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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(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769011

RESUMO

This Special Issue aggregates several high-quality original articles written by renowned researchers [...].

3.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576307

RESUMO

In the era of personalized medicine, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index (BMI; 36.67 ± 6.90); 10 non-obese, non-atopic asthmatic adults with normal BMI (23.88 ± 2.73); and 10 healthy controls with normal BMI (23.62 ± 3.74). All asthmatic patients were considered to represent a low type-2 asthma phenotype according to selective clinical parameters. RNA sequencing (RNA-Seq) was conducted on peripheral blood CD4+ T cells. Thousands of differentially expressed genes were identified in both asthma groups compared with heathy controls. The expression of interferon (IFN)-stimulated genes associated with IFN-related signaling pathways was specifically affected in obese asthmatics, while the gap junction and G protein-coupled receptor (GPCR) ligand binding pathways were enriched in both asthma groups. Furthermore, obesity gene markers were also upregulated in CD4+ T cells from obese asthmatics compared with the two other groups. Additionally, the enriched genes of the three abovementioned pathways showed a unique correlation pattern with various laboratory and clinical parameters. The specific activation of IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in the development of new stratified therapeutic approaches.


Assuntos
Asma/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Interferons/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Adulto , Asma/complicações , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Receptores Acoplados a Proteínas G/metabolismo
5.
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
6.
J Allergy Clin Immunol ; 148(3): 843-857.e6, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33684437

RESUMO

BACKGROUND: Prenatal exposure to infections can modify immune development. These environmental disturbances during early life potentially alter the incidence of inflammatory disorders as well as priming of immune responses. Infection with the helminth Schistosoma mansoni is widely studied for its ability to alter immune responsiveness and is associated with variations in coinfection, allergy, and vaccine efficacy in endemic populations. OBJECTIVE: Exposure to maternal schistosomiasis during early life, even without transmission of infection, can result in priming effects on offspring immune responses to bystander antigenic challenges as related to allergic responsiveness and vaccination, with this article seeking to further clarify the effects and underlying immunologic imprinting. METHODS: Here, we have combined a model of chronic maternal schistosomiasis infection with a thorough analysis of subsequent offspring immune responses to allergy and vaccination models, including viral challenge and steady-state changes to immune cell compartments. RESULTS: We have demonstrated that maternal schistosomiasis alters CD4+ responses during allergic sensitization and challenge in a skewed IL-4/B-cell-dominant response to antigenic challenge associated with limited inflammatory response. Beyond that, we have uncovered previously unidentified alterations to CD8+ T-cell responses during immunization that are dependent on vaccine formulation and have functional impact on the efficacy of vaccination against viral infection in a murine hepatitis B virus model. CONCLUSION: In addition to steady-state modifications to CD4+ T-cell polarization and B-cell priming, we have traced these modified CD8+ responses to an altered dendritic cell phenotype sustained into adulthood, providing evidence for complex priming effects imparted by infection via fetomaternal cross talk.


Assuntos
Efeitos Tardios da Exposição Pré-Natal/imunologia , Hipersensibilidade Respiratória/imunologia , Esquistossomose/imunologia , Alérgenos/imunologia , Animais , Linfócitos B/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Feto/imunologia , Perfilação da Expressão Gênica , Imunização , Pulmão/imunologia , Linfonodos/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Gravidez , Hipersensibilidade Respiratória/genética , Schistosoma mansoni , Baço/imunologia , Linfócitos T/imunologia
7.
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
8.
Front Immunol ; 11: 2141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193294

RESUMO

Specific and adequate nutrition during pregnancy and early life is an important factor in avoiding non-communicable diseases such as obesity, type 2 diabetes, cardiovascular disease, cancers, and chronic allergic diseases. Although epidemiologic and experimental studies have shown that nutrition is important at all stages of life, it is especially important in prenatal and the first few years of life. During the last decade, there has been a growing interest in the potential role of epigenetic mechanisms in the increasing health problems associated with allergic disease. Epigenetics involves several mechanisms including DNA methylation, histone modifications, and microRNAs which can modify the expression of genes. In this study, we focus on the effects of maternal nutrition during pregnancy, the effects of the bioactive components in human and bovine milk, and the environmental factors that can affect early life (i.e., farming, milk processing, and bacterial exposure), and which contribute to the epigenetic mechanisms underlying the persistent programming of immune functions and allergic diseases. This knowledge will help to improve approaches to nutrition in early life and help prevent allergies in the future.


Assuntos
Asma/etiologia , Metilação de DNA , Hipersensibilidade/etiologia , Sistema Imunitário/crescimento & desenvolvimento , Leite Humano/imunologia , Leite/imunologia , Adulto , Animais , Asma/epidemiologia , Asma/genética , Asma/imunologia , Bovinos , Criança , Pré-Escolar , Exposição Ambiental , Fazendas , Ácidos Graxos Voláteis/farmacologia , Feminino , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Lactente , Recém-Nascido , Leite/química , Leite Humano/química , Oligossacarídeos/farmacologia , Prebióticos , Gravidez , Especificidade da Espécie
9.
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
10.
Hum Immunol ; 81(12): 709-713, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32883546

RESUMO

Dendritic cell toll-like receptors (TLRs) and the high-affinity immunoglobulin E (IgE) receptor (FcεRI) may biologically interact with regard to atopic dermatitis (AD) development and, especially, severity. Our aim here was to test if such interaction can be detected on the genetic level. The combined effect of the TLR2 gene (TLR2) rs4696480 and the FcεRI α-chain gene (FCER1A) rs2252226 and rs2251746 polymorphisms on the AD severity as measured by SCORAD was assessed. The FCER1A rs2252226 and TLR2 rs4696480 polymorphisms interacted with regard to SCORAD. Higher SCORAD was observed in patients being the TLR2 rs4696480 major homozygotes and carrying at the same time the FCER1A rs2252226 minor allele, compared to those characterized by (any other of) the remaining combined rs2252226 and rs4696480 genotypes. The observation of the epistatic effect of TLR2 and FCER1A genetic variants on SCORAD is in line with the involvement of the interaction TLRs-FcεRI in the pathophysiology of AD.


Assuntos
Dermatite Atópica/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgE/genética , Índice de Gravidade de Doença , Receptor 2 Toll-Like/genética , Adulto , Alelos , Estudos de Casos e Controles , Dermatite Atópica/sangue , Dermatite Atópica/epidemiologia , Dermatite Atópica/fisiopatologia , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Imunoglobulina E/sangue , Masculino , Polônia/epidemiologia , Regiões Promotoras Genéticas
11.
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
12.
Medicina (Kaunas) ; 56(9)2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32971918

RESUMO

We identified a novel splice site mutation of the PROS1 gene in a Polish family with protein S (PS) deficiency and explored the molecular pathogenesis of this previously undescribed variant. A novel mutation was detected in a 26-year-old woman with a history of venous thromboembolism (VTE) provoked by oral contraceptives. Her family history of VTE was positive. The sequence analysis of the PROS1 gene was performed in the proband and the proband's family. The proband and their asymptomatic father had lower free PS levels (45% and 50%, respectively) and PS activity (48% and 44%, respectively). Total PS levels were normal (65.6% and 62.4%, respectively). The sequence analysis of the PROS1 gene revealed the presence of heterozygous deletion at the nucleotide position c.602-2 in intron 6, just upstream of exon 7, detected in the proband and her father. This variant alters the splice acceptor site of exon 7, and, according to the in silico prediction, it is highly likely to cause in-frame exon 7 skipping. We also presented follow-up data of two other Polish patients with PS deficiency associated with splice site mutations in PROS1 gene.


Assuntos
Sítios de Splice de RNA , Tromboembolia Venosa , Adulto , Éxons/genética , Feminino , Humanos , Íntrons/genética , Mutação , Polônia , Proteína S , Sítios de Splice de RNA/genética , Tromboembolia Venosa/genética
13.
Front Immunol ; 11: 756, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425942

RESUMO

Background: Epigenetic changes in response to allergen exposure are still not well understood. The aim of this study was to evaluate histone acetylation levels in peripheral blood leukocytes from humans naturally infected by intestinal parasites and perennially exposed to house dust mites (HDM). Methods: Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation from 20 infected and 21 non-infected individuals living in a rural/village in Colombia. Histone 3 acetylation (H3Ac) and histone 4 acetylation (H4Ac) levels were measured in six immune genes previously associated with helminth immunity by chromatin immunoprecipitation (ChIP)-quantitative PCR. Then we analyzed the association between histone acetylation levels with total parasite egg burden and IgE levels. Results: We found an inverse correlation between H4Ac levels in the IL13 gene and egg worm burden that remained significant after adjustment by age [-0.20 (-0.32 to -0.09), p < 0.0001]. Moreover, we found significant associations between H4Ac levels in IL4 [0.32 (0.05-0.60), p = 0.02] and CHI3L1 [0.29 (0.08-0.51), p = 0.008] with the IgE levels to Ascaris lumbricoides. In addition, the levels of specific IgE antibodies to HDM were associated with H4Ac levels in the gene TNFSF13B encoding the B cell activating factor (BAFF) [0.51 (0.26-0.76), p < 0.001]. All values are presented as beta (95% CI). Conclusion: Histone acetylation levels at key type-2 immune genes in humans were modified by nematode infection and HDM allergens and are associated with the intensity of the IgE response.


Assuntos
Anticorpos Anti-Helmínticos/imunologia , Antígenos de Dermatophagoides/imunologia , Ascaríase/imunologia , Ascaris/imunologia , Fator Ativador de Células B/genética , Proteína 1 Semelhante à Quitinase-3/genética , Histonas/metabolismo , Imunoglobulina E/imunologia , Interleucina-4/genética , Pyroglyphidae/imunologia , Acetilação , Adolescente , Adulto , Animais , Ascaríase/sangue , Ascaríase/epidemiologia , Ascaríase/parasitologia , Criança , Pré-Escolar , Estudos de Coortes , Colômbia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Dis Markers ; 2020: 7190828, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32076463

RESUMO

Aims: Fibrin formation and histidine-rich glycoprotein (HRG) are involved in primary hemostasis and wound healing. Little is known regarding the relationship of clot characteristics, bleeding time, and wound healing. Methods and Results: We studied 154 patients with coronary artery disease (CAD) and 154 subjects free of CAD matched for age, obesity, and current smoking. We evaluated bleeding time (BT) using standardized skin incisions on a forearm, along with plasma clot permeability (K s), clot lysis time (CLT), and histidine-rich glycoprotein (HRG). Compared with controls, BT was 45% shorter in CAD cases. CAD patients had 32% lower K s), clot lysis time (CLT), and histidine-rich glycoprotein (HRG). Compared with controls, BT was 45% shorter in CAD cases. CAD patients had 32% lower p < 0.001). After adjusting for potential confounders, K s), clot lysis time (CLT), and histidine-rich glycoprotein (HRG). Compared with controls, BT was 45% shorter in CAD cases. CAD patients had 32% lower n = 79, 25.6%) was independently predicted by both short and prolonged BT in CAD cases (OR 21.87, 95% CI 7.41-64.55 and OR 10.17, 95% CI 2.88-35.97) and controls (OR 5.94, 95% CI 2.29-15.41 and OR 14.76, 95% CI 4.29-50.77, respectively). Conclusions: The study shows that plasma fibrin clot density and HRG may influence BT and that appropriate skin wound healing is associated with medium BT. Translational Perspective. Elucidation of the complex relationships between plasma fibrin clot phenotype and wound healing might have important practical implications.


Assuntos
Doença da Artéria Coronariana/metabolismo , Fibrina/metabolismo , Proteínas/metabolismo , Idoso , Tempo de Sangramento , Estudos de Casos e Controles , Feminino , Tempo de Lise do Coágulo de Fibrina , Humanos , Masculino , Pessoa de Meia-Idade , Cicatrização
15.
Cell Signal ; 69: 109523, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31904412

RESUMO

The term (bronchial) asthma describes a disorder syndrome that comprises several disease phenotypes, all characterized by chronic inflammation in the bronchial epithelium, with a variety of subsequent functional consequences. Thus, the epithelium in the conducting airways is the main localization of the complex pathological changes in the disease. In this regard, bronchial epithelial cells are not passively affected by inflammatory mechanisms induced by immunological processes but rather actively involved in all steps of disease development from initiation and perpetuation to chronification. In recent years it turned out that bronchial epithelial cells show a high level of structural and functional diversity and plasticity with epigenetic mechanisms playing a crucial role in the regulation of these processes. Thus, it is quite reasonable that differential functional activities of the bronchial epithelium are involved in the development of different asthma phenotypes and/or stages of disease. The current knowledge on this topic will be discussed in this review article.


Assuntos
Asma , Brônquios , Células Epiteliais , Inflamação , Animais , Asma/metabolismo , Asma/patologia , Brônquios/metabolismo , Brônquios/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio/metabolismo , Epitélio/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia
16.
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
17.
Biomedicines ; 9(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396395

RESUMO

Allergic mechanisms are likely involved in atherosclerosis and its clinical presentations, such as coronary artery disease (CAD). It has been previously reported that CAD severity associates with serum levels of immunoglobulin E (IgE), the molecule that, along with its high-affinity receptor (FcԑRI), plays a central role in allergic reactions. Considering multiple pathophysiological similarities between atherosclerosis and acquired aortic (valve) stenosis (AS), we speculated that allergic pathways could also contribute to the AS mechanisms and grading. To validate this hypothesis, we first checked whether total serum IgE levels associate with echocardiographic markers of AS severity. Having found a positive correlation between serum IgE and aortic valve area (AVA), we further speculated that also total IgE-determining genetic polymorphisms in FCER1A, a locus encoding an allergen-biding FcԑRI subunit, are related to acquired AS severity. Indeed, the major allele of rs2251746 polymorphism, known to associate with higher IgE levels, turned out to correlate with larger AVA, a marker of less severe AS. Our findings surprisingly suggest a protective role of IgE pathways against AS progression. IgE-mediated protective mechanisms in AS require further investigations.

18.
Nutrients ; 11(8)2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349704

RESUMO

Epidemiological studies identified raw cow's milk consumption as an important environmental exposure that prevents allergic diseases. In the present study, we investigated whether raw cow's milk has the capacity to induce tolerance to an unrelated, non-milk, food allergen. Histone acetylation of T cell genes was investigated to assess potential epigenetic regulation. Female C3H/HeOuJ mice were sensitized and challenged to ovalbumin. Prior to sensitization, the mice were treated with raw milk, processed milk, or phosphate-buffered saline for eight days. Allergic symptoms were assessed after challenge and histone modifications in T cell-related genes of splenocyte-derived CD4+ T cells and the mesenteric lymph nodes were analyzed after milk exposure and after challenge. Unlike processed milk, raw milk decreased allergic symptoms. After raw milk exposure, histone acetylation of Th1-, Th2-, and regulatory T cell-related genes of splenocyte-derived CD4+ T cells was higher than after processed milk exposure. After allergy induction, this general immune stimulation was resolved and histone acetylation of Th2 genes was lower when compared to processed milk. Raw milk reduces allergic symptoms to an unrelated, non-milk, food allergen in a murine model for food allergy. The activation of T cell-related genes could be responsible for the observed tolerance induction, which suggested that epigenetic modifications contribute to the allergy-protective effect of raw milk.


Assuntos
Montagem e Desmontagem da Cromatina , Epigênese Genética , Hipersensibilidade Alimentar/dietoterapia , Histonas/metabolismo , Tolerância Imunológica , Ativação Linfocitária , Leite/imunologia , Subpopulações de Linfócitos T/metabolismo , Acetilação , Animais , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Camundongos Endogâmicos C3H , Ovalbumina , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
19.
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
20.
Allergol Int ; 68(4): 450-455, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31064688

RESUMO

BACKGROUND: Given increased risk of cardiovascular events in asthma we hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme involved in atherosclerosis, is associated with proinflammatory and prothrombotic blood alterations in this disease. METHODS: In 164 adult asthmatics (63 with severe asthma) we measured plasma Lp-PLA2 activity using the PLAC test. We determined its relations to inflammation and prothrombotic blood alterations. RESULTS: In asthma, Lp-PLA2 was inversely related to the age (ß = -0.1 [-0.18 to -0.02]) and was lower in women (n = 122 [74%], 205 [182-242] vs. 243 [203-262] nmol/min/ml, p = 0.001). Interestingly, Lp-PLA2 correlated negatively with the asthma severity score (ß = -0.15 [-0.23 to -0.07]), being 10.3% higher in those with non-severe (mild or moderate) asthma (n = 101, 62%) as compared to the severe disease subtype (224 [191-261] vs. 203 [181-229], p = 0.006 after adjustment for potential confounders). Lp-PLA2 activity was positively related to the levels of low-density lipoprotein (ß = 0.1 [0.02-0.18]), triglycerides (ß = 0.11 [0.03-0.19]) and glucose (ß = 0.1 [0.02-0.18]) and inversely to the tumor necrosis factor α (ß = -0.27 [-0.35 to -0.2]), high sensitivity C-reactive protein (ß = -0.1 [-0.19 to -0.02]) and fibrinogen (ß = -0.12 [-0.21 to -0.03]), as well as prothrombin (ß = -0.16 [-0.24 to -0.08]), and parameters describing thrombin generation potential, such as endogenous thrombin potential (ß = -0.14 [-0.21 to -0.06]) and peak thrombin generated (ß = -0.2 [-0.28 to -0.12]). CONCLUSIONS: Elevated Lp-PLA2 activity in non-severe asthmatics suggests increased atherosclerotic risk in this group. Lower Lp-PLA2 activity accompanied by its inverse relationship to inflammatory or prothrombotic blood biomarkers observed in turn in severe asthmatics might be related to the pathogenesis of more severe asthma phenotype.


Assuntos
Antígenos de Plaquetas Humanas/metabolismo , Asma/imunologia , Asma/metabolismo , Adulto , Idoso , Asma/diagnóstico , Asma/tratamento farmacológico , Biomarcadores , Ativação Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
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