating the complex pathways linking gut microbiota to RVD.
UNASSIGNED: This study underscores the intricate and potentially causal relationship between gut microbiota and RVD, mediated through a range of immune and hormonal factors. The use of MVMR in our methodological approach provides a more comprehensive understanding of these interactions, highlighting the gut microbiota\'s potential as therapeutic targets in RVD management. Our findings pave the way for further research to explore these complex relationships and develop targeted interventions for RVD.

OBJECTIVE: Previous studies have reported the potential impact of immune cells on kidney stone disease (KSD), but definitive causal relationships have yet to be established. The purpose of this paper is to elucidate the potential causal association between immune cells and KSD by Mendelian randomization (MR) analysis.
METHODS: In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between immune cell traits and kidney stone disease. We included a total of four immune traits (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)), which are publicly available data. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Cochran\'s Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results.
RESULTS: After FDR correction, the CD8 on HLA DR + CD8br (OR = 0.95, 95% CI = 0.93-0.98, p-value = 7.20 × 10- 4, q-value = 0.088) was determined to be distinctly associated with KSD, and we also found other 25 suggestive associations between immune cells and KSD, of which 13 associations were suggested as protective factors and 12 associations were suggested as risk factors. There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our Cochrane Q-test, MR Egger\'s intercept test, and MR-PRESSO, which were all > 0.05.
CONCLUSIONS: Our study has explored the potential causal connection between immune cells and KSD by Mendelian randomization analysis, thus providing some insights for future clinical studies.

UNASSIGNED: Although Hypertension (HTN) is considered to be a cardiovascular disease caused by multiple factors, the cause of it is still unknown. In this study, we aim to find out whether circulating immune cell characteristics have an impact on susceptibility to HTN.
UNASSIGNED: This study employed a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the causal association between immune cell characteristics and HTN. Utilizing publicly accessible genetic data, we examined the causal relationship between HTN and the susceptibility to 731 immune cell signatures. To ensure the reliability and validity of the findings, a comprehensive sensitivity analysis was conducted to assess heterogeneity, confirm the robustness of the results and evaluate the presence of horizontal pleiotropy.
UNASSIGNED: After FDR correction, immune phenotype had an effect on HTN. In our study, one immunophenotype was identified as being positively associated with HTN risk significance: HLA DR on CD33- HLA DR+. In addition, we examined 8 immune phenotype with no statistically significant effect of HTN, but it is worth mentioning that they had an unadjusted low P-value phenotype.
UNASSIGNED: Our MR study by genetic means demonstrated the close relationship between HTN and immune cells, thus providing guidance for future clinical prediction and subsequent treatment of HTN.

OBJECTIVE: Immune checkpoints have emerged as promising therapeutic targets for autoimmune diseases. However, the specific roles of immune checkpoints in the pathophysiology of ankylosing spondylitis (AS) remain unclear.
METHODS: Hip ligament samples were obtained from two patient groups: those with AS and femoral head deformity, and those with femoral head necrosis but without AS, undergoing hip arthroplasty. Label-Free Quantification (LFQ) Protein Park Analysis was used to identify the protein composition of the ligaments. Peripheral blood samples of 104 AS patients from public database were used to validate the expression of key proteins. KEGG, GO, and GSVA were employed to explore potential pathways regulated by immune checkpoints in AS progression. xCell was used to calculate cell infiltration levels, LASSO regression was applied to select key cells, and the correlation between immune checkpoints and immune cells was analyzed. Drug sensitivity analysis was conducted to identify potential therapeutic drugs targeting immune checkpoints in AS. The expression of key genes was validated through immunohistochemistry (IHC).
RESULTS: HLA-DMB and HLA-DPA1 were downregulated in the ligaments of AS and this has been validated through peripheral blood datasets and IHC. Significant differences in expression were observed in CD8 + Tcm, CD8 + T cells, CD8 + Tem, osteoblasts, Th1 cells, and CD8 + naive T cells in AS. The infiltration levels of CD8 + Tcm and CD8 + naive T cells were significantly positively correlated with the expression levels of HLA-DMB and HLA-DPA1. Immune cell selection using LASSO regression showed good predictive ability for AS, with AUC values of 0.98, 0.81, and 0.75 for the three prediction models, respectively. Furthermore, this study found that HLA-DMB and HLA-DPA1 are involved in Th17 cell differentiation, and both Th17 cell differentiation and the NF-kappa B signaling pathway are activated in the AS group. Drug sensitivity analysis showed that AS patients are more sensitive to drugs such as doramapimod and GSK269962A.
CONCLUSIONS: Immune checkpoints and immune cells could serve as avenues for exploring diagnostic and therapeutic strategies for AS.

UNASSIGNED: The role of different immune cells in autism spectrum disorders (ASD) is still controversial. The purpose of this study was to evaluate the causal effects of different immune cell phenotypes on ASD via Mendelian randomization (MR).
UNASSIGNED: Datasets of immune cell phenotypes were obtained from the European Bioinformatics Institute, and datasets of ASD were obtained from the IEU Open GWAS project. Single nucleotide polymorphisms were selected based on the assumptions of association, independence, and exclusivity. Inverse variance weighted was utilized as the main method for MR analysis. MR-Egger was employed to assess the horizontal pleiotropy of the results. Cochran\'s Q and leave-one-out method were used for heterogeneity analysis and sensitivity analysis of the results, respectively.
UNASSIGNED: MR analysis showed that TD CD8br AC [odds ratio (OR), 1.137; 95% confidence interval (CI), 1.031-1.254; p = 0.010], CD8br %leukocyte (OR, 1.142; 95% CI, 1.067-1.223; p < 0.001), CD8br and CD8dim %leukocyte (OR, 1.117; 95% CI, 1.032-1.210; p = 0.006), naive CD8br %T cell (OR, 1.052; 95% CI, 1.004-1.104; p = 0.035), CD28- CD8dim %T cell (OR, 1.097; 95% CI, 1.038-1.158; p < 0.001), CD127- CD8br AC (OR, 1.086; 95% CI, 1.006-1.171; p = 0.034), CD45 on CD8br (OR, 1.059; 95% CI, 1.021-1.099; p = 0.002), CD3 on HLA DR+ CD8br (OR, 1.098; 95% CI, 1.041-1.158; p < 0.001), CD4 on activated Treg (OR, 1.048; 95% CI, 1.001-1.096; p = 0.046), CD3 on CD39+ resting Treg (OR, 1.070; 95% CI, 1.012-1.131; p = 0.018), IgD+ CD38- %lymphocyte (OR, 1.103; 95% CI, 1.023-1.190; p = 0.011), CD62L- plasmacytoid DC %DC (OR, 1.046; 95% CI, 1.001-1.093; p = 0.046), and FSC-A on plasmacytoid DC (OR, 1.075; 95% CI, 1.003-1.153; p = 0.042) were associated with increased genetic susceptibility to ASD. MR-Egger displayed no horizontal pleiotropy (p ≥ 0.05). Cochran\'s Q revealed no heterogeneity of results (p ≥ 0.05). Sensitivity analysis indicated that the results were robust.
UNASSIGNED: This MR analysis revealed 13 immune cell phenotypes associated with increased genetic susceptibility to ASD and emphasized the importance of CD8 T cells and Tregs, which provides new directions for the pathogenesis and drug research of ASD.