scholarly journals Acetate correlates with disability and immune response in multiple sclerosis

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10220 ◽  
Author(s):  
Silvia Pérez-Pérez ◽  
María Inmaculada Domínguez-Mozo ◽  
Aitana Alonso-Gómez ◽  
Silvia Medina ◽  
Noelia Villarrubia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Short Chain Fatty Acids ◽  
Liquid Chromatography Mass Spectrometry ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Disability Status

Background Gut microbiota has been related to multiple sclerosis (MS) etiopathogenesis. Short-chain fatty acids (SCFA) are compounds derived from microbial metabolism that have a role in gut-brain axis. Objectives To analyse SCFA levels in plasma of MS patients and healthy donors (HD), and the possible link between these levels and both clinical data and immune cell populations. Methods Ninety-five MS patients and 54 HD were recruited. Patients were selected according to their score in the Expanded Disability Status Scale (EDSS) (49 EDSS ≤ 1.5, 46 EDSS ≥ 5.0). SCFA were studied in plasma samples by liquid chromatography-mass spectrometry. Peripheral blood mononuclear cells were studied by flow cytometry. Gender, age, treatments, EDSS and Multiple Sclerosis Severity Score (MSSS) were evaluated at the recruitment. Results Plasma acetate levels were higher in patients than in HD (p = 0.003). Patients with EDSS ≥ 5.0 had higher acetate levels than those with EDSS≤ 1.5 (p = 0.029), and HD (p = 2.97e–4). Acetate levels correlated with EDSS (r = 0.387; p = 1.08e–4) and MSSS (r = 0.265; p = 0.011). In untreated MS patients, acetate levels correlated inversely with CD4+ naïve T cells (r =  − 0.550, p = 0.001) and directly with CD8+ IL-17+ cells (r = 0.557; p = 0.001). Conclusions Plasma acetate levels are higher in MS patients than in HD. In MS there exists a correlation between plasma acetate levels, EDSS and increased IL-17+ T cells. Future studies will elucidate the role of SCFA in the disease.

scholarly journals Pregnancy-Induced Changes in microRNA Expression in Multiple Sclerosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Helle Bach Søndergaard ◽  
Laura Airas ◽  
Jeppe Romme Christensen ◽  
Birgitte Romme Nielsen ◽  
Lars Börnsen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Nk Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Differentially Expressed ◽  
Blood Monocytes ◽  
Third Trimester ◽  
Myeloid Dendritic Cells ◽  
Peripheral Blood Mononuclear

Pregnancy affects the disease course in multiple sclerosis (MS), particularly in the third trimester, where the relapse rate is reduced by as much as two thirds. This study aimed at identifying changes in microRNA (miRNA) and immune cell phenotypes in pregnant MS patients. Discovery and validation studies to detect differentially expressed miRNAs were performed with quantitative real-time PCR on peripheral blood mononuclear cells (PBMC). Flow cytometry analysis was performed on PBMC stained with antibodies directed against surface markers of antigen presenting cells (APCs), NK-cells, NKT cells, CD4+ and CD8+ T cells and subsets of these cell types, including PDL1 and PDL2 expressing subsets. RNA was extracted from whole blood, monocytes, and NK-cells to investigate expression and correlation between regulated miRNAs and mRNAs. In total, 15 miRNAs were validated to be differentially expressed between third trimester pregnant and postpartum MS patients (Benjamini-Hochberg false discovery rate from p = 0.03–0.00004). Of these, 12 miRNAs were downregulated in pregnancy and 6 of the 15 miRNAs were altered by more than ±2-fold (+2.99- to -6.38-fold). Pregnant MS patients had a highly significant increase in the percentage of monocytes and a decrease of NK-cells and myeloid dendritic cells compared to non-pregnant MS patients. We confirm previous reports of a relative increase in CD56-bright NK-cells and a decrease in CD56-dim NK-cells in third trimester of pregnancy and report an increase in non-committed follicular helper cells. PDL1 and PDL2 expression was increased in pregnant patients together with IL10. Also, in monocytes IL10, PDL1, and PDL2 were upregulated whereas miR-1, miR-20a, miR-28, miR-95, miR-146a, miR-335, and miR-625 were downregulated between pregnant and untreated MS patients. IL10, PDL1, and PDL2 were predicted targets of MS pregnancy-changed miRNAs, further supported by their negative correlations. Additionally, previously identified pregnancy-regulated mRNAs were identified as predicted targets of the miRNAs. PDL1 and PDL2 bind PD-1 expressed on T cells with an inhibitory effect on T-cell proliferation and increase in IL10 production. These results indicate that some of the effects behind the disease-ameliorating third trimester of pregnancy might be caused by changed expression of miRNAs and immunoregulatory molecules in monocytes.

scholarly journals Multiple sclerosis patients have reduced resting and increased activated CD4+CD25+FOXP3+T regulatory cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nirupama D. Verma ◽  
Andrew D. Lam ◽  
Christopher Chiu ◽  
Giang T. Tran ◽  
Bruce M. Hall ◽  
...  
Keyword(s):  
T Cells ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Effector Memory ◽  
Regulatory Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Treg Population ◽  
Multiple Sclerosis Patients ◽  
Population Iii

AbstractResting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared. Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer. CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells. Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells. Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg. Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors. Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors. Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD. Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III. In MS, CCR6+Treg were lower in Population III. This study found MS is associated with significant shifts in CD4+T cells subpopulations. MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment. Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.

scholarly journals Endogenous retrovirus-encoded Syncytin-2 contributes to exosome-mediated immunosuppression of T cells†

2019 ◽  
Author(s):  
Adjimon G Lokossou ◽  
Caroline Toudic ◽  
Phuong Trang Nguyen ◽  
Xavier Elisseeff ◽  
Amandine Vargas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Map Kinases ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Endogenous Retrovirus ◽  
Jurkat Cells ◽  
Peripheral Blood Mononuclear ◽  
Interfering Rna

Abstract Modulation of the activation status of immune cell populations during pregnancy depends on placental villous cytotrophoblast (VCT) cells and the syncytiotrophoblast (STB). Failure in the establishment of this immunoregulatory function leads to pregnancy complications. Our laboratory has been studying Syncytin-2 (Syn-2), an endogenous retroviral protein expressed in placenta and on the surface of placental exosomes. This protein plays an important role not only in STB formation through its fusogenic properties, but also through its immunosuppressive domain (ISD). Considering that Syn-2 expression is importantly reduced in preeclamptic placentas, we were interested in addressing its possible immunoregulatory effects on T cells. Activated Jurkat T cells and peripheral blood mononuclear cells (PBMCs) were treated with monomeric or dimerized version of a control or a Syn-2 ISD peptide. Change in phosphorylation levels of ERK1/2 MAP kinases was selectively noted in Jurkat cells treated with the dimerized ISD peptide. Upon incubation with the dimerized Syn-2 ISD peptide, significant reduction in Th1 cytokine production was further demonstrated by ELISA and Human Th1/Th2 Panel Multi-Analyte Flow Assay. To determine if exosome-associated Syn-2 could also be immunosuppressive placental exosomes were incubated with activated Jurkat and PBMCs. Quantification of Th1 cytokines in the supernatants revealed severe reduction in T cell activation. Interestingly, exosomes from Syn-2-silenced VCT incubated with PBMCs were less suppressive when compared with exosome derived from VCT transfected with control small interfering RNA (siRNA). Our results suggest that Syn-2 is an important immune regulator both locally and systemically, via its association with placental exosomes.

scholarly journals Role of T cells in intrauterine administration of activated peripheral blood mononuclear cells in recurrent implantation failure.

2021 ◽  
Author(s):  
Guillaume Ricaud ◽  
Cathy Vaillancourt ◽  
Veronique Blais ◽  
Marjorie Disdier ◽  
Fabien Joao ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Treg Cells ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Intrauterine administration of autologous peripheral blood mononuclear cells (PBMC) has been recently proposed as new immunotherapy for patients with unexplained recurrent implantation failure (RIF). In these patients, administration of activated PBMC 24-h or 72-h before embryo transfer resulted in a 3-fold increase in biochemical pregnancy rate. In this study we evaluated the role of T cells to promotes human endometrial receptivity. On the day of ovulation, PBMC were isolated from and activated with T cells mitogen, the phytohemagglutinin (PHA) and hCG for 48-h in a conditioned culture medium. Distributions of CD4+ T cells were characterized in 157 patients by flow cytometry before and after PHA/hCG activation. Cytokine production was analyzed by cytometric beads array. We observed in RIF patients a significant decrease in Th2 and natural Treg cells before activation with PHA/hCG and an increase of Th17 cells after activation compared to intrauterine sperm insemination (IUI) and in vitro fertilization (IVF) groups. Furthermore, the hCG/PHA treatment increases anti-inflammatory T cells (Th2 and Treg cells) compared to non-treated T cells. Principal component analysis (PCA) performed on CD4 T cell subtypes revealed a different cellular profile in the RIF compared to the IUI and IVF groups. This inflammatory state change could explain how endometrium immunomodulation by hCG-activated PBMC helps patients with unexplained RIF to reach implantation.

scholarly journals Zika virus infects human blood mononuclear cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Carolina V. Messias ◽  
Julia P. Lemos ◽  
Daniela P. Cunha ◽  
Zilton Vasconcelos ◽  
Lidiane M. S. Raphael ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Nervous System ◽  
Zika Virus ◽  
Mononuclear Cells ◽  
Health Concern ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Blood Mononuclear Cells ◽  
The Central Nervous System

Abstract Background Zika virus (ZIKV) infection gained public health concern after the 2015 outbreak in Brazil, when microcephaly rates increased in babies born from infected mothers. It was demonstrated that ZIKV causes a congenital Zika virus syndrome, including various alterations in the development of the central nervous system. Although the infection of cells from the nervous system has been well documented, less is known in respect of ZIKV ability to infect immune cells. Herein, we investigated if peripheral blood mononuclear cells (PBMCs), freshly-isolated from healthy donors, could be infected by ZIKV. Methods PBMCs from healthy donors were isolated and cultured in medium with ZIKV strain Rio-U1 (MOI = 0.1). Infection was analyzed by RT-qPCR and flow cytometry. Results We detected the ZIKV RNA in PBMCs from all donors by RT-qPCR analysis. The detection of viral antigens by flow cytometry revealed that PBMC from more than 50% the donors were infected by ZIKV, with CD3+CD4+ T cells, CD3−CD19+ B cells and CD3+CD8+ T cells being, respectively, the most frequently infected subpopulations, followed by CD14+ monocytes. Additionally, we observed high variability in PBMC infection rates among different donors, either by numbers or type infected cells. Conclusions These findings raise the hypothesis that PBMCs can act as a reservoir of the virus, which may facilitate viral dissemination to different organs, including immune-privileged sites.

scholarly journals Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer

2008 ◽  
Vol 105 (40) ◽  
pp. 15505-15510 ◽  
Author(s):  
Yoshihiro Miyahara ◽  
Kunle Odunsi ◽  
Wenhao Chen ◽  
Guangyong Peng ◽  
Junko Matsuzaki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Cells ◽  
Ovarian Tumor ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Immune Response To Cancer ◽  
Ovarian Tumor Cells

Despite the important role of Th17 cells in the pathogenesis of many autoimmune diseases, their prevalence and the mechanisms by which they are generated and regulated in cancer remain unclear. Here, we report the presence of a high percentage of CD4+ Th17 cells at sites of ovarian cancer, compared with a low percentage of Th17 cells in peripheral blood mononuclear cells from healthy donors and cancer patients. Analysis of cytokine production profiles revealed that ovarian tumor cells, tumor-derived fibroblasts, and antigen-presenting cells (APCs) secreted several key cytokines including IL-1β, IL-6, TNF-α and TGF-β, which formed a cytokine milieu that regulated and expanded human IL-17-producing T-helper (Th17) cells. We further show that IL-1β was critically required for the differentiation and expansion of human Th17 cells, whereas IL-6 and IL-23 may also play a role in the expansion of memory Th17 cells, even though IL-23 levels are low or undetectable in ovarian cancer. Further experiments demonstrated that coculture of naïve or memory CD4+ T cells with tumor cells, APCs, or both could generate high percentages of Th17 cells. Treatment with anti-IL-1 alone or a combination of anti-IL-1 and anti-IL-6 reduced the ability of tumor cells to expand memory Th17 cells. Thus, we have identified a set of key cytokines secreted by ovarian tumor cells and tumor-associated APCs that favor the generation and expansion of human Th17 cells. These findings should accelerate efforts to define the function of this important subset of CD4+ T cells in the human immune response to cancer.

scholarly journals Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Joanne Boldison ◽  
Anna E. Long ◽  
Rachel J. Aitken ◽  
Isabel V. Wilson ◽  
Clare Megson ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Unsupervised Clustering ◽  
Autoimmune Response ◽  
Peripheral Blood Mononuclear ◽  
Slow Progressors ◽  
Healthy Donors

Abstract Aims/hypothesis Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31–72 years), followed up for 18–32 years. Methods Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes. Results Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells. Conclusions/interpretations We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes. Graphical abstract

scholarly journals Role of protein kinases JNK and p38 in regulation of mononuclear leucocytes apoptosis in oxidative stress

2008 ◽  
Vol 7 (3) ◽  
pp. 38-43 ◽  
Author(s):  
N. Yu. Chasovskikh
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Transmembrane Potential ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Stress Induction ◽  
Healthy Donors ◽  
Mononuclear Leucocytes

Programmed cell death of peripheral blood mononuclear leucocytes taken from healthy donors and cultivated with various concentration of Н2О2, selective inhibitors of JNK (SP600125), 38 (ML3403) and in case of pneumonia was investigated. Intensification of intracellular production of reactive oxy р МАРК - gen species was accompanied by the increase in number of apoptotic and TNFR1-presented cells and mononuclears with reduced value of mitochondrial transmembrane potential in a case of oxidative stress induction with 1 mM hydrogen peroxide and in blood taken from patients with pneumonia. Action of inhibitors SP600125 and ML3403 in vitro in oxidative stress conditions prevents the increase in number of annexin- positive mononuclear cells, that confirms the participation of JNK and 38 -kinases in mechanisms of oxidative stress-mediated apoptosis dysregulation.

scholarly journals Sexual-dimorphism in human immune system aging

2019 ◽  
Author(s):  
Eladio J. Márquez ◽  
Cheng-han Chung ◽  
Radu Marches ◽  
Robert J. Rossi ◽  
Djamel Nehar-Belaid ◽  
...  
Keyword(s):  
Immune System ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Rna Seq ◽  
Human Immune System ◽  
Peripheral Blood Mononuclear ◽  
Cell Functions ◽  
Age Related ◽  
Male Specific

AbstractDifferences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow-cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte/cytotoxic cell functions. These changes were greater in magnitude in men and accompanied by a male-specific genomic decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune cell genomes can be visualized at https://immune-aging.jax.org to provide insights into future studies.

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