CCR5+ CD8 T-cell levels and monocyte activation precede the onset of acute coronary syndrome in HIV-infected patients on antiretroviral therapy

SummaryAcute coronary syndrome (ACS) is nowadays one of the leading causes of morbid-mortality in HIV-infected population, but innate and adaptive immune mechanisms preceding this event are unknown. In this work we comprehensively and longitudinally observed, by multi-parametric flow cytometry and following a case-control design, increased CCR5+CD8+ T-cells levels and monocytes expressing activation and adhesion markers in HIV-infected patients who are going to suffer ACS. In addition, we found direct associations between activated CD8+ T-cells and myeloid cells that were only statistically significant in the group of patients with ACS and in the follow up time point just before the ACS. Our data highlight the important role of CCR5 in the onset of ACS and suggest this receptor as a marker of cardiovascular risk and potential therapeutic target to prevent the development of such non-AIDS-related event in HIV-infected patients.Note: This work was presented at the CROI 2016 conference (Boston, USA in February 2016).

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Abstract 4008: PSGL-1-Expressing CD4 T Cells are Enriched in Culprit Coronary Artery Lesion of Acute Coronary Syndrome

Circulation ◽

10.1161/circ.118.suppl_18.s_817-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Keiko Gomita ◽

Kayoko Sato ◽

Kazutaka Kitamura ◽

Nobuhisa Hagiwara

Keyword(s):

T Cells ◽

Acute Coronary Syndrome ◽

Coronary Artery ◽

Adhesion Molecules ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Coronary Artery Lesion ◽

Plaque Instability ◽

Coronary Syndrome

Background: Recently, several evidences on the crucial role of adhesion molecules in the development of atherosclerosis and plaque instability have been reported. While expression of VCAM-1, ICAM-1 and L-selectin has been consistently observed in atherosclerotic plaques it is still uncertain how adhesion molecules on T cells contribute to the incidence of acute coronary syndrome (ACS). In this study, we examined whether adhesion molecules on T cells in ACS have a significant role in the plaque stability and prone to cause ACS. Methods and Results: Fresh CD4 T cells were isolated from the peripheral blood of 76 ACS patients (AMI=35, UAP=41) and 74 age-matched controls (NC). CD69, an activation marker of T cells, was strongly expressed on CD4 T cells from ACS than from NC by FACS (P<0.0001). CD4 T cells from ACS highly expressed p-selectin glycoprotein ligand-1 (PSGL-1) and integrin β (CD18), but not L-selectin by FACS (P < 0.03, P < 0.01, n.s., respectively). Soluble PSGL-1 (sPSGL-1) levels in plasma were lower in ACS patients than in NC (P=0.0001), which correlated negatively with the PSGL-1 expression on CD4 T cells (R=0.405, P<0.02). We further investigated the thrombus-aspirating device samples (n=14) and fresh CD4 T cells derived from both the coronary artery and peripheral blood from the each same patient with ACS. CD4 T cells from the coronary artery strongly expressed PSGL-1 (P<0.002), but not integrin β (CD18) and L-selectin by FACS. Finally, PSGL-1 was expressed on T cells, but not on CD68 positive macrophage, MPO positive neutrophil, or CD41 positive platelets in the thrombus-aspirating device samples. Conclusions: From these results, we demonstrated that PSGL-1-expressing CD4 T cells are enriched in the culprit coronary artery lesion of ACS, contributing to the acceleration of plaque instability and occurrence of ACS.

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Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22158011 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8011

Author(s):

Hyo-Jung Cho ◽

Jae-Youn Cheong

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Inflammation ◽

Cd8 T Cells ◽

Immune Cells ◽

Adaptive Immune ◽

B Virus

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.

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IFN Regulatory Factor-1 Modulates the Function of Dendritic Cells in Patients with Acute Coronary Syndrome

Cellular Physiology and Biochemistry ◽

10.1159/000430123 ◽

2015 ◽

Vol 36 (2) ◽

pp. 599-610 ◽

Cited By ~ 4

Author(s):

Min Guo ◽

Rui Yan ◽

Caixia Wang ◽

Hongtao Shi ◽

Meng Sun ◽

...

Keyword(s):

T Cells ◽

Acute Coronary Syndrome ◽

Dendritic Cells ◽

Mapk Pathway ◽

Human Monocyte ◽

Regulatory Factor ◽

Coronary Syndrome ◽

Artery Disease ◽

And Function

Background: Atherosclerosis is widely recognized as a complex inflammatory disease involving pathogenic immune response of T cells and antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages. Accumulating evidence has revealed that mature DCs play critical roles in the differentiation of effector T cells into CD4+ T cells, which effectively participate in the onset of acute coronary syndrome (ACS). IFN regulatory factor (IRF)-1 has been shown to be involved in various immune processes. The role of IRF-1 in DCs in the pathogenesis of ACS has not been investigated. Methods and Results: We examined the relative mRNA and protein expression of IRF-1 in human monocyte-derived DCs in patients with coronary artery disease (CAD). The overexpression or silencing of IRF-1 expression in DCs in patients with ACS was performed to explore the possible role of IRF-1 in the maturation and function of DCs involved in ACS. The results showed that the relative expression of IRF-1 in DCs is obviously increased in patients with ACS. The overexpression or silencing of IRF-1 expression could effectively promote or attenuate the maturation and function of DCs. In addition, we revealed that the MAPK pathway (phosphorylation of JNK, p38 and ERK1/2) might be downstream of IRF-1 signalling pathway in activation of circulating DCs in ACS patients. Conclusion: The present data demonstrate that IRF-1 could effectively promote the immune maturation and function of DCs in ACS patients.

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ABCA1, TCF7, NFATC1, PRKCZ and PDGFA DNA methylation as potential epigenetic-sensitive targets in acute coronary syndrome via network analysis

European Heart Journal ◽

10.1093/eurheartj/ehab724.1367 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

T Infante ◽

M Franzese ◽

A Ruocco ◽

C Schiano ◽

O Affinito ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Acute Coronary Syndrome ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Molecular Data ◽

Aberrant Methylation ◽

National Budget ◽

Coronary Syndrome ◽

Differentially Methylated Genes

Abstract Background Acute coronary syndrome (ACS) is the most severe clinical manifestation of coronary heart disease and the leading cause of death worldwide. Purpose To perform an epigenome-wide analysis in circulating CD4+ and CD8+ T cells of ACS patients and healthy subjects (HS) enrolled in the DIANA clinical trial (NCT04371809) in order to identify differentially methylated genes (DMGs). Methods Genomic DNA was extracted from CD4+ and CD8+ T cells of all subjects and sequenced by the reduced representation bisulfite sequencing (RRBS) platform. Functional pathway analysis was performed and significant DMGs were selected for gene expression validation by qRT-PCR in ACS patients and HS. GeneMANIA was used to built a prediction gene network. Correlation analyses between molecular data and clinical variables were performed. Results In CD4+ T cells we identified 61 differentially methylated regions (DMRs) associated to 57 annotated genes of which 53% (n=32) were hyper- and 47% (n=29) were hypo-methylated in ACS patients vs HS. In CD8+ T cells we identified 613 DMRs associated to 569 annotated genes of which 28% (n=173) were hyper- and 72% (n=440) were hypo-methylated between two groups. In both cell type of ACS patients, 175 DMRs were associated to 157 annotated genes of which 41% (n=72) were hyper- and 59% (n=103) were hypo-methylated. From functional analysis, we selected the top 5 DMGs in the prevalent pathways with the highest differential of methylation values. Specifically, we considered 6 hub genes: NFATC1, TCF7, PDGFA, PRKCB, PRKCZ and ABCA1 and determined their respective expression levels by q-RT-PCR. We found a significant up-regulation of the selected genes in ACS patients vs HS (P<0.001 for all comparisons). Correlation analysis showed both common and cell specific correlation patterns. In CD4+ T cells, PDGFA promoter methylation was negatively correlated with CK-MB concentrations (r=−0.79, P=0.018). ABCA1, TCF7, PDGFA and PRKCZ gene expression was positively associated to CK-MB concentrations (r=0.75, P=0.03; r=0.760, P=0.029; r=0.72, P=0.044; r=0.74, P=0.035, respectively). Conlusions This study is the first single-base resolution map of DNA methylome by RRBS in CD4+ and CD8+ T cells, providing specific methylation signatures that could help to clarify the role of aberrant methylation in ACS pathogenesis, and provide the basis for the search of novel epigenetic-sensitive biomarkers in the prevention and early diagnosis of this pathology. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health;Italian Ministry of Research and University

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Role of unusual CD4+ CD28− T cells in acute coronary syndrome

Molecular Biology Reports ◽

10.1007/s11033-011-1103-9 ◽

2011 ◽

Vol 39 (3) ◽

pp. 3337-3342 ◽

Cited By ~ 6

Author(s):

Wenjie Sun ◽

Lihui Zheng ◽

Lijuan Huang

Keyword(s):

T Cells ◽

Acute Coronary Syndrome ◽

Coronary Syndrome

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The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

Frontiers in Immunology ◽

10.3389/fimmu.2020.575577 ◽

2020 ◽

Vol 11 ◽

Author(s):

Fernando Chernomordik ◽

Bojan Cercek ◽

Wai Man Lio ◽

Peter M. Mihailovic ◽

Juliana Yano ◽

...

Keyword(s):

T Cells ◽

Acute Coronary Syndrome ◽

Antimicrobial Peptide ◽

Coronary Syndrome

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Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study

European Heart Journal ◽

10.1093/eurheartj/ehaa703 ◽

2020 ◽

Vol 41 (37) ◽

pp. 3549-3560 ◽

Cited By ~ 2

Author(s):

David M Leistner ◽

Nicolle Kränkel ◽

Denitsa Meteva ◽

Youssef S Abdelwahed ◽

Claudio Seppelt ◽

...

Keyword(s):

T Cells ◽

Acute Coronary Syndrome ◽

T Cell ◽

T Lymphocytes ◽

Cd8 T Cells ◽

Coronary Plaque ◽

Effector Molecules ◽

Coronary Syndrome ◽

Fibrous Cap ◽

Cd8 T Lymphocytes

Abstract Aims Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping. Methods and results The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS. Conclusions The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC. Trial registration The study was registered at clinicalTrials.gov (NCT03129503).

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CXCR4 in melanoma: A prognostic biomarker and a target of therapy

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.8051 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 8051-8051

Author(s):

S. Scala ◽

M. Napolitano ◽

F. Fulciniti ◽

P. Giuliano ◽

F. Mauro ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Cd8 T Cells ◽

Chemokine Receptors ◽

Primary Melanoma ◽

Melanoma Cells ◽

Peripheral Blood Lymphocytes ◽

Level Of Invasion

8051 Background: The chemokine receptor CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma. In melanoma metastases CXCR4 is also expressed and functional suggesting that CXCR4 has a role in the melanoma biology. Differential chemokine receptors expression by activated tumor specific CD8+ T cells can be associated with divergent clinical outcomes. Expression of CXCR3 by CD8+ T cells was reported to be associated with survival in melanoma patients with stage III disease. To further characterize the role of CXCR4 in the melanoma metastatization we analyzed Fine Needle Ago Biopsy (FNAB) from disease involved lymph nodes. Moreover, we are currently evaluating CD8+ subpopulation for the expression of CXCR4 during the follow up Methods: FNAB of suspicious disease involved lymphnodes. was performed and the cell suspension was analyzed by flow cytometry and .immunocytochemistry. Peripheral blood lymphocytes (PBL) was analyzed by flow cytometry Results: FNAB were performed on 25. suspicious lymphnodes. Out of 25 FNAB 19 were positive per melanoma cells (HMB45 positive). Concomitant expression of HMB45 and CXCR4 was detected in 15 out of 19 samples.with the percentage of cells CXCR4 positive being the large majority ( 40–100%) of the detected melanoma cells. Ongoing studies are further characterizing the biology of the CXCR4/HMB45 cells. The inhibition of this cells migrating through the lymphnode may interfere with the metastatization. In relation to the CD8+ subpopulation for the expression of CXCR4 during the follow up preliminary data at the time of diagnosis showed a correlation between the activated CD8 + lymphocytes (HLA-DR+) /CXCR4 + and the level of invasion of the lesion. Conclusion: Altoghether these evidences confirm a role of CXCR4 in melanoma biology and as therapeuthic target . No significant financial relationships to disclose.

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