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1.
Neurobiol Stress ; : 100296, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33527083

RESUMO

The COVID-19 pandemic continues to strongly affect people with health disadvantages, creating a heavy burden on medical systems and societies worldwide. Research is growing rapidly and recently revealed that stress-related factors such as socio-economic status, may also play a pivotal role. However, stress research investigating the underlying psychoneuroimmune interactions is missing. Here we address the question whether stress-associated neuroendocrine-immune mechanisms can possibly contribute to an increase in SARS-CoV-2 infections and influence the course of COVID-19 disease. Additionally, we discuss that not all forms of stress (e.g. acute versus chronic) are detrimental and that some types of stress could attenuate infection-risk and -progression. The overall aim of this review is to motivate future research efforts to clarify whether psychosocial interventions have the potential to optimize neuroendocrine-immune responses against respiratory viral infections during and beyond the COVID-19 pandemic. The current state of research on different types of stress is summarized in a comprehensive narrative review to promote a psychoneuroimmune understanding of how stress and its mediators cortisol, (nor)adrenaline, neuropeptides and neurotrophins can shape the immune defense against viral diseases. Based on this understanding, we describe how people with high psychosocial stress can be identified, which behaviors and psychosocial interventions may contribute to optimal stress management, and how psychoneuroimmune knowledge can be used to improve adequate care for COVID-19 and other patients with viral infections.

2.
Psychother Psychosom Med Psychol ; 71(2): 61-71, 2021 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-33440452

RESUMO

OBJECTIVE: The COVID-19 pandemic is on the rise and causes many concerns and fears in the population as well as among medical care givers. This raises the question as to how psychosocial stress associated with the pandemic can be managed, and also if certain forms of stress can contribute to an increase in infections and critical illnesses. METHODS: Against the background of the current state of research on stress and the immune response, we provide a narrative review of studies addressing the question as to how stress can influence the immune defence against viral diseases. RESULTS: Excessive stress can compromise the barrier function of the airways and alter neuroendocrine control of immune function, which can create a virus-permissive immune response. DISCUSSION: Because certain forms of stress can play a role in the successful immune defence against viral respiratory disease, it is important to identify people with high psychosocial stress and to help them manage their stress. Conclusion Psychosocial measures that contribute to improved stress management may have a positive effect on the immune response against viral respiratory infections.

3.
Mol Ther ; 28(12): 2691-2702, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33186542

RESUMO

Preventing the progression to acute respiratory distress syndrome (ARDS) in COVID-19 is an unsolved challenge. The involvement of T cell immunity in this exacerbation remains unclear. To identify predictive markers of COVID-19 progress and outcome, we analyzed peripheral blood of 10 COVID-19-associated ARDS patients and 35 mild/moderate COVID-19 patients, not requiring intensive care. Using multi-parametric flow cytometry, we compared quantitative, phenotypic, and functional characteristics of circulating bulk immune cells, as well as SARS-CoV-2 S-protein-reactive T cells between the two groups. ARDS patients demonstrated significantly higher S-protein-reactive CD4+ and CD8+ T cells compared to non-ARDS patients. Of interest, comparison of circulating bulk T cells in ARDS patients to non-ARDS patients demonstrated decreased frequencies of CD4+ and CD8+ T cell subsets, with activated memory/effector T cells expressing tissue migration molecule CD11a++. Importantly, survival from ARDS (4/10) was accompanied by a recovery of the CD11a++ T cell subsets in peripheral blood. Conclusively, data on S-protein-reactive polyfunctional T cells indicate the ability of ARDS patients to generate antiviral protection. Furthermore, decreased frequencies of activated memory/effector T cells expressing tissue migratory molecule CD11a++ observed in circulation of ARDS patients might suggest their involvement in ARDS development and propose the CD11a-based immune signature as a possible prognostic marker.

4.
Curr Protoc Immunol ; 131(1): e111, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33147370

RESUMO

Cellular interactions are often essential to regulate immune cell activities during an immune response. To understand the details of this process, it is necessary to study individual receptor/ligand interactions in a quantitative fashion. However, this is often very difficult or even impossible when using real cells for stimulation. Here, we present a method to use cell-sized latex beads for such studies. These beads can be coated with agonistic antibodies or specific ligands in a defined and quantifiable fashion. This creates the possibility of titrating the strength of the stimulation for a specific receptor in a three-dimensional system. Using natural killer (NK) cells as an example, we demonstrate how these beads can be used to stimulate NK cell responses. © 2020 The Authors. Basic Protocol 1: Covalent coating of latex beads with antibodies Basic Protocol 2: Quantification of the amount of antibodies on the beads with the QIFIKIT® Alternate Protocol 1: Covalent coating of latex beads with streptavidin to bind biotinylated proteins Alternate Protocol 2: Quantification of the amount of protein on the beads with the QIFIKIT® Support Protocol: Functional testing of the beads in a natural killer cell degranulation assay.

5.
Cell Rep Med ; 1(6): 100092, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32904468

RESUMO

T cell immunity toward SARS-CoV-2 spike (S-), membrane (M-), and nucleocapsid (N-) proteins may define COVID-19 severity. Therefore, we compare the SARS-CoV-2-reactive T cell responses in moderate, severe, and critical COVID-19 patients and unexposed donors. Overlapping peptide pools of all three proteins induce SARS-CoV-2-reactive T cell response with dominance of CD4+ over CD8+ T cells and demonstrate interindividual immunity against the three proteins. M-protein induces the highest frequencies of CD4+ T cells, suggesting its relevance for diagnosis and vaccination. The T cell response of critical COVID-19 patients is robust and comparable or even superior to non-critical patients. Virus clearance and COVID-19 survival are not associated with either SARS-CoV-2 T cell kinetics or magnitude of T cell responses, respectively. Thus, our data do not support the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. Conversely, it indicates that activation of differentiated memory effector T cells could cause hyperreactivity and immunopathogenesis in critical patients.

6.
Cell Mol Immunol ; 17(7): 705-711, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32503998

RESUMO

The immune system and the nervous system are highly complex organs composed of various different cells that must interact with each other for proper function of the system. This communication can be mediated by soluble factors. The factors released by the nervous system (neurotransmitters) differ from those released by the immune system (cytokines). Nevertheless, the nervous and immune systems can influence each other's activity because immune cells express neurotransmitter receptors, and neurons express cytokine receptors. Moreover, immune cells can synthesize and release neurotransmitters themselves, thus using neurotransmitter-mediated pathways via autocrine and paracrine mechanisms. Natural killer (NK) cells are innate lymphocytes that are important for early and effective immune reactions against infections and cancer. Many studies have shown the strong influence of stress and the nervous system on NK cell activity. This phenomenon may be one reason why chronic stress leads to a higher incidence of infections and cancer. Here, we review the effects of neuroendocrine factors on the different activities of NK cells. Understanding the effects of neuroendocrine factors on NK cell activities during physiological and pathophysiological conditions may result in novel therapeutic strategies to enhance NK cell functions against tumors.

7.
Arch Toxicol ; 94(5): 1375-1415, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32382957

RESUMO

Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.

8.
EXCLI J ; 19: 430-441, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32327961

RESUMO

Hereditary hemochromatosis (HH) is an autosomal-recessive disorder of the iron metabolism. Patients are typically affected by dysregulated iron levels, which can lead to iron accumulation within essential organs, such as liver, heart and pancreas. Furthermore, many HH patients are also afflicted by several immune defects and increased occurrence of autoimmune diseases that are linked to human homeostatic iron regulator protein (HFE) in the immune response. Here we examined immune cell phenotype and function in 21 HH patients compared to 21 healthy controls with a focus on Natural Killer (NK) cells. We observed increased basal and stimulated production of pro-inflammatory cytokines such as IL-1ß or IL-18 in HH patients compared to healthy controls. However, we did not find major changes in the phenotype, the amount or the cytotoxic function of NK cells in HH patients. Instead, our data show a general decrease in the total number of granulocytes in HH patients (2774 ± 958 per µl versus 3457 ± 1122 per µl in healthy controls). These data demonstrate that NK cells of HH patients are not significantly affected and that the patients' treatment by regular phlebotomy is sufficient to avoid systemic iron overload and its consequences to the immune system.

9.
Eur J Immunol ; 50(5): 656-665, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32027754

RESUMO

Natural Killer (NK) cell responses are regulated by a variety of different surface receptors. While we can determine the overall positive or negative effect of a given receptor on NK cell functions, investigating NK cell regulation in a quantitative way is challenging. To quantitatively investigate individual receptors for their effect on NK cell activation, we chose to functionalize latex beads that have approximately the same size as lymphocytes with defined amounts of specific antibodies directed against distinct activating receptors. This enabled us to investigate NK cell reactivity in a defined, clean, and controllable system. Only CD16 and NKp30 could activate the degranulation of resting human NK cells. CD16, NKG2D, NKp30, NKp44, and NKp46 were able to activate cultured NK cells. NK cell activation resulted in the induction of polyfunctional cells that degranulated and produced IFN-γ and MIP-1ß. Interestingly, polyfunctional NK cells were only induced by triggering ITAM-coupled receptors. NKp44 showed a very sensitive response pattern, where a small increase in receptor stimulation caused maximal NK cell activity. In contrast, stimulation of 2B4 induced very little NK cell degranulation, while providing sufficient signal for NK cell adhesion. Our data demonstrate that activating receptors differ in their effectiveness to stimulate NK cells.


Assuntos
Anticorpos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Anticorpos/química , Adesão Celular/efeitos dos fármacos , Degranulação Celular/efeitos dos fármacos , Células Cultivadas , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Microesferas , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/genética , Receptor 2 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 3 Desencadeador da Citotoxicidade Natural/genética , Receptor 3 Desencadeador da Citotoxicidade Natural/imunologia , Ligação Proteica , Receptores de IgG/genética , Receptores de IgG/imunologia , Transdução de Sinais
10.
Arch Toxicol ; 94(2): 439-448, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32060585

RESUMO

Drug-induced liver injury (DILI) represents one of the major causes why drugs have to be withdrawn from the market. In this study, we describe a new interaction between drug-exposed hepatocytes and natural killer (NK) cells. In a previous genome-wide expression analysis of primary human hepatocytes that had been exposed to clinically relevant concentrations of 148 drugs, we found that several activating ligands for NK cell receptors were regulated by various drugs (e.g., valproic acid, ketoconazole, promethazine, isoniazid). Especially expression of the activating NKG2D ligands (MICA, MICB and ULBPs) and the NKp30 ligand B7-H6 were upregulated in primary human hepatocytes upon exposure to many different drugs. Using the human hepatocyte cell lines Huh7 and HepG2, we confirmed that protein levels of activating NK cell ligands were elevated after drug exposure. Hepatocyte cell lines or primary human hepatocytes co-cultivated with NK cells caused enhanced NK cell activation after pretreatment with drugs at in vivo relevant concentrations compared to solvent controls. Enhanced NK cell activation was evident by increased cytotoxicity against hepatocytes and interferon (IFN)-γ production. NK cell activation could be blocked by specific antibodies against activating NK cell receptors. These data support the hypothesis that NK cells can modulate drug-induced liver injury by direct interaction with hepatocytes resulting in cytotoxicity and IFN-γ production.

11.
Trials ; 21(1): 117, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996235

RESUMO

INTRODUCTION: Depression and fatigue are common in breast cancer survivors, and their presence is associated with personal suffering and worse prognosis. While many women receive short-term psychological support in the acute treatment phase, this is rarely available in subsequent phases. Internet interventions for breast cancer survivors could provide additional psychological support, as they are easily accessible and may be effective. However, no trial has yet examined the effectiveness of an Internet intervention that provides cognitive behavioural therapy techniques plus lifestyle advice for this population. This trial aims to test whether Optimune, a novel Internet intervention we developed for that purpose, leads to improvements in quality of life and relevant lifestyle habits over the course of 3 to 6 months. METHODS: This randomized controlled trial (RCT) will include 360 female breast cancer survivors who have completed the active tumour eradication phase. Participants will be recruited from various settings, including web-based advertisements and Internet forums in German-speaking countries. The main inclusion criteria are a breast cancer diagnosis less than 5 years ago and completion of acute treatment at least 1 month ago, as verified by discharge letter from an oncology treatment centre. Participants will be randomly assigned to either (1) a control group, in which they receive care as usual (CAU) and are given access to Optimune after a delay of 3 months (CAU/wait list control), or (2) a treatment group that may also use CAU and will receive 12-month access to Optimune immediately after randomization. The three primary endpoints are quality of life, physical activity and diet quality, assessed with the World Health Organization Quality of Life Questionnaire, the International Physical Activity Questionnaire and the Food Quality Questionnaire, at 3 months post-baseline; secondary outcomes include cancer-related fatigue, emotional stress, depression, anxiety, fear of progression, insomnia, usefulness of the programme and negative treatment effects. Online assessments are conducted at baseline (T0), 3 months (T1) and 6 months (T2). DISCUSSION: Results of this RCT are expected to extend the body of knowledge with regard to the effectiveness of CBT-based Internet interventions for female breast cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03643640. Registered on 23 August 2018.


Assuntos
Neoplasias da Mama/reabilitação , Terapia Cognitivo-Comportamental/métodos , Dieta , Exercício Físico , Intervenção Baseada em Internet , Qualidade de Vida , Ansiedade/psicologia , Neoplasias da Mama/fisiopatologia , Neoplasias da Mama/psicologia , Sobreviventes de Câncer/psicologia , Depressão/psicologia , Fadiga/fisiopatologia , Fadiga/psicologia , Feminino , Estilo de Vida Saudável , Humanos , Angústia Psicológica , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/psicologia
12.
Cell Mol Immunol ; 17(4): 347-355, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31471588

RESUMO

Natural killer (NK) cells participate in early immune defenses against pathogens and tumors and play a major role as immune effector and regulatory cells. The NK cell-mediated elimination of an infected or cancerous cell is a highly regulated process that requires the formation of a cell contact, the establishment of an immunological synapse and the polarization and release of lytic granules. Additionally, the detachment of NK cells from target cells is important for NK cells to bind and kill other cells in a process called serial killing. However, very little is known about this detachment process. Here, we show that NK detachment is directly connected to the successful killing of a target cell. The inhibition of killing due to reduced NK cell cytotoxicity or increased target cell resistance results in defective detachment and prolonged contact times. This effect leads to sustained Ca2+ flux in NK cells and the hypersecretion of proinflammatory cytokines. Linking defective cytotoxicity with enhanced cytokine secretion via reduced detachment may explain inflammatory pathologies in several diseases.

13.
Arthritis Res Ther ; 21(1): 277, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829278

RESUMO

OBJECTIVE: In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab's mechanism of action in GPA. METHODS: B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry. RESULTS: NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions. CONCLUSION: B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab's mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.


Assuntos
Granulomatose com Poliangiite/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Rituximab/uso terapêutico , Granulomatose com Poliangiite/imunologia , Humanos , Células Matadoras Naturais/imunologia
14.
J Exp Med ; 216(9): 2113-2127, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270246

RESUMO

NK cells eliminate virus-infected and tumor cells by releasing cytotoxic granules containing granzyme B (GrzB) or by engaging death receptors that initiate caspase cascades. The orchestrated interplay between both cell death pathways remains poorly defined. Here we simultaneously measure the activities of GrzB and caspase-8 in tumor cells upon contact with human NK cells. We observed that NK cells switch from inducing a fast GrzB-mediated cell death in their first killing events to a slow death receptor-mediated killing during subsequent tumor cell encounters. Target cell contact reduced intracellular GrzB and perforin and increased surface-CD95L in NK cells over time, showing how the switch in cytotoxicity pathways is controlled. Without perforin, NK cells were unable to perform GrzB-mediated serial killing and only killed once via death receptors. In contrast, the absence of CD95 on tumor targets did not impair GrzB-mediated serial killing. This demonstrates that GrzB and death receptor-mediated cytotoxicity are differentially regulated during NK cell serial killing.


Assuntos
Citotoxicidade Imunológica , Granzimas/metabolismo , Células Matadoras Naturais/imunologia , Receptores de Morte Celular/metabolismo , Caspase 8/metabolismo , Células HeLa , Humanos , Cinética , Perforina/metabolismo , Receptor fas/metabolismo
15.
J Leukoc Biol ; 105(6): 1319-1329, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31107565

RESUMO

Cellular cytotoxicity, the ability to kill other cells, is an important effector mechanism of the immune system to combat viral infections and cancer. Cytotoxic T cells and natural killer (NK) cells are the major mediators of this activity. Here, we summarize the cytotoxic mechanisms of NK cells. NK cells can kill virally infected of transformed cells via the directed release of lytic granules or by inducing death receptor-mediated apoptosis via the expression of Fas ligand or TRAIL. The biogenesis of perforin and granzymes, the major components of lytic granules, is a highly regulated process to prevent damage during the synthesis of these cytotoxic molecules. Additionally, NK cells have developed several strategies to protect themselves from the cytotoxic activity of granular content upon degranulation. While granule-mediated apoptosis is a fast process, death receptor-mediated cytotoxicity requires more time. Current data suggest that these 2 cytotoxic mechanisms are regulated during the serial killing activity of NK cells. As many modern approaches of cancer immunotherapy rely on cellular cytotoxicity for their effectiveness, unraveling these pathways will be important to further progress these therapeutic strategies.


Assuntos
Imunidade Celular , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Viroses/imunologia , Animais , Proteína Ligante Fas/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Células Matadoras Naturais/patologia , Proteínas de Neoplasias/imunologia , Neoplasias/patologia , Viroses/patologia
16.
EBioMedicine ; 43: 380-391, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30992245

RESUMO

BACKGROUND: Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. METHODS: NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis. FINDINGS: During systemic inflammation, the expression of the IL-12 receptor ß2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24 h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor ß receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor ß2 expression on NK cells and was enhanced in patients who later acquired septic complications. INTERPRETATION: GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.


Assuntos
Antígeno CD56/metabolismo , Infecção Hospitalar/etiologia , Infecção Hospitalar/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Adulto , Biomarcadores , Comorbidade , Infecção Hospitalar/sangue , Infecção Hospitalar/diagnóstico , Feminino , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-12/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação , Receptores de Interleucina-12/metabolismo , Fator de Transcrição STAT4/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo
17.
Int J Cancer ; 145(4): 901-915, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30653260

RESUMO

Endothelial lipase (LIPG) is a cell surface associated lipase that displays phospholipase A1 activity towards phosphatidylcholine present in high-density lipoproteins (HDL). LIPG was recently reported to be expressed in breast cancer and to support proliferation, tumourigenicity and metastasis. Here we show that severe oxidative stress leading to AMPK activation triggers LIPG upregulation, resulting in intracellular lipid droplet accumulation in breast cancer cells, which supports survival. Neutralizing oxidative stress abrogated LIPG upregulation and the concomitant lipid storage. In human breast cancer, high LIPG expression was observed in a limited subset of tumours and was significantly associated with shorter metastasis-free survival in node-negative, untreated patients. Moreover, expression of PLIN2 and TXNRD1 in these tumours indicated a link to lipid storage and oxidative stress. Altogether, our findings reveal a previously unrecognized role for LIPG in enabling oxidative stress-induced lipid droplet accumulation in tumour cells that protects against oxidative stress, and thus supports tumour progression.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Lipase/metabolismo , Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Linhagem Celular Tumoral , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipoproteínas HDL/metabolismo , Células MCF-7 , Pessoa de Meia-Idade , Regulação para Cima/fisiologia
18.
Clin Immunol ; 204: 37-42, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30359773

RESUMO

SLAM family receptors are important for the fine-tuning of immune reactions. Their expression is restricted to cells of hematopoietic origin and most SLAM family receptors are their own ligand. Here we review how these receptors are involved in regulating the functions of Natural Killer (NK) cells. We discuss that promoting cellular adhesion may be a main function of SLAM family receptors in NK cells. The homophilic interactions of SLAM family receptors can not only occur in trans between different cells, but also in cis on the surface of the same cell. This cis interaction additionally modulates the function of the receptors and subsequently affects the activities of NK cells. Finally, SLAM-family receptors can also mediate inhibitory signals under certain conditions. These inhibitory signals can contribute to the functional maturation of NK cells during NK cell education. Therefore, SLAM family receptors are critically involved in many aspects of NK cell functionality.


Assuntos
Adesão Celular/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Animais , Humanos
19.
Front Neurosci ; 12: 687, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30333720

RESUMO

This study aimed to investigate the impact of mental stress on salivary cytokines and attention to emotional stimuli, as well as associations between stress-induced changes of immune and cognitive parameters. In a randomized order a total of 60 young adults were assigned to one of two stress conditions with varying stress intensity. High stress was induced by a socially evaluated Paced Auditory Serial Addition Test (PASAT). As a low stress task a paper-and-pencil version of PASAT was administered. Salivary cytokines were measured before, 5 min after, and 45 min after completion of the stress task, and were assayed for pro- and anti-inflammatory cytokines. Three distinct types of attention - alerting, orienting, and executive control - were measured by the modified Emotional Attention Network Test Integration (E-ANTI). IL-1ß and IL-6 increased only in the high-stress group. Significant increases in IFN-α, IFN-γ, TNF-α, and IL-10 at 45 min after stress induction (all p's < 0.05) were observed in both the high-stress and the low-stress group. Alerting attention was positively related to more pronounced increases in IFN-α and TNF-α in both groups. Further, better orienting attention after presentation of negative cues was associated with higher increases in IFN-α, TNF-α, IL-2, IL-5, and IL-10 in both groups, and higher overall levels of IFN-α, IFN-γ, and IL-12p70 in the high-stress group. There were no systematic gender differences in cytokine responses. We conclude that attention processes modulate the increases of salivary cytokines after stress exposure, and that these effects depend on stress level, particular attention network, and stimulus valence.

20.
Front Immunol ; 9: 1840, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30135688

RESUMO

Natural killer (NK) cells eliminate infected and tumorigenic cells through delivery of granzymes via perforin pores or by activation of caspases via death receptors. In order to understand how NK cells combine different cell death mechanisms, it is important to quantify target cell responses on a single cell level. However, currently existing reporters do not allow the measurement of several protease activities inside the same cell. Here, we present a strategy for the comparison of two different proteases at a time inside individual target cells upon engagement by NK cells. We developed single-fluorescent protein reporters containing the RIEAD or the VGPD cleavage site for the measurement of granzyme B activity. We show that these two granzyme B reporters can be applied in combination with caspase-8 or caspase-3 reporters. While we did not find that caspase-8 was activated by granzyme B, our method revealed that caspase-3 activity follows granzyme B activity with a delay of about 6 min. Finally, we illustrate the comparison of several different reporters for granzyme A, M, K, and H. The approach presented here is a valuable means for the investigation of the temporal evolution of cell death mediated by cytotoxic lymphocytes.


Assuntos
Caspases/metabolismo , Expressão Gênica , Genes Reporter , Granzimas/metabolismo , Células Matadoras Naturais/metabolismo , Apoptose , Morte Celular , Humanos , Células Matadoras Naturais/imunologia , Proteólise , Análise de Célula Única
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