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1.
Handb Exp Pharmacol ; 268: 331-357, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34223997

RESUMO

There has been a substantial increase in the incidence and the prevalence of allergic disorders in the recent decades, which seems to be related to rapid environmental and lifestyle changes, such as higher exposure to factors thought to exert pro-allergic effects but less contact with factors known to be associated with protection against the development of allergies. Pollution is the most remarkable example of the former, while less contact with microorganisms, lower proportion of unprocessed natural products in diet, and others resulting from urbanization and westernization of the lifestyle exemplify the latter. It is strongly believed that the effects of environmental factors on allergy susceptibility and development are mediated by epigenetic mechanisms, i.e. biologically relevant biochemical changes of the chromatin carrying transcriptionally-relevant information but not affecting the nucleotide sequence of the genome. Classical epigenetic mechanisms include DNA methylation and histone modifications, for instance acetylation or methylation. In addition, microRNA controls gene expression at the mRNA level. Such epigenetic mechanisms are involved in crucial regulatory processes in cells playing a pivotal role in allergies. Those include centrally managing cells, such as T lymphocytes, as well as specific structural and effector cells in the affected organs, responsible for the local clinical presentation of allergy, e.g. epithelial or airway smooth muscle cells in asthma. Considering that allergic disorders possess multiple clinical (phenotypes) and mechanistic (endotypes) forms, targeted, stratified treatment strategies based on detailed clinical and molecular diagnostics are required. Since conventional diagnostic or therapeutic approaches do not suffice, this gap could possibly be filled out by epigenetic approaches.


Assuntos
Asma , Hipersensibilidade , Metilação de DNA , Epigênese Genética , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/genética , Hipersensibilidade/prevenção & controle , Processamento de Proteína Pós-Traducional
2.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067156

RESUMO

Extracellular vesicles (EVs) are membranous structures, which are secreted by almost every cell type analyzed so far. In addition to their importance for cell-cell communication under physiological conditions, EVs are also released during pathogenesis and mechanistically contribute to this process. Here we summarize their functional relevance in asthma, one of the most common chronic non-communicable diseases. Asthma is a complex persistent inflammatory disorder of the airways characterized by reversible airflow obstruction and, from a long-term perspective, airway remodeling. Overall, mechanistic studies summarized here indicate the importance of different subtypes of EVs and their variable cargoes in the functioning of the pathways underlying asthma, and show some interesting potential for the development of future therapeutic interventions. Association studies in turn demonstrate a good diagnostic potential of EVs in asthma.


Assuntos
Asma/metabolismo , Vesículas Extracelulares/metabolismo , Animais , Asma/genética , Asma/microbiologia , Asma/fisiopatologia , Biomarcadores/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos
3.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671836

RESUMO

NKp30 (Natural Cytotoxicity Receptor 1, NCR1) is a powerful cytotoxicity receptor expressed on natural killer (NK) cells which is involved in tumor cell killing and the regulation of antitumor immune responses. Ligands for NKp30, including BAG6 and B7-H6, are upregulated in virus-infected and tumor cells but rarely detectable on healthy cells. These ligands are released by tumor cells as part of the cellular secretome and interfere with NK cell activity. BAG6 is secreted via the exosomal pathway, and BAG6-positive extracellular vesicles (EV-BAG6) trigger NK cell cytotoxicity and cytokine release, whereas the soluble protein diminishes NK cell activity. However, the extracellular format and activity of B7-H6 remain elusive. Here, we used HEK293 as a model cell line to produce recombinant ligands and to study their impact on NK cell activity. Using this system, we demonstrate that soluble B7-H6 (sB7-H6), like soluble BAG6 (sBAG6), inhibits NK cell-mediated target cell killing. This was associated with a diminished cell surface expression of NKG2D and NCRs (NKp30, NKp40, and NKp46). Strikingly, a reduced NKp30 mRNA expression was observed exclusively in response to sBAG6. Of note, B7-H6 was marginally released in association with EVs, and EVs collected from B7-H6 expressing cells did not stimulate NK cell-mediated killing. The molecular analysis of EVs on a single EV level using nano flow cytometry (NanoFCM) revealed a similar distribution of vesicle-associated tetraspanins within EVs purified from wildtype, BAG6, or B7-H6 overexpressing cells. NKp30 is a promising therapeutic target to overcome NK cell immune evasion in cancer patients, and it is important to unravel how extracellular NKp30 ligands inhibit NK cell functions.


Assuntos
Antígenos B7/metabolismo , Chaperonas Moleculares/metabolismo , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Antígenos B7/genética , Vesículas Extracelulares/metabolismo , Células HEK293 , Humanos , Integrina beta1/metabolismo , Células K562 , Células Matadoras Naturais/metabolismo , Ligantes , Chaperonas Moleculares/genética , Receptor 3 Desencadeador da Citotoxicidade Natural/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Evasão Tumoral
4.
Nutrients ; 13(3)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668787

RESUMO

Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.


Assuntos
Epigênese Genética/imunologia , Hipersensibilidade , Fenômenos Fisiológicos da Nutrição do Lactente , Fenômenos Fisiológicos da Nutrição Materna , Feminino , Humanos , Recém-Nascido , Gravidez
5.
Nutrients ; 12(10)2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33086571

RESUMO

Immunoglobulin E (IgE)-mediated allergy against cow's milk protein fractions such as whey is one of the most common food-related allergic disorders of early childhood. Histone acetylation is an important epigenetic mechanism, shown to be involved in the pathogenesis of allergies. However, its role in food allergy remains unknown. IgE-mediated cow's milk allergy was successfully induced in a mouse model, as demonstrated by acute allergic symptoms, whey-specific IgE in serum, and the activation of mast cells upon a challenge with whey protein. The elicited allergic response coincided with reduced percentages of regulatory T (Treg) and T helper 17 (Th17) cells, matching decreased levels of H3 and/or H4 histone acetylation at pivotal Treg and Th17 loci, an epigenetic status favoring lower gene expression. In addition, histone acetylation levels at the crucial T helper 1 (Th1) loci were decreased, most probably preceding the expected reduction in Th1 cells after inducing an allergic response. No changes were observed for T helper 2 cells. However, increased histone acetylation levels, promoting gene expression, were observed at the signal transducer and activator of transcription 6 (Stat6) gene, a proallergic B cell locus, which was in line with the presence of whey-specific IgE. In conclusion, the observed histone acetylation changes are pathobiologically in line with the successful induction of cow's milk allergy, to which they might have also contributed mechanistically.


Assuntos
Histonas/metabolismo , Imunoglobulina E/imunologia , Hipersensibilidade a Leite/imunologia , Células Th1 , Acetilação , Animais , Linfócitos B/imunologia , Modelos Animais de Doenças , Epigenômica , Feminino , Expressão Gênica , Imunoglobulina E/sangue , Mastócitos/imunologia , Camundongos Endogâmicos C3H , Hipersensibilidade a Leite/genética , Fator de Transcrição STAT6 , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Soro do Leite/imunologia
6.
Int J Mol Sci ; 21(19)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022971

RESUMO

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor-stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor-stroma interactions will one day lead to a significant advancement in patient care.


Assuntos
Adenocarcinoma/imunologia , Carcinoma Ductal Pancreático/imunologia , Microambiente Tumoral/imunologia , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Humanos , Imunoterapia
7.
Front Immunol ; 11: 1747, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973742

RESUMO

Asthma is a chronic inflammatory disease of the respiratory tract characterized by recurrent breathing problems resulting from airway obstruction and hyperresponsiveness. Human airway epithelium plays an important role in the initiation and control of the immune responses to different types of environmental factors contributing to asthma pathogenesis. Using pattern recognition receptors airway epithelium senses external stimuli, such as allergens, microbes, or pollutants, and subsequently secretes endogenous danger signaling molecules alarming and activating dendritic cells. Hence, airway epithelial cells not only mediate innate immune responses but also bridge them with adaptive immune responses involving T and B cells that play a crucial role in the pathogenesis of asthma. The effects of environmental factors on the development of asthma are mediated, at least in part, by epigenetic mechanisms. Those comprise classical epigenetics including DNA methylation and histone modifications affecting transcription, as well as microRNAs influencing translation. The common feature of such mechanisms is that they regulate gene expression without affecting the nucleotide sequence of the genomic DNA. Epigenetic mechanisms play a pivotal role in the regulation of different cell populations involved in asthma pathogenesis, with the remarkable example of T cells. Recently, however, there is increasing evidence that epigenetic mechanisms are also crucial for the regulation of airway epithelial cells, especially in the context of epigenetic transfer of environmental effects contributing to asthma pathogenesis. In this review, we summarize the accumulating evidence for this very important aspect of airway epithelial cell pathobiology.


Assuntos
Asma/genética , Asma/imunologia , Epigênese Genética , Células Epiteliais/imunologia , Pulmão/imunologia , Acetilação , Animais , Asma/metabolismo , Asma/fisiopatologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstrição , Metilação de DNA , Células Epiteliais/metabolismo , Histonas/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , MicroRNAs/genética , MicroRNAs/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais
8.
Curr Opin Allergy Clin Immunol ; 20(1): 48-55, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31633569

RESUMO

PURPOSE OF REVIEW: Epigenetic mechanisms are known to play a crucial role in the pathogenesis of asthma, allergic rhinitis, atopic dermatitis, food allergy, and other allergic disorders, especially through mediating the effects of the environmental factors, well recognized allergy-risk modifiers. The aim of this work was to provide a concise but comprehensive review of the recent progress in the epigenetics of allergic diseases. RECENT FINDINGS: Recent few years have substantially expanded our knowledge on the role of epigenetics in the pathogenesis and clinical picture of allergies. Specifically, it has been shown that epigenetic marks, especially DNA methylation, possess a diagnostic potential for atopic sensitization, asthma, allergic rhinitis, and food allergy. DNA methylation can be a predictor of clinical responses in controlled allergen challenges, including oral food challenges. Furthermore, direct or indirect targeting epigenetic mechanisms, this time especially histone modifications, was able to favorably affect expression of the genes underlying allergies and generally improve airway biology in allergic diseases or their animal models. SUMMARY: Further studies are needed to explore the diagnostic and therapeutic potential of epigenetic modifications in allergies and to develop respective clinical tools.


Assuntos
Asma/genética , Hipersensibilidade/genética , Alérgenos/imunologia , Animais , Asma/diagnóstico , Biomarcadores , Metilação de DNA , Epigênese Genética , Histonas/metabolismo , Humanos , Hipersensibilidade/diagnóstico , Processamento de Proteína Pós-Traducional
9.
Biomed Res Int ; 2019: 1315257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31111043

RESUMO

Prenatal environmental exposures are considered to contribute to the development of allergic sensitization by epigenetic mechanisms. The role of histone acetylation in the placenta has not been examined yet. We hypothesized that placental histone acetylation at the promoter regions of allergy-related immune regulatory genes is associated with the development of sensitization to allergens in the child. Histones H3 and H4 acetylation at the promoter regions of 6 selected allergy-related immune regulatory genes was assessed by a chromatin immunoprecipitation assay in 173 term placentas collected in the prospective birth-cohort ALADDIN. The development of IgE sensitization to allergens in the children was followed from 6 months up to 5 years of age. We discovered significant associations of histone acetylation levels with decreased risk of allergic sensitization in 3 genes. Decreased risk of sensitization to food allergens was associated with higher H3 acetylation levels in placentas at the IFNG and SH2B3 genes, and for H4 acetylation in HDAC4. Higher HDAC4 H4 acetylation levels were also associated with a decreased risk of sensitization to aeroallergens. In conclusion, our results suggest that acetylation of histones in placenta has a potential to predict the development of sensitization to allergens in children.


Assuntos
Hipersensibilidade Alimentar/genética , Histona Desacetilases/genética , Interferon gama/genética , Proteínas/genética , Proteínas Repressoras/genética , Acetilação , Proteínas Adaptadoras de Transdução de Sinal , Alérgenos/efeitos adversos , Pré-Escolar , Cromatina/genética , Epigênese Genética/genética , Epigênese Genética/imunologia , Feminino , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/patologia , Histona Desacetilases/imunologia , Histonas/genética , Histonas/imunologia , Humanos , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Lactente , Recém-Nascido , Interferon gama/imunologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Placenta/imunologia , Placenta/patologia , Gravidez , Regiões Promotoras Genéticas/genética , Proteínas/imunologia , Proteínas Repressoras/imunologia
10.
Int J Mol Sci ; 20(5)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823645

RESUMO

Maternal diet modifies epigenetic programming in offspring, a potentially critical factor in the immune dysregulation of modern societies. We previously found that prenatal fish oil supplementation affects neonatal T-cell histone acetylation of genes implicated in adaptive immunity including PRKCZ, IL13, and TBX21. In this study, we measured H3 and H4 histone acetylation levels by chromatin immunoprecipitation in 173 term placentas collected in the prospective birth cohort, ALADDIN, in which information on lifestyle and diet is thoroughly recorded. In anthroposophic families, regular olive oil usage during pregnancy was associated with increased H3 acetylation at FOXP3 (p = 0.004), IL10RA (p = 0.008), and IL7R (p = 0.007) promoters, which remained significant after adjustment by offspring gender. Furthermore, maternal fish consumption was associated with increased H4 acetylation at the CD14 gene in placentas of female offspring (p = 0.009). In conclusion, prenatal olive oil intake can affect placental histone acetylation in immune regulatory genes, confirming previously observed pro-acetylation effects of olive oil polyphenols. The association with fish consumption may implicate ω-3 polyunsaturated fatty acids present in fish oil. Altered histone acetylation in placentas from mothers who regularly include fish or olive oil in their diets could influence immune priming in the newborn.


Assuntos
Óleos de Peixe/farmacologia , Histonas/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Azeite de Oliva/farmacologia , Placenta/metabolismo , Processamento de Proteína Pós-Traducional , Acetilação , Feminino , Óleos de Peixe/administração & dosagem , Óleos de Peixe/metabolismo , Produtos Pesqueiros , Humanos , Imunidade Inata/genética , Interleucina-13/genética , Interleucina-13/metabolismo , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Azeite de Oliva/administração & dosagem , Placenta/efeitos dos fármacos , Gravidez , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
11.
J Allergy Clin Immunol ; 143(4): 1403-1415, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30114391

RESUMO

BACKGROUND: Infections with human rhinoviruses (RVs) are responsible for millions of common cold episodes and the majority of asthma exacerbations, especially in childhood. No drugs specifically targeting RVs are available. OBJECTIVE: We sought to identify specific anti-RV molecules based on DNAzyme technology as candidates to a clinical study. METHODS: A total of 226 candidate DNAzymes were designed against 2 regions of RV RNA genome identified to be sufficiently highly conserved between virus strains (ie, the 5'-untranslated region and cis-acting replication element) by using 3 test strains: RVA1, RVA16, and RVA29. All DNAzymes were screened for their cleavage efficiency against in vitro-expressed viral RNA. Those showing any catalytic activity were subjected to bioinformatic analysis of their reverse complementarity to 322 published RV genomic sequences. Further molecular optimization was conducted for the most promising candidates. Cytotoxic and off-target effects were excluded in HEK293 cell-based systems. Antiviral efficiency was analyzed in infected human bronchial BEAS-2B cells and ex vivo-cultured human sinonasal tissue. RESULTS: Screening phase-generated DNAzymes characterized by either good catalytic activity or by high RV strain coverage but no single molecule represented a satisfactory combination of those 2 features. Modifications in length of the binding domains of 2 lead candidates, Dua-01(-L12R9) and Dua-02(-L10R11), improved their cleavage efficiency to an excellent level, with no loss in eminent strain coverage (about 98%). Both DNAzymes showed highly favorable cytotoxic/off-target profiles. Subsequent testing of Dua-01-L12R9 in BEAS-2B cells and sinonasal tissue demonstrated its significant antiviral efficiency. CONCLUSIONS: Effective and specific management of RV infections with Dua-01-L12R9 might be useful in preventing asthma exacerbations, which should be verified by clinical trials.


Assuntos
Antivirais/farmacologia , DNA Catalítico/farmacologia , RNA Viral/efeitos dos fármacos , Rhinovirus , Replicação Viral/efeitos dos fármacos , Resfriado Comum/prevenção & controle , Descoberta de Drogas , Humanos
12.
J Allergy Clin Immunol ; 142(3): 804-814, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29132960

RESUMO

BACKGROUND: The hygiene hypothesis is the leading concept to explain the current asthma epidemic, which is built on the observation that a lack of bacterial contact early in life induces allergic TH2 immune responses. OBJECTIVE: Because little is known about the contribution of respiratory tract viruses in this context, we evaluated the effect of prior influenza infection on the development of allergic asthma. METHODS: Mice were infected with influenza and, once recovered, subjected to an ovalbumin- or house dust mite-induced experimental asthma protocol. Influenza-polarized effector memory T (Tem) cells were transferred adoptively to allergen-sensitized animals before allergen challenge. A comprehensive in silico analysis assessed homologies between virus- and allergen-derived proteins. Influenza-polarized Tem cells were stimulated ex vivo with candidate peptides. Mice were immunized with a pool of virus-derived T-cell epitopes. RESULTS: In 2 murine models we found a long-lasting preventive effect against experimental asthma features. Protection could be attributed about equally to CD4+ and CD8+ Tem cells from influenza-infected mice. An in silico bioinformatic analysis identified 4 influenza- and 3 allergen-derived MHC class I and MHC class II candidate T-cell epitopes with potential antigen-specific cross-reactivity between influenza and allergens. Lymphocytes from influenza-infected mice produced IFN-γ and IL-2 but not IL-5 on stimulation with the aforementioned peptides. Immunization with a mixture of the influenza peptides conferred asthma protection, and peptide-immunized mice transferred protection through CD4+ and CD8+ Tem cells. CONCLUSION: For the first time, our results illustrate heterologous immunity of virus-infected animals toward allergens. This finding extends the original hygiene hypothesis.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Vírus da Influenza A Subtipo H1N1/metabolismo , Infecções por Orthomyxoviridae/imunologia , Peptídeos/imunologia , Animais , Epitopos de Linfócito T/imunologia , Feminino , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Pyroglyphidae/imunologia , Linfócitos T/imunologia
13.
Curr Opin Pediatr ; 28(6): 754-763, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27662207

RESUMO

PURPOSE OF REVIEW: The goal of this review was to systematically analyze recent studies updating our knowledge on the role of epigenetic mechanisms in childhood asthma. RECENT FINDINGS: A systematic literature search was conducted that identified 23 fresh articles published within the last 5 years reporting the results of human studies on the relationships between epigenetic modifications and childhood asthma or its/related phenotypes. In almost all these studies, meaningful associations between levels of epigenetic marks (DNA methylation and/or histone modifications) and pediatric asthma or its/related phenotypes have been observed. In addition, many studies identified by our screening analyzed those associations in the context of environmental factors, such as pollution, tobacco smoke, farming, or diet, showing in a huge majority a modifying effect of those exposures. SUMMARY: The results of our systematic literature search provide a strong support for the role of epigenetic mechanisms in (mediating the effects of environmental exposure on) pediatric asthma. This knowledge may possibly be translated into diagnostic and/or therapeutic approaches.


Assuntos
Asma/genética , Epigênese Genética , Criança , Metilação de DNA , Interação Gene-Ambiente , Código das Histonas , Humanos , Fenótipo , Fatores de Risco
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