scholarly journals Immune Mechanisms of Dietary Salt-Induced Hypertension and Kidney Disease: Harry Goldblatt Award for Early Career Investigators 2020

Hypertension ◽  
2021 ◽  
Vol 78 (2) ◽  
pp. 252-260
Author(s):  
Fernando Elijovich ◽  
Thomas R. Kleyman ◽  
Cheryl L. Laffer ◽  
Annet Kirabo
Keyword(s):  
Blood Pressure ◽  
Mononuclear Cells ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Extracellular Fluid ◽  
Antigen Presenting Cells ◽  
Salt Sensitivity ◽  
Early Career ◽  
Water Excretion ◽  
Sequence Of Events ◽  
Antigen Presenting

Salt sensitivity of blood pressure is an independent risk factor for cardiovascular mortality not only in hypertensive but also in normotensive adults. The diagnosis of salt sensitivity of blood pressure is not feasible in the clinic due to lack of a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to understand the mechanisms of salt sensitivity of blood pressure have focused on renal regulation of sodium. However, salt retention or plasma volume expansion is not different between salt-sensitive and salt-resistant individuals. In addition, over 70% of extracellular fluid is interstitial and, therefore, not directly controlled by renal salt and water excretion. We discuss in this review how the seminal work by Harry Goldblatt paved the way for our attempts at understanding the mechanisms that underlie immune activation by salt in hypertension. We describe our findings that sodium, entering antigen-presenting cells via an epithelial sodium channel, triggers a PKC (protein kinase C)- and SGK1 (serum/glucocorticoid kinase 1)-stimulated activation of nicotinamide adenine dinucleotide phosphate oxidase, which, in turn, enhances lipid oxidation with generation of highly reactive isolevuglandins. Isolevuglandins adduct to proteins, with the potential to generate degraded peptide neoantigens. Activated antigen-presenting cells increase production of the TH17 polarizing cytokines, IL (interleukin)-6, IL-1β, and IL-23, which leads to differentiation and proliferation of IL-17A producing T cells. Our laboratory and others have shown that this cytokine contributes to hypertension. We also discuss where this sodium activation of antigen-presenting cells may occur in vivo and describe the multiple experiments, with pharmacological antagonists and knockout mice that we used to unravel this sequence of events in rodents. Finally, we describe experiments in mononuclear cells obtained from normotensive or hypertensive volunteers, which confirm that analogous processes of salt-induced immunity take place in humans.

scholarly journals Dendritic cells are potent antigen-presenting cells for microbial superantigens.

1992 ◽  
Vol 175 (1) ◽  
pp. 267-273 ◽  
Author(s):  
N Bhardwaj ◽  
S M Friedman ◽  
B C Cole ◽  
A J Nisanian
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Antigen Presenting Cells ◽  
Small Subset ◽  
Cell Functions ◽  
Cell Responses ◽  
Antigen Presenting

Dendritic cells are a small subset of human blood mononuclear cells that are potent stimulators of several T cell functions. Here we show they are 10-50-fold more potent than monocytes or B cells in inducing T cell responses to a panel of superantigens. Furthermore, dendritic cells can present femtomolar concentrations of superantigen to T cells even at numbers where other antigen-presenting cells (APCs) are inactive. Although dendritic cells express very high levels of the major histocompatibility complex products that are required to present superantigens, it is only necessary to pulse these APCs for 1 hour with picomolar levels of one superantigen, staphylococcal enterotoxin B, to maximally activate T cells. Our results suggest that very small amounts of superantigen will be immunogenic in vivo if presented on dendritic cells.

Cytotoxic Effects of CML28 Specific T Cells on Acute Leukemia Cells In Vitro.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4886-4886
Author(s):  
Hanwen Mao ◽  
Wenli Liu ◽  
Zhe Gen ◽  
Wei Huang ◽  
Yicheng Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Leukemia ◽  
Mononuclear Cells ◽  
Antigen Presenting Cells ◽  
Leukemia Cells ◽  
Cytotoxic Effects ◽  
Artificial Antigen ◽  
Leukemia Treatment ◽  
Antigen Presenting

Abstract The antigen-specific cytotoxic T lymphocyte activated by antigen presenting cell is widely used in cell immunotherapy recently. CML28, which was screened from chronic myelogenous leukemia (CML) patients, was reported to be a specific tumour antigen and over-expressed on CML cells and acute leukemia cells. Therefore, CML28 could be a potential target for leukemia treatment. Dendritic cells (DC) are the most important antigen present cells, but it is hard to isolate and culture DCs for clinical use, which hampers the specific cell immunotherapy. Our investigation aimed to study the cytotoxic effects of CML28 specific T cells activated by artificial antigen presenting cells, on acute leukemia cells in vitro. Artificial antigen presenting cells were prepared by connecting CML28 to magnetic superbead that containing HLA-A2-Ig and B7-1 molecule. Mononuclear cells were isolated from the bone marrow or peripheral blood of healthy donors with positive HLA-A2. The artificial antigen-presenting cells were co-cultured with isolated mononuclear cells for four weeks. The activation and proliferation of CML28-specific T cells were measured by dimmer binding technique using flow cytometry. The cytotoxic effects of CML28-specific T cells on leukemia cells, which were isolated from leukemia patient, were evaluated by lactate dehydrogenase (LDH) releasing assay. Increased proportion of CML28-specific T cells was observed in artificial antigen-presenting group than in control group (29.27±3.54% vs 2.95±0.66%, p<0.05). For cytotoxic effects assay, significant higher killing efficiency was seen in artificial antigen-presenting group (41.47±4.23%vs3.56±0.71%, when the effector: target ration is 40:1, p<0.01). Therefore, we concluded that the artificial antigen presenting cells could mimic antigen presenting cells to induce specific T cell activation and proliferation, and cytotoxic effects on target cells, indicating that artificial antigen presenting cell-induced cytotocix T cells could be an option for leukemia treatment.

scholarly journals Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells

2005 ◽  
Vol 202 (4) ◽  
pp. 529-539 ◽  
Author(s):  
Stephanie K. Dougan ◽  
Azucena Salas ◽  
Paul Rava ◽  
Amma Agyemang ◽  
Arthur Kaser ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Microsomal Triglyceride Transfer Protein ◽  
Antigen Presenting Cells ◽  
Human Monocyte ◽  
Lipid Transfer ◽  
Mouse Splenocytes ◽  
Transfer Protein ◽  
Er Chaperone ◽  
Antigen Presenting

Microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum (ER) chaperone that loads lipids onto apolipoprotein B, also regulates CD1d presentation of glycolipid antigens in the liver and intestine. We show MTP RNA and protein in antigen-presenting cells (APCs) by reverse transcription–polymerase chain reaction and by immunoblotting of mouse liver mononuclear cells and mouse and human B cell lines. Functional MTP, demonstrated by specific triglyceride transfer activity, is present in both mouse splenocytes and a CD1d-positive mouse NKT hybridoma. In a novel in vitro transfer assay, purified MTP directly transfers phospholipids, but not triglycerides, to recombinant CD1d. Chemical inhibition of MTP lipid transfer does not affect major histocompatibility complex class II presentation of ovalbumin, but considerably reduces CD1d-mediated presentation of α-galactosylceramide (α-galcer) and endogenous antigens in mouse splenic and bone marrow–derived dendritic cells (DCs), as well as in human APC lines and monocyte-derived DCs. Silencing MTP expression in the human monocyte line U937 affects CD1d function, as shown by diminished presentation of α-galcer. We propose that MTP acts upstream of the saposins and functions as an ER chaperone by loading endogenous lipids onto nascent CD1d. Furthermore, our studies suggest that a small molecule inhibitor could be used to modulate the activity of NKT cells.

scholarly journals Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling

2017 ◽  
Vol 312 (4) ◽  
pp. R451-R466 ◽  
Author(s):  
John S. Clemmer ◽  
W. Andrew Pruett ◽  
Thomas G. Coleman ◽  
John E. Hall ◽  
Robert L. Hester
Keyword(s):  
Mathematical Modeling ◽  
Blood Pressure ◽  
Salt Intake ◽  
Peripheral Resistance ◽  
Extracellular Fluid ◽  
Physiological Model ◽  
Salt Sensitivity ◽  
Sodium Reabsorption ◽  
Ang Ii ◽  
Bilateral Renal Artery Stenosis

Mathematical modeling is an important tool for understanding quantitative relationships among components of complex physiological systems and for testing competing hypotheses. We used HumMod, a large physiological model, to test hypotheses of blood pressure (BP) salt sensitivity. Systemic hemodynamics, renal, and neurohormonal responses to chronic changes in salt intake were examined during normal renal function, fixed low or high plasma angiotensin II (ANG II) levels, bilateral renal artery stenosis, increased renal sympathetic nerve activity (RSNA), and decreased nephron numbers. Simulations were run for 4 wk at salt intakes ranging from 30 to 1,000 mmol/day. Reducing functional kidney mass or fixing ANG II increased salt sensitivity. Salt sensitivity, associated with inability of ANG II to respond to changes in salt intake, occurred with smaller changes in renal blood flow but greater changes in glomerular filtration rate, renal sodium reabsorption, and total peripheral resistance (TPR). However, clamping TPR at normal or high levels had no major effect on salt sensitivity. There were no clear relationships between BP salt sensitivity and renal vascular resistance or extracellular fluid volume. Our robust mathematical model of cardiovascular, renal, endocrine, and sympathetic nervous system physiology supports the hypothesis that specific types of kidney dysfunction, associated with impaired regulation of ANG II or increased tubular sodium reabsorption, contribute to BP salt sensitivity. However, increased preglomerular resistance, increased RSNA, or inability to decrease TPR does not appear to influence salt sensitivity. This model provides a platform for testing competing concepts of long-term BP control during changes in salt intake.

Abstract 18: Excess Dietary Salt-induced Blood Pressure Elevation Is Associated With Impaired Bile Acid Signaling And Human Monocyte Activation

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Jeanne A Ishimwe ◽  
Jane F Ferguson ◽  
Annet Kirabo
Keyword(s):  
Blood Pressure ◽  
Bile Acids ◽  
Antigen Presenting Cells ◽  
High Salt ◽  
Farnesoid X Receptor ◽  
Dietary Sodium ◽  
P Value ◽  
Dietary Salt ◽  
Blood Pressure Elevation ◽  
Antigen Presenting

Excess dietary sodium (Na + ) is a major risk for hypertension and cardiovascular disease. We previously found that excess dietary salt induces gut microbial dysbiosis and leads to activation of antigen presenting cells and hypertension, but the mechanisms are not known. The gut microbiome metabolizes bile acids, and these have been implicated in activation of antigen presenting cells. We hypothesized that high dietary Na + -induced inflammation leading to hypertension is associated with impaired bile acids signaling. We measured plasma bile acids via a metabolomics analysis in 75 volunteers. Blood pressure was also monitored. Based on the recommendations by the American Heart Association, we classified daily Na + intake <2.3g as normal salt (NS, n=23), and high salt (HS, n=52) for subjects consuming ≥ 2.3g Na + . Spearman correlation was used to assess the relationship between Na + intake and blood pressure. We found that elevated diastolic (r=0.331, p=0.003), systolic (r=0.383, p<0.001) and mean arterial pressure (r=0.278, p=0.014) were associated with increased Na + intake. Five taurine and glycine-conjugated secondary bile acids including taurodeoxycholate (1.320 ± 0.238 vs. 2.820 ± 0.669; p=0.010); glycodeoxycholate (1.197± 0.154 vs. 1.998± 0.432; p= 0.033); glycodeoxycholate sulfate (1.037± 0.132 vs. 1.521± 0.192; p= 0.044); glycolithocholate (0.829± 0.094 vs. 1.622± 0.363; p= 0.006) and glycolithocholate sulfate (1.083± 0.127 vs. 1.598± 0.205; p= 0.030) were lower in the HS when compared to the NS group. Interestingly, using RNA sequencing in human monocytes, we found that the NR1H4 gene which encodes the farnesoid X receptor, a nuclear receptor activated by bile acids, was significantly downregulated by high salt treatment, and this was associated with a pro-inflammatory phenotype (9.80± 1.65 vs. 11.82± 1.64; adjusted p-value=0.043). Our findings suggest that high salt impairs bile acids signaling leading to inflammation and salt-induced hypertension.

scholarly journals Dendritic Cells of Leukemic Origin: Specialized Antigen-Presenting Cells as Potential Treatment Tools for Patients with Myeloid Leukemia

2020 ◽  
Vol 47 (6) ◽  
pp. 432-443
Author(s):  
Daniel Christoph Amberger ◽  
Helga Maria Schmetzer
Keyword(s):  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Vaccination Strategy ◽  
Antigen Presenting Cells ◽  
Adoptive Cell Transfer ◽  
Peripheral Blood Mononuclear ◽  
Ongoing Research ◽  
Promising Treatment ◽  
Antigen Presenting

The prognosis of elderly patients with acute myeloid leukemia (AML) and high-grade myelodysplastic syndrome (MDS) is limited due to the lack of therapy options and high relapse rates. Dendritic cell (DC)-based immunotherapy seems to be a promising treatment tool. DC are potent antigen-presenting cells and play a pivotal role on the interface of the innate and the adaptive immune system. Myeloid leukemia blasts can be converted to DC of leukemic origin (DC<sub>leu</sub>), expressing costimulatory molecules along with the whole leukemic antigen repertoire of individual patients. These generated DC<sub>leu</sub> are potent stimulators of various immune reactive cells and increase antileukemic immunity ex vivo. Here we review the generating process of DC/DC<sub>leu</sub> from leukemic peripheral blood mononuclear cells as well as directly from leukemic whole blood with “minimized” Kits to simulate physiological conditions ex vivo. The purpose of adoptive cell transfer of DC/DC<sub>leu</sub> as a vaccination strategy is discussed. A new potential therapy option with Kits for patients with myeloid leukemia, which would render an adoptive DC/DC<sub>leu</sub> transfer unnecessary, is presented. In summary, DC/DC<sub>leu</sub>-based therapies seem to be promising treatment tools for patients with AML or MDS but ongoing research including trials in animals and humans have to be performed.

scholarly journals Regulation of Blood Pressure and Salt Homeostasis by Endothelin

2011 ◽  
Vol 91 (1) ◽  
pp. 1-77 ◽  
Author(s):  
Donald E. Kohan ◽  
Noreen F. Rossi ◽  
Edward W. Inscho ◽  
David M. Pollock
Keyword(s):  
Blood Pressure ◽  
Extracellular Fluid ◽  
Systemic Blood Pressure ◽  
Physiological Control ◽  
Water Excretion ◽  
Venous Capacitance ◽  
Physiological Regulation ◽  
Regulation Of Blood Pressure ◽  
Salt Homeostasis

Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

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