The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1. Indeed, EBNA1 is essential for viral genome maintenance but is also highly antigenic. Hence, EBV seemingly evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA to the minimal level to ensure its essential function, thereby, at the same time, minimizing immune recognition. Therefore, defining intervention points at which to interfere with GAr-based inhibition of translation is an important step to trigger an immune response against EBV-carrying cancers. The host protein nucleolin (NCL) plays a critical role in this process via a direct interaction with G-quadruplexes (G4) formed in the GAr-encoding sequence of the viral EBNA1 mRNA. Here we show that the C-terminal arginine-glycine-rich (RGG) motif of NCL is crucial for its role in GAr-based inhibition of translation by mediating interaction of NCL with G4 of EBNA1 mRNA. We also show that this interaction depends on the type I arginine methyltransferase family, notably PRMT1 and PRMT3: drugs or small interfering RNA that target these enzymes prevent efficient binding of NCL on G4 of EBNA1 mRNA and relieve GAr-based inhibition of translation and of antigen presentation. Hence, this work defines type I arginine methyltransferases as therapeutic targets to interfere with EBNA1 and EBV immune evasion.
- MeSH
- imunitní systém metabolismus MeSH
- infekce onkogenními viry * farmakoterapie metabolismus MeSH
- infekce virem Epsteina-Barrové * genetika MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- onkogenní viry genetika metabolismus MeSH
- proteinarginin-N-methyltransferasy MeSH
- represorové proteiny MeSH
- virus Epsteinův-Barrové - jaderné antigeny genetika metabolismus MeSH
- virus Epsteinův-Barrové * genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Immune cells are an inseparable component of adipose tissue intimately involved in most of its functions. Physiologically, they regulate adipose tissue homeostasis, while in case of adipose tissue stress, immune cells are able to change their phenotype, enhance their count and subsequently contribute to the development and maintenance of local adipose tissue inflammation. Immune cells are an important source of inflammatory cytokines and other pro-inflammatory products that further influence not only surrounding tissues but via systemic circulation also the whole organism being thus one of the main factors responsible for the transition from simple obesity to associated metabolic and cardiovascular complications. The purpose of this review is to summarize current knowledge on different adipose tissue immune cell subsets and their role in the development of obesity, type 2 diabetes mellitus and cardiovascular diseases.
- MeSH
- cytokiny metabolismus MeSH
- diabetes mellitus 2. typu imunologie metabolismus MeSH
- imunitní systém metabolismus fyziologie MeSH
- kardiovaskulární nemoci etiologie imunologie metabolismus MeSH
- lidé MeSH
- makrofágy patologie fyziologie MeSH
- obezita imunologie metabolismus MeSH
- rizikové faktory MeSH
- tuková tkáň imunologie metabolismus MeSH
- zánět imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
O-methylation is an unusual sugar modification with a function that is not fully understood. Given its occurrence and recognition by lectins involved in the immune response, methylated sugars were proposed to represent a conserved pathogen-associated molecular pattern. We describe the interaction of O-methylated saccharides with two β-propeller lectins, the newly described PLL2 from the entomopathogenic bacterium Photorhabdus laumondii, and its homologue PHL from the related human pathogen Photorhabdus asymbiotica. The crystal structures of PLL2 and PHL revealed up to 10 out of 14 potential binding sites per protein subunit to be occupied with O-methylated structures. The avidity effect strengthens the interaction by 4 orders of magnitude. PLL2 and PHL also interfere with the early immune response by modulating the production of reactive oxygen species and phenoloxidase activity. Since bacteria from Photorhabdus spp. have a complex life cycle involving pathogenicity towards different hosts, the involvement of PLL2 and PHL might contribute to the pathogen overcoming insect and human immune system defences in the early stages of infection. DATABASES: Structural data are available in PDB database under the accession numbers 6RG2, 6RGG, 6RFZ, 6RG1, 6RGU, 6RGW, 6RGJ, and 6RGR.
- MeSH
- bakteriální proteiny chemie metabolismus MeSH
- cukry metabolismus MeSH
- gramnegativní bakteriální infekce imunologie metabolismus mikrobiologie MeSH
- hemocyty imunologie metabolismus MeSH
- hemolymfa imunologie metabolismus MeSH
- imunita imunologie MeSH
- imunitní systém imunologie metabolismus MeSH
- interakce hostitele a patogenu imunologie MeSH
- lektiny chemie metabolismus MeSH
- lidé MeSH
- metylace MeSH
- můry MeSH
- Photorhabdus imunologie metabolismus fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The observation of the immunomodulatory effects of opioid drugs opened the discussion about possible mechanisms of action and led researchers to consider the presence of opioid receptors (OR) in cells of the immune system. To date, numerous studies analyzing the expression of OR subtypes in animal and human immune cells have been performed. Some of them confirmed the expression of OR at both the mRNA and protein level, while others did not detect the receptor mRNA either. Although this topic remains controversial, further studies are constantly being published. The most recent articles suggested that the expression level of OR in human peripheral blood lymphocytes could help to evaluate the success of methadone maintenance therapy in former opioid addicts, or could serve as a biomarker for chronic pain diagnosis. However, the applicability of these findings to clinical practice needs to be verified by further investigations.
- MeSH
- biologické markery MeSH
- chronická bolest farmakoterapie etiologie metabolismus MeSH
- imunitní systém účinky léků imunologie metabolismus MeSH
- kmenové buňky účinky léků metabolismus MeSH
- lidé MeSH
- opioidní analgetika farmakologie MeSH
- receptory opiátové genetika metabolismus MeSH
- regulace genové exprese * MeSH
- zánět komplikace etiologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Deoxynivalenol (DON)-contaminated feed represents a serious problem for pigs due to their high sensitivity to its toxicological effects. The aim of the present study was to evaluate the impact of intrauterine DON exposure on the immune system of piglets. Pure DON was intravenously administered to sows at the end of gestation (during the last 2-3 days of gestation, one dose of 300 µg per day). The plasma concentration of DON was analyzed using liquid chromatography combined with high-resolution Orbitrap-based mass spectrometry (LC-MS/MS (HR)) and selected immune parameters were monitored six times in piglets from birth to 18 weeks. DON was found in the plasma of 90% of newborn piglets at a mean concentration of 6.28 ng/mL and subsequently, at one, three, and seven weeks after birth with decreasing concentrations. Trace amounts were still present in the plasma 14 weeks after birth. Flow cytometry revealed a significant impact of DON on T lymphocyte subpopulations during the early postnatal period. Lower percentages of regulatory T cells, T helper lymphocytes, and their double positive CD4+CD8+ subset were followed by increased percentages of cytotoxic T lymphocytes and γδ T cells. The capacity to produce pro-inflammatory cytokines was also significantly lower after intrauterine DON exposure. In conclusion, this study revealed a long-term persistence of DON in the plasma of the piglets as a consequence of short-term intrauterine exposure, leading to altered immune parameters.
- MeSH
- časové faktory MeSH
- cytokiny metabolismus MeSH
- fenotyp MeSH
- gestační stáří MeSH
- imunitní systém účinky léků imunologie metabolismus MeSH
- injekce intravenózní MeSH
- maternofetální výměna látek * MeSH
- matka - expozice noxám MeSH
- mediátory zánětu metabolismus MeSH
- Sus scrofa MeSH
- T-lymfocyty - podskupiny účinky léků imunologie metabolismus MeSH
- těhotenství MeSH
- trichotheceny aplikace a dávkování krev toxicita MeSH
- zpožděný efekt prenatální expozice * MeSH
- zvířata MeSH
- Check Tag
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The role of the immune system as an integral component of the inflammatory response in the pathophysiology of migraine remains unclear. The aim of this study was to evaluate the differences in immune system parameters (acquired immunity parameters) in patients with episodic migraine (EM) and in healthy controls. In EM patients, we aimed to determine whether the changes found in peripheral blood parameters were related to migraine severity according to the standardised MIDAS and HIT-6 tests. Forty-nine patients with EM and 50 healthy controls were included in this study. The authors compared different lymphocyte parameters obtained by multicolor flow cytometry in the EM and control groups by performing statistical tests. The relationship between the changes in peripheral blood parameters and migraine severity in EM patients was investigated using correlation and regression analysis. EM patients showed higher values than healthy controls, especially in nine parameters: relative count of lymphocytes, relative and absolute counts of CD3 T cells, relative and absolute counts of CD8 suppressor cytotoxic T cells, relative and absolute counts of CD4 + TEMRA (terminally differentiated helper T lymphocytes), absolute count of CD8 naïve T cells, and absolute count of CD19 switched memory B cells. Among the lymphocyte parameters, CD4 + TEM (effector memory helper T lymphocytes) and CD8 + TEMRA (terminally differentiated cytotoxic T lymphocytes) were statistically significantly associated with HIT-6. Patients with a CD4 + TEM value below 15 had a high probability (90%) that the HIT-6 value would be higher than 60. The results of this study show that EM patients have changes in immune system parameters measured in the peripheral blood. Changes in the abundance of CD4 + TEM could be used as a biomarker for disease severity.
- MeSH
- biologické markery MeSH
- dospělí MeSH
- imunitní systém imunologie metabolismus MeSH
- imunofenotypizace MeSH
- komorbidita MeSH
- lidé středního věku MeSH
- lidé MeSH
- migréna diagnóza etiologie metabolismus MeSH
- mladiství MeSH
- mladý dospělý MeSH
- náchylnost k nemoci * MeSH
- průtoková cytometrie MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- stupeň závažnosti nemoci MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The growing use of medical devices (e.g., vascular grafts, stents, and cardiac catheters) for temporary or permanent purposes that remain in the body's circulatory system demands a reliable and multiparametric approach that evaluates the possible hematologic complications caused by these devices (i.e., activation and destruction of blood components). Comprehensive in vitro hemocompatibility testing of blood-contacting implants is the first step towards successful in vivo implementation. Therefore, extensive analysis according to the International Organization for Standardization 10993-4 (ISO 10993-4) is mandatory prior to clinical application. The presented flow loop describes a sensitive model to analyze the hemostatic performance of stents (in this case, neurovascular) and reveal adverse effects. The use of fresh human whole blood and gentle blood sampling are essential to avoid the preactivation of blood. The blood is perfused through a heparinized tubing containing the test specimen by using a peristaltic pump at a rate of 150 mL/min at 37 °C for 60 min. Before and after perfusion, hematologic markers (i.e., blood cell count, hemoglobin, hematocrit, and plasmatic markers) indicating the activation of leukocytes (polymorphonuclear [PMN]-elastase), platelets (β-thromboglobulin [β-TG]), the coagulation system (thombin-antithrombin III [TAT]), and the complement cascade (SC5b-9) are analyzed. In conclusion, we present an essential and reliable model for extensive hemocompatibility testing of stents and other blood-contacting devices prior to clinical application.
- MeSH
- beta-thromboglobulin metabolismus MeSH
- biologické markery metabolismus MeSH
- biologické modely * MeSH
- cévní protézy * MeSH
- heparin farmakologie MeSH
- imunitní systém metabolismus MeSH
- komplement metabolismus MeSH
- krevní oběh účinky léků fyziologie MeSH
- krevní obraz MeSH
- krevní plazma MeSH
- lidé MeSH
- odběr vzorku krve MeSH
- pankreatická elastasa metabolismus MeSH
- stenty MeSH
- testování materiálů metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
The immune system plays an important role under both physiological and pathological conditions. Immune surveillance as well as defense and healing processes are crucial for the organism, but the immune system has a natural tendency to act aggressively when excessively stimulated. We may assume that the immune system is not designed to deal with severe conditions, such as polytrauma or severe stroke, because these are not compatible with life in the wilderness and evolution has no chance to act in such cases. These conditions are associated with exaggerated/deregulated inflammatory response, which may cause more damage than initial pathology. In this article, we would like to sketch a basic concept of the immune system-brain interactions from the evolutionary point of view and to discuss some implications related to stroke.
- MeSH
- biologická evoluce MeSH
- cévní mozková příhoda metabolismus patologie MeSH
- imunitní systém metabolismus patologie MeSH
- lidé MeSH
- mozek metabolismus patologie MeSH
- zánět metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
There is no doubt that immunotherapy lies in the spotlight of current cancer research and clinical trials. However, there are still limitations in the treatment response in certain types of tumors largely due to the presence of the complex network of immunomodulatory and immunosuppressive pathways. These limitations are not likely to be overcome by current immunotherapeutic options, which often target isolated steps in immune pathways preferentially involved in adaptive immunity. Recently, we have developed an innovative anti-cancer immunotherapeutic strategy that initially elicits a strong innate immune response with subsequent activation of adaptive immunity in mouse models. Robust primary innate immune response against tumor cells is induced by toll-like receptor ligands and anti-CD40 agonistic antibodies combined with the phagocytosis-stimulating ligand mannan, anchored to a tumor cell membrane by biocompatible anchor for membrane. This immunotherapeutic approach results in a dramatic therapeutic response in large established murine subcutaneous tumors including melanoma, sarcoma, pancreatic adenocarcinoma, and pheochromocytoma. Additionally, eradication of metastases and/or long-lasting resistance to subsequent re-challenge with tumor cells was also accomplished. Current and future advantages of this immunotherapeutic approach and its possible combinations with other available therapies are discussed in this review.
- MeSH
- adaptivní imunita MeSH
- fagocytóza účinky léků imunologie MeSH
- imunitní systém imunologie metabolismus MeSH
- imunomodulace MeSH
- imunoterapie * metody MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- ligandy MeSH
- nádorové mikroprostředí účinky léků genetika imunologie MeSH
- nádory etiologie metabolismus patologie terapie MeSH
- přirozená imunita MeSH
- protinádorové látky imunologicky aktivní farmakologie terapeutické užití MeSH
- toll-like receptory metabolismus MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Research Support, N.I.H., Intramural MeSH
