scholarly journals Defining the relationship between lipids and immune traits in TwinsUK

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
P Christofidou ◽  
T Liechti ◽  
M Roederer ◽  
M Beddall ◽  
C Menni ◽  
...  
Keyword(s):  
Immune Responses ◽  
Total Cholesterol ◽  
Linear Mixed Model ◽  
Immune Cell ◽  
Cell Subset ◽  
P Value ◽  
Resonance Spectroscopy ◽  
Immune Traits ◽  
Lipid Metabolites ◽  
Classical Monocytes

Abstract Introduction Lipid metabolism plays a crucial role in both innate and adaptive immune responses. Blood lipids are well known biomarkers of heart disease and atherosclerosis. Given that immune responses are involved in atherosclerosis development and progression, it is of utmost importance to explore the mutual relationship between circulating lipid measures and immunology markers, to better manage cardiovascular disease (CVD). Purpose The aim of this work was to evaluate relationships of distinct immune cell subtypes and circulating lipids in a general population setting. Methods We investigated the associations between 3,734 immune traits and circulating lipids [LDL-C, HDL-C, total cholesterol (TC), triglycerides (TG), non-HDL-C) in 2,056 individuals from the TwinsUK cohort. Immune traits were defined by high-dimensional flow-cytometry which enabled in-depth assessment of all major lymphocyte and myeloid subsets in peripheral blood. Information on immune cell subset frequency (FREQ) and mean fluorescence intensity (MFI) was available. A linear mixed model regression analysis adjusted for family structure, gender, age and BMI was used to examine the associations between immune traits and lipids. We then undertook a sub-analysis in 608 individuals and 131 lipid metabolites quantified using nuclear magnetic resonance spectroscopy to investigate the associations of specific immune traits and lipoprotein particles. Results We observed 18 significant associations (Bonferroni P-value <7.3x10–6) between 9 MFI immune traits and lipids. These involved associations between circulating lipids and 7 different myeloid or lymphoid subsets of immune cells including monocytes and natural killer cells. The top associations were found between CD14+ classical monocytes and non-HDL-C, LDL-C, HDL-C and TG. Increased levels of non-HDL-C (P=4.7x10–14), HDL-C (P=1.9x10–13) and TG (P=8.5x10–10) were associated with lower expression of CD14+ monocytes whereas increased LDL-C was associated with elevated expression of both CD14+ monocytes (P=1.0x10–13) and CD16+CD14+ monocytes (P=2.7x10–8). No significant association was detected between FREQ traits and lipids. We also observed 39 associations (Bonferroni P-value <3.1x10–4) between 19 lipid metabolites and CD14+ classical monocytes. The top associations were linked to different HDL particles (Free cholesterol in L-HDL: P=3.5x10–6; Total cholesterol in L-HDL: P=3.5x10–6; Cholesterol esters in L-HDL: P=4.1x10–6). Different subclasses of VLDL particles were also associated with CD14+ monocytes. Conclusion The present study provides the first comprehensive picture of lipid-immune cell associations in the circulatory system. We observed a link between expression levels of CD14+ classical monocytes and circulating lipid metabolites. The same lipid metabolites were previously associated with risk of developing myocardial infarction and stroke speculating a link between CD14+ classical monocytes and CVD risk. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): SYSCID - A Systems medicine approach to chronic inflammatory diseases

scholarly journals Immune Trait Shifts in Association With Tobacco Smoking: A Study in Healthy Women

2021 ◽  
Vol 12 ◽  
Author(s):  
Giulia Piaggeschi ◽  
Simona Rolla ◽  
Niccolò Rossi ◽  
Davide Brusa ◽  
Alessio Naccarati ◽  
...  
Keyword(s):  
T Cells ◽  
Tobacco Smoking ◽  
Immune Cell ◽  
Memory T Cells ◽  
Smoking Status ◽  
Cell Subset ◽  
Activation Marker ◽  
Healthy Women ◽  
Immune Traits ◽  
Cd8 Memory T Cells

Tobacco smoking is known to impact circulating levels of major immune cells populations, but its effect on specific immune cell subsets remains poorly understood. Here, using high-resolution data from 223 healthy women (25 current and 198 never smokers), we investigated the association between smoking status and 35,651 immune traits capturing immune cell subset frequencies. Our results confirmed that active tobacco smoking is associated with increased frequencies of circulating CD8+ T cells expressing the CD25 activation marker. Moreover, we identified novel associations between smoking status and relative abundances of CD8+ CD25+ memory T cells, CD8+ memory T cells expressing the CCR4 chemokine receptor, and CD4+CD8+ (double-positive) CD25+ T cells. We also observed, in current smokers, a decrease in the relative frequencies of CD4+ T cells expressing the CD38 activation marker and an increase in class-switched memory B cell isotypes IgA, IgG, and IgE. Finally, using data from 135 former female smokers, we showed that the relative frequencies of immune traits associated with active smoking are usually completely restored after smoking cessation, with the exception of subsets of CD8+ and CD8+ memory T cells, which persist partially altered. Our results are consistent with previous findings and provide further evidence on how tobacco smoking shapes leukocyte cell subsets proportion toward chronic inflammation.

scholarly journals 91 Impact of ultra-fast ‘FLASH’ radiotherapy on single cell immunogenomics in diffuse intrinsic pontine glioma (DIPG)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A100-A100
Author(s):  
Oscar Padilla ◽  
Hanna Minns ◽  
Hong-Jian Wei ◽  
Andrea Webster-Carrion ◽  
Masih Tazhibi ◽  
...  
Keyword(s):  
Immune Responses ◽  
Single Cell ◽  
Dose Rate ◽  
Preliminary Analysis ◽  
Immune Cell ◽  
Cell Subset ◽  
High Dose ◽  
Antibody Treatment ◽  
Immune Phenotypes ◽  
Key Genes

BackgroundDiffuse intrinsic pontine gliomas (DIPG’s) are immunologically inert tumors with a median survival of 9–15 months. Radiation therapy (RT) is the mainstay treatment for DIPG but is associated with immunodepletion of the tumor microenvironment (TME) at high dose ranges. FLASH, or ultra-fast dose rate RT, represents a novel ablative technique that may spare TME immune responses while decreasing tumor burden. Here, we present single-cell immune profiling of DIPG tumors treated with FLASH, conventional dose rate RT (CONV) or no RT (SHAM).MethodsMurine H3.3K27M mutant DIPG cells were stereotactically injected and tumor induction confirmed by magnetic resonance imaging (MRI) 15 days later. DIPG-bearing mice were randomly assigned to one of three treatment groups (n=4/group), FLASH, CONV or SHAM. A fourth group with no tumor (NML) was included as a negative biological control. A modified linear accelerator was used to deliver 15 Gy of electron RT to the brainstem at dose rates of 90 Gy/second and 2 Gy/minute, for the FLASH and CONV groups, respectively. Four days post-RT, mice brainstems were harvested, homogenized, stained for CD45 and tagged with a hashtag antibody specific to each group. CD45+ immune cells were isolated and sequenced using the 10X Genomics chromium single-cell 3’ platform. After processing and alignment of the reads using CellRanger with default parameters, the data was quality checked and filtered before hashtag demultiplexing, unsupervised clustering and downstream analysis was implemented following the Seurat R package. Differential expression evaluated based on the non-parametric Wilcoxon rank sum test. Key genes determine by an adjusted p value of < 0.05 based on bonferroni correction and |avg log2FC| > 0.8.ResultsPreliminary analysis identifies 15 clusters with distinct CD45 immune phenotypes (figure 1). Differential gene expression analysis by hashtag antibody (treatment group) reveals 14 clusters differentially expressing key genes, including 3 clusters upregulated in DIPG compared to NML, and 2 clusters upregulated in irradiated tumors compared to SHAM and NML (figure 2). Notably, analysis demonstrates an individual cluster upregulated in FLASH versus all other groups (p = 3.07E-171). Further deconvolution of specific immune phenotypes represented by each cluster is ongoing.Abstract 91 Figure 1tSNE plot based on clustering of RNA signatures, grouped by RNAAbstract 91 Figure 2tSNE plot based on clustering of RNA signatures, grouped by hashtag antibodyConclusionsOur preliminary analysis shows differential immune responses among DIPG tumors compared to NML. We also find several immune cell subsets that are unique to DIPG treated with CONV or FLASH compared to unirradiated samples. Most notably, we identify a single immune cell subset that is exclusive to FLASH alone, indicating that FLASH elicits a unique immune response in murine DIPG.

scholarly journals Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

2020 ◽  
Author(s):  
Suhas Sureshchandra ◽  
Nicole E. Marshall ◽  
Norma Mendoza ◽  
Allen Jankeel ◽  
Michael Z. Zulu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Immune Cell ◽  
Cell Subset ◽  
Myeloid Cell ◽  
Chromatin Accessibility ◽  
Blood Monocytes ◽  
Increased Risk ◽  
Th1 And Th2 Cytokines ◽  
The Impact

ABSTRACTPre-pregnancy obesity is associated with several adverse maternal health outcomes, notably increased risk of infection as well as the incidence of gestational diabetes, preeclampsia, and preterm birth. However, the mechanisms by which pregravid obesity disrupts the pregnancy associated “immune clock” are still unknown. To address this question, we collected blood samples from women during the first and third trimesters and determined the impact of both pregnancy and pregravid obesity on circulating immune mediators, immune cell subset frequencies, and peripheral immune responses. While regardless of BMI, pregnancy was associated with an elevation in both Th1 and Th2 cytokines, pregravid obesity was associated with a dysregulation in circulating myeloid factors at term. Moreover, pregnancy in lean subjects was associated with enhanced monocyte activation, augmented chromatin accessibility at inflammatory loci, and heightened responses to LPS. Pregravid obesity disrupted this trajectory and was accompanied by a lack of transcriptional and epigenetic changes and alterations in metabolic status strongly suggesting a skewing towards immunotolerance. These findings provide novel insight into the increased susceptibility to infections observed with obesity during pregnancy.SUMMARYA healthy pregnancy is associated with progressive innate immune activation. Maternal factors such as obesity compromise this myeloid cell activation trajectory at genomic, epigenomic, functional, and metabolic levels, resulting in stagnant immune responses, suggestive of a state of tolerance.

scholarly journals Effects of Age and Social Adversity on Immune Cell Populations in a Non-Human Primate Model of Human Aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 532-533
Author(s):  
Mitchell Sanchez-Rosado ◽  
Noah Snyder-Mackler ◽  
James Higham ◽  
Lauren Brent ◽  
Nicole Marzan-Rivera ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Function ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Older Individuals ◽  
Primate Model ◽  
Hla Dr ◽  
Social Adversity ◽  
Classical Monocytes

Abstract Significant hallmarks of aging are immune function decline and rising cumulative inflammation. These immunosenescent signatures are also found in individuals who experience chronic social adversity, independently of age. However, no studies to date have examined how social adversity alters immune function across the lifespan –data that are essential to identify the molecular routes through which social adversity might lead to increased aging-related disease. Over a two-year period, we investigated how age and social adversity (quantified by low social status) affected immunity. We measured immune cell proportions at baseline and their gene regulation after in vitro stimulation with pathogen molecules that stimulated both Th1 and Th2 immune responses in a population of free-ranging rhesus macaques. We first performed flow cytometry on peripheral whole blood to quantify changes on immune cell proportions across the lifespan (n=235) and in animals of different social statuses (n=141). We found significant decreases in CD20+ B cells and CD3+/CD4+ T cell proportions with age, suggesting diminished antibody production and adaptive immune responses in older individuals. Age-associated increases in CD3+/CD8+, CD3+/CD4+/CD25+ T regulatory cells and CD14-/CD16+/HLA-DR+ non-classical monocytes indicated heightened baseline inflammation in older animals. Social adversity recapitulated the effects of aging in CD14+/CD16-/HLA-DR+ classical monocytes, indicating immune deficits in phagocytosis and pathogen clearance in older and lower status individuals. Using RNA-seq, our stimulations (n=1,320) will allow us to identify molecular immune pathways that are disrupted by age and social adversity, similarities in response between age and adversity, and how the effect of adversity varies across the lifespan.

Hubungan Kadar Kolesterol Total Dan Hipertensi Dengan Kejadian Penyakit Jantung Koroner DI RSUD dr. Soedarso Pontianak

2018 ◽  
Vol 1 (2) ◽  
pp. 99
Author(s):  
Laila Kamila ◽  
Maulidiyah Salim
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Total Cholesterol ◽  
Blood Vessels ◽  
Public Hospital ◽  
Sampling Technique ◽  
P Value ◽  
Chi Square ◽  
Cross Sectional ◽  
Purposive Sampling

Abstract: Coronary heart is a disease that offense to blood vessels and heart attack due to constriction of blood vessels. A high level of cholesterol in blood or exceeds the normal limit can form sediment in wall of blodd vessels which cause blood vessels constriction or blockage. This research object to determine whether there is a correlation between cholesterol level total and hypertension with coronary heart disease in patients who hospitalized in Regional Public Hospital of dr. Soedarso Pontianak. This study was used cross sectional design, purposive sampling technique, it gained 50 people as samples. The measurement of blood pressure was done in heart poly and cholesterol total level in clinic laboratory of Regional Public Hospital of dr. Soedarso by using enzymatic CHOD-PAP method. It can be obtained that 10 people had hypertension and 40 people did not.the average of total cholesterol was 224 mg/dl. Maximum value of total cholesterol was 224 mg/dl and 152 mg/dl as minimum value. Data has been analyzed by using statistical test, Chi-Square, to determine the correlation of total cholesterol wit coronary heart disease, obtained p value=0,024 (less than α=0,05). Correlation of hypertension and coronary heart disease gained p value=0,923 (more than α=0,05), it can be concluded that total cholesterol correlated with coronary heart disease, and there was not a correlation between hypertension and coronary heart disease.Abstrak: Jantung koroner adalah penyakit yang  menyerang pembuluh darah dan serangan jantung, karena penyempitan pada pembuluh darah. Kadar kolesterol yang tinggi dalam darah melebihi normal dapat membentuk endapan pada dinding pembuluh darah sehingga menyebabkan penyempitan dan tersumbatnya pembuluh darah. Penelitian ini bertujuan untuk mengetahui hubungan kadar kolesterol total dan hipertensi dengan penyakit jantung koroner pada pasien di RSUD dr. Soedarso Pontianak. Disain penelitian  ini menggunakan cross sectional, teknik pengambilan sampel yaitu purposive sampling, didapat jumlah sampel 50 orang. Pengukuran Tensi Darah dilakukan di poli Jantung dan pemeriksaan kadar kolesterol total di laboratorium klinik RSUD dr. Soedarso Pontianak dengan metode enzimatik CHOD-PAP. Hasil penelitian didapatkan 10 orang mengalami hipertensi dan 40 orang non hipertensi. Rata-rata kadar kolesterol total 224 mg/ dl. Nilai maksimum kadar kolesterol total yaitu 224 mg/dl dan nilai minimum yaitu 152 mg/dl. Analisa data dengan uji statistik Chi-square untuk mengetahui hubungan kolesterol total dengan penyakit jantung koroner didapatkan nilai p = 0,024 (lebih kecil dari  α 0,05). Uji hubungan hipertensi dengan penyakit jantung koroner didapat nilai p = 0,923 (lebih besar dari α 0,05), dapat disimpulkan terdapat hubungan kadar kolesterol total dengan penyakit jantung koroner dan tidak ada hubungan hipertensi dengan penyakit jantung koroner.

scholarly journals Interleukin-17A Triggers the Release of Platelet-Derived Factors Driving Vascular Endothelial Cells toward a Pro-Angiogenic State

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1855
Author(s):  
Aikaterini Gatsiou ◽  
Kateryna Sopova ◽  
Alexandros Tselepis ◽  
Konstantinos Stellos
Keyword(s):  
Endothelial Cells ◽  
Immune Cell ◽  
Vascular Endothelial Cells ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Aortic Ring ◽  
Inflammatory Factor ◽  
Vascular Endothelial ◽  
Monocyte Chemoattractant Protein 1 ◽  
Vascular Regeneration

Platelets comprise a highly interactive immune cell subset of the circulatory system traditionally known for their unique haemostatic properties. Although platelets are considered as a vault of growth factors, cytokines and chemokines with pivotal role in vascular regeneration and angiogenesis, the exact mechanisms by which they influence vascular endothelial cells (ECs) function remain underappreciated. In the present study, we examined the role of human IL-17A/IL-17RA axis in platelet-mediated pro-angiogenic responses. We reveal that IL-17A receptor (IL-17RA) mRNA is present in platelets transcriptome and a profound increase is documented on the surface of activated platelets. By quantifying the protein levels of several factors, involved in angiogenesis, we identified that IL-17A/IL17RA axis selectively induces the release of vascular endothelial growth factor, interleukin -2 and -4, as well as monocyte chemoattractant protein -1 from treated platelets. However, IL-17A exerted no effect on the release of IL-10, an anti-inflammatory factor with potentially anti-angiogenic properties, from platelets. Treatment of human endothelial cell two-dimensional tubule networks or three-dimensional spheroid and mouse aortic ring structures with IL-17A-induced platelet releasate evoked pro-angiogenic responses of ECs. Our findings suggest that IL-17A may critically affect platelet release of pro-angiogenic factors driving ECs towards a pro-angiogenic state.

scholarly journals Oxidative Stress Compromises Lymphocyte Function in Neonatal Dairy Calves

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 255
Author(s):  
Wilmer Cuervo ◽  
Lorraine M. Sordillo ◽  
Angel Abuelo
Keyword(s):  
Oxidative Stress ◽  
Immune Responses ◽  
Immune Cell ◽  
Lymphocyte Activation ◽  
Dairy Calves ◽  
Lymphocyte Function ◽  
Newborn Calves ◽  
Ifn Γ ◽  
The Impact

Dairy calves are unable to mount an effective immune response during their first weeks of life, which contributes to increased disease susceptibility during this period. Oxidative stress (OS) diminishes the immune cell capabilities of humans and adult cows, and dairy calves also experience OS during their first month of life. However, the impact that OS may have on neonatal calf immunity remains unexplored. Thus, we aimed to evaluate the impact of OS on newborn calf lymphocyte functions. For this, we conducted two experiments. First, we assessed the association of OS status throughout the first month of age and the circulating concentrations of the cytokines interferon-gamma (IFN-γ) and interleukin (IL) 4, as well as the expression of cytokine-encoding genes IFNG, IL2, IL4, and IL10 in peripheral mononuclear blood cells (PBMCs) of 12 calves. Subsequently, we isolated PBMCs from another 6 neonatal calves to investigate in vitro the effect of OS on immune responses in terms of activation of lymphocytes, cytokine expression, and antibody production following stimulation with phorbol 12-myristate 13-acetate or bovine herpesvirus-1. The results were compared statistically through mixed models. Calves exposed to high OS status in their first month of age showed higher concentrations of IL-4 and expression of IL4 and IL10 and lower concentrations of IFN-γ and expression of IFNG and IL2 than calves exposed to lower OS. In vitro, OS reduced lymphocyte activation, production of antibodies, and protein and gene expression of key cytokines. Collectively, our results demonstrate that OS can compromise some immune responses of newborn calves. Hence, further studies are needed to explore the mechanisms of how OS affects the different lymphocyte subsets and the potential of ameliorating OS in newborn calves as a strategy to augment the functional capacity of calf immune cells, as well as enhance calves’ resistance to infections.

scholarly journals A Serum Metabolomics Classifier Derived from Elderly Patients with Metastatic Colorectal Cancer Predicts Relapse in the Adjuvant Setting

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2762
Author(s):  
Samantha Di Donato ◽  
Alessia Vignoli ◽  
Chiara Biagioni ◽  
Luca Malorni ◽  
Elena Mori ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Stratification ◽  
Elderly Patients ◽  
Metastatic Colorectal Cancer ◽  
Early Stage ◽  
Prospective Trial ◽  
Proton Nuclear Magnetic Resonance ◽  
P Value ◽  
Resonance Spectroscopy ◽  
Metabolomic Fingerprinting

Adjuvant treatment for patients with early stage colorectal cancer (eCRC) is currently based on suboptimal risk stratification, especially for elderly patients. Metabolomics may improve the identification of patients with residual micrometastases after surgery. In this retrospective study, we hypothesized that metabolomic fingerprinting could improve risk stratification in patients with eCRC. Serum samples obtained after surgery from 94 elderly patients with eCRC (65 relapse free and 29 relapsed, after 5-years median follow up), and from 75 elderly patients with metastatic colorectal cancer (mCRC) obtained before a new line of chemotherapy, were retrospectively analyzed via proton nuclear magnetic resonance spectroscopy. The prognostic role of metabolomics in patients with eCRC was assessed using Kaplan–Meier curves. PCA-CA-kNN could discriminate the metabolomic fingerprint of patients with relapse-free eCRC and mCRC (70.0% accuracy using NOESY spectra). This model was used to classify the samples of patients with relapsed eCRC: 69% of eCRC patients with relapse were predicted as metastatic. The metabolomic classification was strongly associated with prognosis (p-value 0.0005, HR 3.64), independently of tumor stage. In conclusion, metabolomics could be an innovative tool to refine risk stratification in elderly patients with eCRC. Based on these results, a prospective trial aimed at improving risk stratification by metabolomic fingerprinting (LIBIMET) is ongoing.

scholarly journals Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

2021 ◽  
Author(s):  
Leoni Rolfes ◽  
Tobias Ruck ◽  
Christina David ◽  
Stine Mencl ◽  
Stefanie Bock ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Neurological Deficits ◽  
In Vitro Assays ◽  
Experimental Stroke ◽  
Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

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