Cytotoxic CD8+ T Cells Are Involved in the Thrombo-Inflammatory Response during First-Diagnosed Atrial Fibrillation

Friebel, Julian; Witkowski, Marco; Wegner, Max; Blöbaum, Leon; Lammel, Stella; Schencke, Philipp-Alexander; Reißner, Daniela; Steffens, Daniel; Moos, Verena; Schutheiss, Heinz-Peter; Landmesser, Ulf; Puccini, Marianna

doi:10.3390/cells12010141

Cited by 6 publications

(16 citation statements)

References 79 publications

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“…In an observational study of 100 consecutive patients, including 80 patients with a first diagnosis of AF and 20 control patients, it was found that pro-inflammatory and cytotoxic T-lymphocyte subpopulations (CD8+) circulate more frequently during early AF compared with patients without AF and are accompanied by increased levels of plasma CD8 + effector molecules. [18] Activated CD8 + T cells perform by releasing cytotoxins (perforin, granzyme and granulysin) or by releasing the secretion of pro-inflammatory cytokines, such as TNF-α and IFN-γ to induce apoptosis in target cells. [39,40] Peripheral monocytes trigger an inflammatory cascade that releases TGF-β, ROS, complement proteins, and chemokines, ultimately contributing to cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…[9,[11][12][13][14][15] Previous clinical studies have established a correlation between immunity and AF. [16][17][18] However, the capacity of observational studies to address potential confounding factors and mitigate reverse causality is limited. Mendelian randomization (MR) can be considered as an alternative to randomized controlled trials that use genetic variants to show causality between exposure and outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Causal relationship between immune cells and atrial fibrillation: A Mendelian randomization study

Chu,

Guo,

et al. 2024

Medicine

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Atrial fibrillation (AF) is a prevalent cardiac arrhythmia, with recent research indicating a correlation between immune system characteristics and the development of AF. However, it remains uncertain whether the immunological response is the primary underlying component or a secondary consequence of AF. Initially, we investigated the effect of immune cells on AF by performing forward Mendelian randomization (MR) analyses with immune cells as the exposure variable and their associated genetic variants as instrumental variables. Subsequently, we performed reverse MR analyses with AF as the exposure variable and immune cells as the outcome variable to exclude the interference of reverse causality, to distinguish between primary and secondary effects, and to further elucidate the causal relationship between the immune system and AF. We discovered that membrane proteins on specific immune cells, such as CD25 on memory B cells—which functions as a part of the interleukin-2 receptor—may be risk factors for AF development, with odds ratios of 1.0233 (95% confidence interval: 1.0012–1.0458, P = .0383). In addition, certain immune cell counts, such as the CD4 regulatory T cell Absolute Count, play a protective factor in the development of AF (odds ratio: 0.9513, 95% confidence interval: 0.9165–0.9874; P = .0086). More detailed results are elaborated in the main text. Our MR study has yielded evidence that substantiates a genetically inferred causal association between the immune system and AF. Identifying the risk factors associated with AF is vital to facilitate the development of innovative pharmaceutical treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Causal relationship between immune cells and atrial fibrillation: A Mendelian randomization study

Chu,

Guo,

et al. 2024

Medicine

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“…The activation and infiltration of CD8 T cells into the atrial tissue can lead to the release of pro-inflammatory cytokines and chemokines, promoting atrial remodeling and electrical disturbances. This immune response mediated by CD8 T cells may contribute to the perpetuation of AF and its progression to a more chronic and persistent state ( 45 , 46 ). Macrophages contribute to the pathogenesis of AF by releasing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as phagocytosing apoptotic cardiomyocytes, which can lead to fibrosis ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis reveals the potential crosstalk genes and immune relationship between Crohn’s disease and atrial fibrillation

Qiu,

Teng,

Wang

et al. 2024

J Thorac Dis

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Background At present, there is a paucity of research on the link between Crohn’s disease (CD) and atrial fibrillation (AF). Nevertheless, both ailments are thought to entail inflammatory and autoimmune processes, and emerging evidence indicates that individuals with CD may face an elevated risk of AF. To shed light on this issue, our study seeks to explore the possibility of shared genes, pathways, and immune cells between these two conditions. Methods We retrieved the gene expression profiles of both CD and AF from the Gene Expression Omnibus (GEO) database and subjected them to analysis. Afterward, we utilized the weighted gene co-expression network analysis (WGCNA) to identify shared genes, which were then subjected to further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Furthermore, we employed a rigorous analytical approach by screening hub genes through both least absolute shrinkage and selection operator (LASSO) regression and support vector machine (SVM), and subsequently constructing a receiver operating characteristic (ROC) curve based on the screening outcomes. Finally, we utilized single-sample gene set enrichment analysis (ssGSEA) to comprehensively evaluate the levels of infiltration of 28 immune cells within the expression profile and their potential association with the shared hub genes. Results Using the WGCNA method, we identified 30 genes that appear to be involved in the pathological progression of both AF and CD. Through GO enrichment analysis on the key gene modules derived from WGCNA, we observed a significant enrichment of pathways related to major histocompatibility complex (MHC) and antigen processing. By leveraging the intersection of LASSO and SVM algorithms, we were able to pinpoint two overlapping genes, namely CXCL16 and HLA-DPB1 . Additionally, we evaluated the infiltration of immune cells and observed the upregulation of CD4 + and CD8 + T cells, as well as dendritic cells in patients with AF and CD. Conclusions By employing bioinformatics tools, we conducted an investigation with the objective of elucidating the genetic foundations that connect AF and CD. This study culminated in the identification of CXCL16 and HLA-DPB1 as the most substantial genes implicated in the development of both disorders. Our findings suggest that the immune responses mediated by CD4 + and CD8 + T cells, along with dendritic cells, may hold a crucial role in the intricate interplay between AF and CD.

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“… 5 One study suggests that CD8T cells control monogenesis and macrophage accumulation in early atherosclerosis and play a cytotoxic role therein, and contribute to macrophage death and formation of the necrotic core of the plaque. 6 Another study verified that peroxisome proliferator-activated receptor γ (PPAR γ) can reduce inflammation by activating the recruitment of regulatory T cells. Thus, immune cell infiltration is involved in the occurrence and development of CAD.…”

Section: Introductionmentioning

confidence: 99%

Immune Cell Infiltration Analysis Based on Bioinformatics Reveals Novel Biomarkers of Coronary Artery Disease

He,

Muhetaer,

et al. 2023

JIR

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Background: Coronary artery disease (CAD) is a multifactorial immune disease, but research into the specific immune mechanism is still needed. The present study aimed to identify novel immune-related markers of CAD. Methods: Three CAD-related datasets (GSE12288, GSE98583, GSE113079) were downloaded from the Gene Expression Integrated Database. Gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and weighted gene coexpression network analysis were performed on the common significantly differentially expressed genes (DEGs) of these three data sets, and the most relevant module genes for CAD obtained. The immune cell infiltration of module genes was evaluated with the CIBERSORT algorithm, and characteristic genes accompanied by their diagnostic effectiveness were screened by the machine-learning algorithm least absolute shrinkage and selection operator (LASSO) regression analysis. The expression levels of characteristic genes were evaluated in the peripheral blood mononuclear cells of CAD patients and healthy controls for verification. Results: A total of 204 upregulated and 339 downregulated DEGs were identified, which were mainly enriched in the following pathways: "Apoptosis", "Th17 cell differentiation", "Th1 and Th2 cell differentiation", "Glycerolipid metabolism", and "Fat digestion and absorption". Five characteristic genes, LMAN1L, DOK4, CHFR, CEL and CCDC28A, were identified by LASSO analysis, and the results of the immune cell infiltration analysis indicated that the proportion of immune infiltrating cells (activated CD8 T cells and CD56 DIM natural killer cells) in the CAD group was lower than that in the control group. The expressions of CHFR, CEL and CCDC28A in the peripheral blood of the healthy controls and CAD patients were significantly different. Conclusion:We identified CHFR, CEL and CCDC28A as potential biomarkers related to immune infiltration in CAD based on public data sets and clinical samples. This finding will contribute to providing a potential target for early noninvasive diagnosis and immunotherapy of CAD.

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Cytotoxic CD8+ T Cells Are Involved in the Thrombo-Inflammatory Response during First-Diagnosed Atrial Fibrillation

Cited by 6 publications

References 79 publications

Causal relationship between immune cells and atrial fibrillation: A Mendelian randomization study

Causal relationship between immune cells and atrial fibrillation: A Mendelian randomization study

Transcriptomic analysis reveals the potential crosstalk genes and immune relationship between Crohn’s disease and atrial fibrillation

Immune Cell Infiltration Analysis Based on Bioinformatics Reveals Novel Biomarkers of Coronary Artery Disease

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