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1.
Front Immunol ; 12: 655122, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408743

RESUMO

FOXP3+ regulatory T cells (Tregs) are central for maintaining peripheral tolerance and immune homeostasis. Because of their immunosuppressive characteristics, Tregs are a potential therapeutic target in various diseases such as autoimmunity, transplantation and infectious diseases like COVID-19. Numerous studies are currently exploring the potential of adoptive Treg therapy in different disease settings and novel genome editing techniques like CRISPR/Cas will likely widen possibilities to strengthen its efficacy. However, robust and expeditious protocols for genome editing of human Tregs are limited. Here, we describe a rapid and effective protocol for reaching high genome editing efficiencies in human Tregs without compromising cell integrity, suitable for potential therapeutic applications. By deletion of IL2RA encoding for IL-2 receptor α-chain (CD25) in Tregs, we demonstrated the applicability of the method for downstream functional assays and highlighted the importance for CD25 for in vitro suppressive function of human Tregs. Moreover, deletion of IL6RA (CD126) in human Tregs elicits cytokine unresponsiveness and thus may prevent IL-6-mediated instability of Tregs, making it an attractive target to potentially boost functionality in settings of adoptive Treg therapies to contain overreaching inflammation or autoimmunity. Thus, our rapid and efficient protocol for genome editing in human Tregs may advance possibilities for Treg-based cellular therapies.


Assuntos
Edição de Genes/métodos , Subunidade alfa de Receptor de Interleucina-2/genética , Receptores de Interleucina-6/genética , Linfócitos T Reguladores/metabolismo , Buffy Coat/citologia , Sistemas CRISPR-Cas/genética , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Voluntários Saudáveis , Humanos , Imunoterapia Adotiva/métodos , Cultura Primária de Células , RNA Guia/genética , Fatores de Tempo
2.
J Invest Dermatol ; 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34237339

RESUMO

Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17‒producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4+ cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A‒driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34224053

RESUMO

Autoimmunity is caused by an unbalanced immune system, giving rise to a variety of organ-specific to system disorders. Patients with autoimmune diseases are commonly treated with broad-acting immunomodulatory drugs, with the risk of severe side effects. Regulatory T cells (Tregs) have the inherent capacity to induce peripheral tolerance as well as tissue regeneration and are therefore a prime candidate to use as cell therapy in patients with autoimmune disorders. (Pre)clinical studies using Treg therapy have already established safety and feasibility, and some show clinical benefits. However, Tregs are known to be functionally impaired in autoimmune diseases. Therefore, ex vivo manipulation to boost and stably maintain their suppressive function is necessary when considering autologous transplantation. Similar to autoimmunity, severe coronavirus disease 2019 (COVID-19) is characterized by an exaggerated immune reaction and altered Treg responses. In light of this, Treg-based therapies are currently under investigation to treat severe COVID-19. This review provides a detailed overview of the current progress and clinical challenges of Treg therapy for autoimmune and hyperinflammatory diseases, with a focus on recent successes of ex vivo Treg manipulation.

4.
Circulation ; 144(2): 144-158, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-33906377

RESUMO

BACKGROUND: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes. METHODS: Using Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichia coli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo. RESULTS: Extracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of [Formula: see text] and [Formula: see text] respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. CONCLUSIONS: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.

5.
Nat Commun ; 12(1): 1970, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785752

RESUMO

Periods of fasting and refeeding may reduce cardiometabolic risk elevated by Western diet. Here we show in the substudy of NCT02099968, investigating the clinical parameters, the immunome and gut microbiome exploratory endpoints, that in hypertensive metabolic syndrome patients, a 5-day fast followed by a modified Dietary Approach to Stop Hypertension diet reduces systolic blood pressure, need for antihypertensive medications, body-mass index at three months post intervention compared to a modified Dietary Approach to Stop Hypertension diet alone. Fasting alters the gut microbiome, impacting bacterial taxa and gene modules associated with short-chain fatty acid production. Cross-system analyses reveal a positive correlation of circulating mucosa-associated invariant T cells, non-classical monocytes and CD4+ effector T cells with systolic blood pressure. Furthermore, regulatory T cells positively correlate with body-mass index and weight. Machine learning analysis of baseline immunome or microbiome data predicts sustained systolic blood pressure response within the fasting group, identifying CD8+ effector T cells, Th17 cells and regulatory T cells or Desulfovibrionaceae, Hydrogenoanaerobacterium, Akkermansia, and Ruminococcaceae as important contributors to the model. Here we report that the high-resolution multi-omics data highlight fasting as a promising non-pharmacological intervention for the treatment of high blood pressure in metabolic syndrome patients.


Assuntos
Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Jejum/fisiologia , Microbioma Gastrointestinal/fisiologia , Síndrome Metabólica/fisiopatologia , Idoso , Akkermansia/fisiologia , Índice de Massa Corporal , Desulfovibrionaceae/fisiologia , Dieta , Fezes/microbiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/microbiologia , Hipertensão/fisiopatologia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/microbiologia , Pessoa de Meia-Idade , Ruminococcus/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/fisiologia
6.
J Transl Autoimmun ; 3: 100032, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32743517

RESUMO

Multiple sclerosis (MS) is a genetically mediated autoimmune disease characterized by inflammation in the central nervous system (CNS). Disease onset is thought to occur when autoreactive T cells orchestrate a cascade of events in the CNS resulting in white and grey matter inflammation and axonal degeneration. It is unclear what triggers the activation of CNS-reactive T cells and their polarization into inflammatory subsets. Mounting evidence from animal and human studies supports the hypothesis that the gut microbiome affects MS pathogenesis. We investigated the association between the gut microbiome and inflammatory T cell subsets in relapsing-remitting MS patients and healthy controls. Gut microbiome composition was characterized by sequencing the V4 region of the 16S rRNA gene from fecal DNA, and inflammatory T cell subsets were characterized by flow cytometry. We identified an altered gut microbiome in MS patients, including decreased abundance of Coprococcus, Clostridium, and an unidentified Ruminococcaceae genus. Among circulating immune cells, patients had increased expression of CXCR3 in both CD4 and CD8 T cells, and both CD4+CXCR3+ and CD8+CXCR3+ populations expressing the gut-homing α4ß7 integrin receptor were increased. Finally, we show that alpha diversity inversely correlated with a CXCR3+ Th1 phenotype in MS. These findings indicate the presence of an aberrant gut-immune axis in patients with MS.

7.
Front Immunol ; 11: 253, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32153577

RESUMO

The rise in the prevalence of autoimmune diseases in developed societies has been associated with a change in lifestyle patterns. Among other factors, increased consumption of certain dietary components, such as table salt and fatty acids and excessive caloric intake has been associated with defective immunological tolerance. Dietary nutrients have shown to modulate the immune response by a direct effect on the function of immune cells or, indirectly, by acting on the microbiome of the gastrointestinal tract. FOXP3+ regulatory T cells (Tregs) suppress immune responses and are critical for maintaining peripheral tolerance and immune homeostasis, modulating chronic tissue inflammation and autoimmune disease. It is now well-recognized that Tregs show certain degree of plasticity and can gain effector functions to adapt their regulatory function to different physiological situations during an immune response. However, plasticity of Tregs might also result in conversion into effector T cells that may contribute to autoimmune pathogenesis. Yet, which environmental cues regulate Treg plasticity and function is currently poorly understood, but it is of significant importance for therapeutic purposes. Here we review the current understanding on the effect of certain dietary nutrients that characterize Western diets in Treg metabolism, stability, and function. Moreover, we will discuss the role of Tregs linking diet and autoimmunity and the potential of dietary-based interventions to modulate Treg function in disease.


Assuntos
Dietoterapia , Dieta , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Microbiota
8.
J Extracell Vesicles ; 10(1): e12022, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33708355

RESUMO

Microglia, the immunocompetent cells of the central nervous system (CNS), play an important role in maintaining cellular homeostasis in the CNS. These cells secrete immunomodulatory factors including nanovesicles and participate in the removal of cellular debris by phagocytosis or autophagy. Accumulating evidence indicates that specifically the cellular exchange of small extracellular vesicles (EVs), participates in physiology and disease through intercellular communication. However, the contribution of microglial-derived extracellular vesicles (M-EVs) to the maintenance of microglia homeostasis and how M-EVs could influence the phenotype and gene function of other microglia subtypes is unclear. In addition, knowledge of canonical signalling pathways of inflammation and immunity gene expression patterns in human microglia exposed to M-EVs is limited. Here, we analysed the effects of M-EVs produced in vitro by either tumour necrosis factor alpha (TNFα) activated or non-activated microglia BV2 cells. We showed that M-EVs are internalized by both mouse and human C20 microglia cells and that the uptake of M-EVs in microglia induced autophagic vesicles at various stages of degradation including autophagosomes and autolysosomes. Consistently, stimulation of microglia with M-EVs increased the protein expression of the autophagy marker, microtubule-associated proteins 1A/1B light chain 3B isoform II (LC3B-II), and promoted autophagic flux in live cells. To elucidate the biological activities occurring at the transcriptional level in C20 microglia stimulated with M-EVs, the gene expression profiles, potential upstream regulators, and enrichment pathways were characterized using targeted RNA sequencing. Inflammation and immunity transcriptome gene panel sequencing of both activated and normal microglia stimulated with M-EVs showed involvement of several canonical pathways and reduced expression of key genes involved in neuroinflammation, inflammasome and apoptosis signalling pathways compared to control cells. In this study, we provide the perspective that a beneficial activity of in vitro cell culture produced EVs could be the modulation of autophagy during cellular stress. Therefore, we use a monoculture system to study microglia-microglia crosstalk which is important in the prevention and propagation of inflammation in the brain. We demonstrate that in vitro produced microglial EVs are able to influence multiple biological pathways and promote activation of autophagy in order to maintain microglia survival and homeostasis.

9.
Front Immunol ; 10: 1141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214164

RESUMO

Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function in vitro. Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy.


Assuntos
Imunidade , Neoplasias/imunologia , Neoplasias/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Animais , Apoptose , Biomarcadores , Modelos Animais de Doenças , Progressão da Doença , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/patologia
10.
Nat Rev Immunol ; 19(4): 243-254, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30644452

RESUMO

During tissue inflammation, immune cells infiltrate the interstitial space of target organs, where they sense and adapt to local environmental stimuli. Such stimuli include not only pathogens but also local factors such as the levels of oxygenation, nutrients and electrolytes. An important electrolyte in this regard is sodium (Na+). Recent in vivo findings have shown a role of Na+ storage in the skin for electrolyte homeostasis. Thereby, Na+ intake may influence the activation status of the immune system through direct effects on T helper cell subsets and innate immune cells in tissues such as the skin and other target organs. Furthermore, high Na+ intake has been shown to alter the composition of the intestinal microbiota, with indirect effects on immune cells. The results suggest regulatory roles for Na+ in cardiovascular disease, inflammation, infection and autoimmunity.


Assuntos
Microambiente Celular/imunologia , Homeostase/imunologia , Sistema Imunitário/imunologia , Sódio/imunologia , Animais , Microbioma Gastrointestinal/imunologia , Humanos
11.
J Neuroimmunol ; 329: 9-13, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29983198

RESUMO

The detrimental effects of a high-salt diet on human health have received much attention in the past few years. While it has been well established that high dietary salt intake is related to cardiovascular diseases, there is growing evidence that excess salt also affects the immune system and might be considered as a risk factor in autoimmune diseases such as multiple sclerosis (MS). Several studies have implicated T helper 17 cells (Th17) in the pathogenesis of MS. We and others recently demonstrated that excessive salt enhances the differentiation of Th17 cells, inducing a highly pathogenic phenotype that aggravates experimental neuroinflammation. Moreover, a diet rich in sodium affects intestinal microbiota alongside increased intestinal Th17 cells, thus linking the detrimental effects of high salt consumption to the gut-immune axis. First human studies revealed an association of increased MS disease activity with elevated sodium chloride consumption, while more recent epidemiology studies in larger cohorts suggest no correlation between salt intake and MS. However, it is known that ordinary urinary sodium analyses and nutritional questionnaires do not necessarily correspond to the actual sodium load and more sophisticated analyses are needed. Moreover, studies revealed that sodium can temporarily be stored in the body. This review summarizes recent findings on the impact of salt on the immune system and discusses potential challenges investigating dietary salt intake as a risk factor in MS.


Assuntos
Autoimunidade/imunologia , Microbioma Gastrointestinal/imunologia , Esclerose Múltipla/imunologia , Cloreto de Sódio na Dieta/efeitos adversos , Células Th17/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Esclerose Múltipla/induzido quimicamente , Cloreto de Sódio na Dieta/administração & dosagem , Células Th17/efeitos dos fármacos
12.
Front Immunol ; 9: 2819, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555484

RESUMO

Background: Physical activity might attenuate inflammation and neurodegeneration in multiple sclerosis (MS). Erythropoietin, which is produced upon exposure to hypoxia, is thought to act as a neuroprotective agent in MS. Therefore, we studied the effects of intermittent hypoxic training on activity energy expenditure, maximal workload, serum erythropoietin, and immunophenotype focusing on regulatory and IL-17A-producing T cells. Methods: We assigned 34 relapsing-remitting MS patients within a randomized, single blind, parallel-group study to either normoxic (NO) or hypoxic (HO) treadmill training, both 3 times/week for 1 h over 4 weeks (Clinicaltrials.gov identifier: NCT02509897). Before and after training, activity energy expenditure (metabolic chamber), maximal workload (incremental treadmill test), walking ability, depressive symptoms (Beck Depression Inventory I), serum erythropoietin concentrations, and immunophenotype of peripheral blood mononuclear cells (PBMCs) were assessed. Results: Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training (P = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both P < 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO P = 0.02; HO P = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO P = 0.03; HO P = 0.0003). NO training shifted Treg subpopulations by increasing and decreasing the frequency of CD39+ and CD31+ Tregs, respectively, and decreased IL-17A-producing CD4+ cells. HO training provoked none of these immunological changes. Erythropoietin concentrations were within normal range and did not significantly change in either group. Conclusion: 4 weeks of moderate treadmill training had considerable effects on fitness level and mood in MS patients, both under normoxic and hypoxic conditions. Additionally, NO training improved Th17/Treg profile and HO training improved fatty acid oxidation during exercise. These effects could not be attributed to an increase of erythropoietin. Clinical Trial Registration: ClinicalTrials.gov; NCT02509897; http://www.clinicaltrials.gov.


Assuntos
Eritropoetina , Terapia por Exercício , Hipóxia , Esclerose Múltipla , Linfócitos T Reguladores , Células Th17 , Adulto , Eritropoetina/sangue , Eritropoetina/imunologia , Feminino , Humanos , Hipóxia/sangue , Hipóxia/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/psicologia , Esclerose Múltipla/terapia , Projetos Piloto , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
13.
Front Immunol ; 9: 439, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29559977

RESUMO

B cells possess a predominant role in adaptive immune responses via antibody-dependent and -independent functions. The microbiome of the gastrointestinal tract is currently being intensively investigated due to its profound impact on various immune responses, including B cell maturation, activation, and IgA antibody responses. Recent findings have demonstrated the interplay between dietary components, gut microbiome, and autoantibody production. "Western" dietary patterns, such as high fat and high salt diets, can induce alterations in the gut microbiome that in turn affects IgA responses and the production of autoantibodies. This could contribute to multiple pathologies including autoimmune and inflammatory diseases. Here, we summarize current knowledge on the influence of various dietary components on B cell function and (auto)antibody production in relation to the gut microbiota, with a particular focus on the gut-brain axis in the pathogenesis of multiple sclerosis.


Assuntos
Autoanticorpos/metabolismo , Linfócitos B/imunologia , Dieta , Encefalomielite Autoimune Experimental/imunologia , Microbioma Gastrointestinal/imunologia , Esclerose Múltipla/imunologia , Animais , Diferenciação Celular , Modelos Animais de Doenças , Humanos , Imunidade Humoral
14.
Immunology ; 154(3): 346-353, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29465812

RESUMO

The immune system evolved to protect organisms from invading pathogens. A network of pro- and anti-inflammatory cell types equipped with special effector molecules guarantees efficient elimination of intruders like viruses and bacteria. However, imbalances can lead to an excessive response of effector cells incurring autoimmune or allergic diseases. An interplay of genetic and environmental factors contributes to autoimmune diseases and recent studies provided evidence for an impact of dietary habits on the immune status and related disorders. Western societies underwent a change in lifestyle associated with changes in food consumption. Salt (sodium chloride) is one component prevalent in processed food frequently consumed in western countries. Here we summarize recent advances in understanding the mechanisms behind the effects of sodium chloride on immune cells like regulatory T cells (Tregs) and T helper (TH ) 17 cells and its implication as a risk factor for several diseases.


Assuntos
Suscetibilidade a Doenças , Sistema Imunitário/citologia , Sistema Imunitário/fisiologia , Imunomodulação , Sais/metabolismo , Imunidade Adaptativa , Animais , Humanos , Imunidade Inata , Cloreto de Sódio na Dieta/metabolismo
15.
Ann N Y Acad Sci ; 1417(1): 71-86, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29377214

RESUMO

There is increasing evidence for a sudden and unprecedented rise in the incidence of multiple sclerosis (MS) in Westernized countries over the past decades, emphasizing the role of environmental factors. Among many candidates, rapid changes in dietary habits seem to play a role in the pathogenesis of MS. Here, we summarize and discuss the available evidence for the role of dietary nutrients, such as table salt, fatty acids, and flavonoids, in the development and pathogenesis of MS. We also discuss new and emerging risk factors accompanying Western lifestyle, such as shift work, sleep, and circadian disruption.


Assuntos
Dieta Ocidental/efeitos adversos , Estilo de Vida , Esclerose Múltipla/etiologia , Autoimunidade , Transtornos Cronobiológicos/complicações , Transtornos Cronobiológicos/imunologia , Ácidos Graxos/química , Ácidos Graxos/imunologia , Flavonoides/imunologia , Interação Gene-Ambiente , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Fatores de Risco , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/efeitos adversos
16.
Nature ; 551(7682): 585-589, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29143823

RESUMO

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Lactobacillus/efeitos dos fármacos , Lactobacillus/isolamento & purificação , Cloreto de Sódio/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/microbiologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Fezes/microbiologia , Humanos , Hipertensão/induzido quimicamente , Ácidos Indolacéticos/metabolismo , Indóis/metabolismo , Intestinos/citologia , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/microbiologia , Lactobacillus/imunologia , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Camundongos , Projetos Piloto , Cloreto de Sódio/administração & dosagem , Simbiose , Células Th17/citologia , Triptofano/metabolismo
17.
J Neuroinflammation ; 14(1): 184, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28899400

RESUMO

BACKGROUND: There has been a marked increase in the incidence of autoimmune diseases like multiple sclerosis (MS) in the last decades which is most likely driven by a change in environmental factors. Here, growing evidence suggests that ingredients of a Western diet like high intake of sodium chloride (NaCl) or saturated fatty acids may impact systemic immune responses, thus increasing disease susceptibility. Recently, we have shown that high dietary salt or long-chain fatty acid (LCFA) intake indeed aggravates T helper (Th) cell responses and neuroinflammation. METHODS: Naïve CD4+ T cells were treated with an excess of 40 mM NaCl and/or 250 µM lauric acid (LA) in vitro to analyze effects on Th cell differentiation, cytokine secretion, and gene expression. We employed ex vivo analyses of the model disease murine experimental autoimmune encephalomyelitis (EAE) to investigate whether salt and LCFA may affect disease severity and T cell activation in vivo. RESULTS: LCFA, like LA, together with NaCl enhance the differentiation of Th1 and Th17 cells as well as pro-inflammatory cytokine and gene expression in vitro. In cell culture, we observed an additive effect of LA and hypertonic extracellular NaCl (NaCl + LA) in Th17 differentiation assays as well as on IL-17, GM-CSF, and IL-2 gene expression. In contrast, NaCl + LA reduced Th2 frequencies. We employed EAE as a model of Th1/Th17 cell-mediated autoimmunity and show that the combination of a NaCl- and LA-rich diet aggravated the disease course and increased T cell infiltration into the central nervous system (CNS) to the same extent as dietary NaCl. CONCLUSIONS: Our findings demonstrate a partially additive effect of NaCl and LA on Th cell polarization in vitro and on Th cell responses in autoimmune neuroinflammation. These data may help to better understand the pathophysiology of autoimmune diseases such as MS.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Encefalomielite Autoimune Experimental/imunologia , Ácidos Graxos/farmacologia , Cloreto de Sódio/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/patologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/citologia
18.
Front Immunol ; 8: 311, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28377767

RESUMO

Interleukin-17-producing T helper (Th17) cells are critical for the host defense of bacterial and fungal pathogens and also play a major role in driving pathogenic autoimmune responses. Recent studies have indicated that the generation of Th17 cells from naïve CD4+ T cells is coupled with massive cellular metabolic adaptations, necessary to cope with different energy and metabolite requirements associated with switching from a resting to proliferative state. Furthermore, Th17 cells have to secure these metabolic adaptations when facing nutrient-limiting environments, such as at the sites of inflammation. Accumulating data indicates that this metabolic reprogramming is significantly linked to the differentiation of T helper cells and, particularly, that the metabolic changes of Th17 cells and anti-inflammatory Forkhead box P3+ regulatory T cells are tightly and reciprocally regulated. Thus, a better understanding of these processes could offer potential new targets for therapeutic interventions for autoimmune diseases. In this mini-review, we will highlight some of the recent advances and discoveries in the field, with a particular focus on metabolic demands of Th17 cells and their implications for autoimmunity.

19.
Cell Mol Life Sci ; 73(24): 4611-4622, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27491297

RESUMO

An increase in autoimmune diseases poses a socioeconomic challenge worldwide. Predisposing genetic risk has been identified, yet environmental factors make up a significant part of the risk in disease initiation and propagation. Next to improved hygiene and a gross reduction of infections, changes in dietary habits are one of the most evident Western lifestyle factors potentially associated with the increase in autoimmune diseases. Growing evidence suggests that particularly a typical 'Western diet', rich in saturated fat and salt and related pathologies can have a profound impact on local and systemic immune responses under physiologic and autoimmune conditions such as in multiple sclerosis (MS). In this review, we discuss recent findings on environmental factors influencing autoimmunity with an emphasis on the impact of 'Western diet' on immune homeostasis and gut microbiota in MS.


Assuntos
Meio Ambiente , Esclerose Múltipla/etiologia , Animais , Ácidos Graxos/efeitos adversos , Humanos , Linfócitos/imunologia , Esclerose Múltipla/imunologia , Fatores de Risco
20.
J Immunol ; 196(10): 4040-51, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27183637

RESUMO

A subset of human regulatory T cells (Tregs) can secrete IFN-γ or IL-17, and thus share features of TH1 or TH17 effector cells and lose suppressive function. The main factors driving this differentiation of Tregs toward a proinflammatory phenotype include IL-12 for TH1-like and IL-6 for TH17-type Tregs. In this study we show that Tregs of patients with de novo autoimmune hepatitis (dAIH) display increased frequencies of proinflammatory IFN-γ and IL-17 cytokines. Irrespective of a fully demethylated FOXP3 locus, Tregs of subjects with dAIH are functionally impaired. In line with the observed Treg phenotype, we detected the presence of two dominant cytokines (IL-12 and IL-6) clustering with CD68(+) monocyte/macrophage cells in livers of subjects with dAIH, and isolated monocytes of subjects with dAIH secrete high levels of proinflammatory IL-12 and IL-6, suggesting that this inflammatory milieu is key for functional impairment of Tregs. Importantly, the blockade of IFN-γ partially restores suppressive function of Tregs of subjects with dAIH, indicating that monocyte/macrophage-derived triggers might play a central role in Treg dysfunction and pathogenesis of dAIH.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Hepatite Autoimune/imunologia , Transplante de Fígado , Monócitos/imunologia , Complicações Pós-Operatórias/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Adolescente , Células Cultivadas , Criança , Citocinas/metabolismo , Metilação de DNA , Feminino , Fatores de Transcrição Forkhead/genética , Hepatite Autoimune/etiologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Transplante Homólogo
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