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Atopic dermatitis, or eczema, is the most common chronic skin disorder, characterized by red and pruritic lesions. Its etiology is multifaceted, involving an interplay of factors, such as the allergic immune response, skin barrier dysfunction, and dysbiosis of the skin microbiota. Recent studies have explored the role of extracellular vesicles (EVs), which are lipid bilayer-delimitated particles released by all cells, in atopic dermatitis. Examination of the available literature identified that most studies investigated EVs released by Staphylococcus aureus, which were found to impact the skin barrier and promote the release of cytokines that contribute to atopic dermatitis development. In addition, EVs released by the skin fungus, Malassezia sympodialis, were found to contain allergens, suggesting a potential contribution to allergic sensitization via the skin. The final major finding was the role of EVs released by mast cells, which were capable of activating various immune cells and attenuating the allergic response. While research in this area is still in its infancy, the studies examined in this review provide encouraging insights into how EVs released from a variety of cells play a role in both contributing to and protecting against atopic dermatitis. [ABSTRACT FROM AUTHOR]

The first nine months from conception to birth involves greater changes than at any other time in life, affecting organogenesis, endocrine, metabolic and immune programming. It has led to the concept that the "first 1000 days" from conception to the second birthday are critical in establishing long term health or susceptibility to disease. Immune ontogeny is predominantly complete within that time and is influenced by the maternal genome, health, diet and environment pre-conception and during pregnancy and lactation. Components of the immunological protection of the pregnancy is the generation of Th-2 and T-regulatory cytokines with the consequence that neonatal adaptive responses are also biased towards Th-2 (allergy promoting) and T-regulatory (tolerance promoting) responses. Normally after birth Th-1 activity increases while Th-2 down-regulates and the evolving normal human microbiome likely plays a key role. This in turn will have been affected by maternal health, diet, exposure to antibiotics, mode of delivery, and breast or cow milk formula feeding. Complex gene/environment interactions affect outcomes. Many individual nutrients affect immune mechanisms and variations in levels have been associated with susceptibility to allergic disease. However, intervention trials employing single nutrient supplementation to prevent allergic disease have not achieved the expected outcomes suggested by observational studies. Investigation of overall dietary practices including fresh fruit and vegetables, fish, olive oil, lower meat intake and home cooked foods as seen in the Mediterranean and other healthy diets have been associated with reduced prevalence of allergic disease. This suggests that the "soup" of overall nutrition is more important than individual nutrients and requires further investigation both during pregnancy and after the infant has been weaned. Amongst all the potential factors affecting allergy outcomes, modification of maternal and infant nutrition and the microbiome are easier to employ than changing other aspects of the environment but require large controlled trials before recommending changes to current practice. [ABSTRACT FROM AUTHOR]

One third of all toddlers are in need of medical care because of acute wheeze and many of these children have persistent asthma at school age. Our aims were to assess risk factors for and the prevalence of asthma at age 7 in a cohort of children suffering from an acute wheezing episode as toddlers. A total of 113 children, included during an acute wheezing episode (cases), and 54 healthy controls were followed prospectively from early pre-school age to 7 years. The protocol included questionnaires, ACT, FeNO, nasopharyngeal virus samples, blood sampling for cell count, vitamin D levels, and IgE to food and airborne allergens. The prevalence of asthma at age 7 was 70.8% among cases and 1.9% among controls (p < 0.001). Acute wheeze caused by rhinovirus (RV) infection at inclusion was more common among cases with asthma at age 7 compared to cases without asthma (p = 0.011) and this association remained significant following adjustment for infection with other viruses (OR 3.8, 95% CI 1.4–10.5). Cases with asthma at age 7 had been admitted to hospital more often (p = 0.024) and spent more days admitted (p = 0.01) during the year following inclusion compared to cases without asthma. RV infection stands out as the main associated factor for wheeze evolving to persistent asthma. Cases who developed asthma also had an increased need of hospital time and care for wheeze during the year after inclusion. [ABSTRACT FROM AUTHOR]

Early-life nutrition is an important modifiable determinant in the development of a child's immune system, and may thereby influence the risk of allergic sensitization and atopic diseases. However, associations between overall dietary patterns and atopic diseases in childhood remain unclear. We examined associations of diet quality in early life with allergic sensitization, self-reported physician-diagnosed inhalant and food allergies, eczema, and asthma among 5225 children participating in a population-based cohort in the Netherlands. Diet was assessed during pregnancy, infancy, and childhood using validated food-frequency questionnaires. We calculated food-based diet quality scores (0-10 or 0-15), reflecting adherence to dietary guidelines. At age 10 years, allergic sensitization was assessed with skin prick tests. Information on physician-diagnosed inhalant and food allergies, eczema, and asthma was obtained with questionnaires. We observed no associations between diet quality during pregnancy and allergic sensitization (odds ratio (OR) = 1.05 per point in the diet score, 95% confidence interval (CI): 0.99,1.13), allergies (0.96, 95% CI: 0.88,1.04), eczema (0.99,95% CI: 0.93, 1.06), or asthma (0.93,95% CI: 0.85,1.03) in childhood. Also, diet quality in infancy or childhood were not associated with atopic outcomes in childhood. Our findings do not support our hypothesis that a healthy dietary pattern in early life is associated with a lower risk of allergic sensitization or atopic diseases in childhood. [ABSTRACT FROM AUTHOR]

Since the discovery that Der p 1 is a cysteine protease, the role of proteolytic activity in allergic sensitization has been explored. There are many allergens with proteolytic activity; however, exposure from dust mites is not limited to allergens. In this paper, genomic, transcriptomic and proteomic data on Dermatophagoides pteronyssinus (DP) was mined for information regarding the complete degradome of this house dust mite. D. pteronyssinus has more proteases than the closely related Acari, Dermatophagoides farinae (DF) and Sarcoptes scabiei (SS). The group of proteases in D. pteronyssinus is found to be more highly transcribed than the norm for this species. The distribution of protease types is dominated by the cysteine proteases like Der p 1 that account for about half of protease transcription by abundance, and Der p 1 in particular accounts for 22% of the total protease transcripts. In an analysis of protease stability, the group of allergens (Der p 1, Der p 3, Der p 6, and Der p 9) is found to be more stable than the mean. It is also statistically demonstrated that the protease allergens are simultaneously more highly expressed and more stable than the group of D. pteronyssinus proteases being examined, consistent with common assumptions about allergens in general. There are several significant non-allergen outliers from the normal group of proteases with high expression and high stability that should be examined for IgE binding. This paper compiles the first holistic picture of the D. pteronyssinus degradome to which humans may be exposed. [ABSTRACT FROM AUTHOR]

The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform's higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization. [ABSTRACT FROM AUTHOR]

Allergies arise from aberrant T helper type 2 responses to allergens. Several respiratory allergens possess proteolytic activity, which has been recognized to act as an adjuvant for the development of a Th2 response. Allergen source-derived proteases can activate the protease-activated receptor-2, have specific effects on immune cells by cleaving cell membrane-bound regulatory molecules, and can disrupt tight junctions. The protease activity can induce a non-allergen-specific inflammatory response in the airways, which will set the stage for an allergen-specific Th2 response. In this review, we will discuss the evidence for the induction of oxidative stress as an underlying mechanism in Th2 sensitization to proteolytic allergens. We will discuss recent data linking the proteolytic activity of an allergen to its potential to induce oxidative stress and how this can facilitate allergic sensitization. Based on experimental data, we propose that a less proficient anti-oxidant response to allergen-induced oxidative stress contributes to the susceptibility to allergic sensitization. Besides the effect of oxidative stress on the immune response, we will also discuss how oxidative stress can increase the immunogenicity of an allergen by chemical modification. [ABSTRACT FROM AUTHOR]

This study aimed to explore associations between non-cholesterol sterol concentrations in breast milk and allergic outcomes in children aged two. Data from the KOALA Birth Cohort Study, the Netherlands, were used. Non-cholesterol sterols were analyzed by gas–liquid chromatography–mass spectrometry in breast milk sampled one-month postpartum (N = 311). Sterols were selected for each allergic outcome, i.e., eczema, wheeze, and allergic sensitization, prior to analyses. Associations between the selected sterols with allergic outcomes were analyzed using multiple logistic regression to calculate odds ratios (ORs). The odds of eczema in the first two years of life were lower with higher concentrations of cholestanol (OR (95%CI): 0.98 (0.95; 1.00), p = 0.04), lanosterol (0.97 (0.95; 1.00), p = 0.02), lathosterol (0.93 (0.87; 0.99), p = 0.02), and stigmasterol (0.51 (0.29; 0.91), p = 0.02) in breast milk sampled one-month postpartum. None of the sterols were associated with wheeze in the first two years of life. The odds of allergic sensitization at age two were lower with higher concentrations of campesterol in breast milk (OR (95%CI): 0.81 (0.70; 0.95), p = 0.01). In conclusion, our data suggest that exposure to higher non-cholesterol sterol concentrations in breast milk may indeed be associated with the prevention of allergic outcomes in the first two years of life. [ABSTRACT FROM AUTHOR]

Allergen-specific T helper (Th)2 cells orchestrate upon allergen challenge the development of allergic eosinophilic lung inflammation. Sensitization with alum adjuvant, a type 2 adjuvant, has been used extensively in animal models of allergic lung disease. In contrast, type 1 adjuvants like CpG-ODN, a synthetic toll-like receptor 9 agonist, inhibit the development of Th2 immunity. CpG-ODN induce type 1 and suppressive cytokines that influence Th2 cell differentiation. Here, we investigated the immune modulatory effect of CpG-ODN on allergic sensitization to OVA with alum focusing on dendritic cells (DCs) expressing the MyD88 molecule and the suppressive IL-10 cytokine. Using mice with specific cell deletion of MyD88 molecule, we showed that CpG-ODN suppressed allergic sensitization and consequent lung allergic inflammation signaling through the MyD88 pathway on dendritic cells, but not on B-cells. This inhibition was associated with an increased production of IL-10 in the bronchoalveolar lavage fluid. Sensitization to OVA with CpG-ODN of IL-10-deficient, but not wild-type mice, induced a shift towards Th1 pattern of inflammation. Employing bone marrow-derived dendritic cells (BM-DCs) pulsed with OVA for sensitizations with or without CpG-ODN, we showed that IL-10 is dispensable for the inhibition of allergic lung Th2 responses by CpG-ODN. Moreover, the lack of IL-10 on DCs was not sufficient for the CpG-ODN-induced immune-deviation towards a Th1 pattern. Accordingly, we confirmed directly the role of MyD88 pathway on DCs in the inhibition of allergic sensitization. [ABSTRACT FROM AUTHOR]

Rats were exposed to nickel oxide nano-aerosol at a concentration of 2.4 ± 0.4 µg/m3 in a "nose only" inhalation setup for 4 h at a time, 5 times a week, during an overall period of 2 weeks to 6 months. Based on the majority of the effects assessed, this kind of exposure may be considered as close to LOAEL (lowest observed adverse effect level), or even to NOAEL (no observed adverse effect level). At the same time, the experiment revealed genotoxic and allergic effects as early as in the first weeks of exposure, suggesting that these effects may have no threshold at all. [ABSTRACT FROM AUTHOR]

While allergy, asthma and rhinitis do not inevitably co-exist, there are strong associations. Not all those with asthma are allergic, rhinitis may exist without asthma, and allergy commonly exists in the absence of asthma and/or rhinitis. This is likely due to the separate gene/environment interactions which influence susceptibility to allergic sensitization and allergic airway diseases. Allergic sensitization, particularly to foods, and eczema commonly manifest early in infancy, and not infrequently are followed by the development of allergic rhinitis and ultimately asthma. This has become known as the "allergic march". However, many infants with eczema never develop asthma or rhinitis, and both the latter conditions can evolve without prior eczema or food allergy. Understanding the mechanisms underlying the ontogeny of allergic sensitization and allergic disease will facilitate rational approaches to the prevention and management of asthma and allergic rhinitis. Furthermore, a range of new, so-called biological, therapeutic approaches, targeting specific allergy-promoting and pro-inflammatory molecules, are now in clinical trials or have been recently approved for use by regulatory authorities and could have a major impact on disease prevention and control in the future. Understanding basic mechanisms will be essential to the employment of such medications. This review will explain the concept of the united airway (rhinitis/asthma) and associations with allergy. It will incorporate understanding of the role of genes and environment in relation to the distinct but interacting origins of allergy and rhinitis/asthma. Understanding the patho-physiological differences and varying therapeutic requirements in patients with asthma, with or without rhinitis, and with or without associated allergy, will aid the planning of a personalized evidence-based management strategy. [ABSTRACT FROM AUTHOR]

In asthmatic adults, monoclonals directed against Type 2 airway inflammation have led to major improvements in quality of life, reductions in asthma attacks and less need for oral corticosteroids. The paediatric evidence base has lagged behind. All monoclonals currently available for children are anti-eosinophilic, directed against the T helper (TH2) pathway. However, in children and in low and middle income settings, eosinophils may have important beneficial immunological actions. Furthermore, there is evidence that paediatric severe asthma may not be TH2 driven, phenotypes may be less stable than in adults, and adult biomarkers may be less useful. Children being evaluated for biologicals should undergo a protocolised assessment, because most paediatric asthma can be controlled with low dose inhaled corticosteroid if taken properly and regularly. For those with severe therapy resistant asthma, and refractory asthma which cannot be addressed, the two options if they have TH2 inflammation are omalizumab and mepolizumab. There is good evidence of efficacy for omalizumab, particularly in those with multiple asthma attacks, but only paediatric safety, not efficacy, data for mepolizumab. There is an urgent need for efficacy data in children, as well as data on biomarkers to guide therapy, if the right children are to be treated with these powerful new therapies. [ABSTRACT FROM AUTHOR]

Several metabolomics studies have identified altered metabolic pathways that are related to asthma. However, an integrative analysis of the metabolic responses across blood and urine for a comprehensive framework of asthma in early childhood remains lacking. Fifty-four age-matched children with asthma (n = 28) and healthy controls (n = 26) were enrolled. Metabolome analysis of the plasma and urine samples was performed using 1H-nuclear magnetic resonance (NMR) spectroscopy coupled with partial least-squares discriminant analysis (PLS-DA). Integrated analysis of blood and urine metabolic profiling related to IgE reactions for childhood asthma was investigated. A significantly higher plasma histidine level was found, in parallel with lower urinary 1-methylnicotinamide and trimethylamine N-oxide (TMAO) levels, in children with asthma compared to healthy controls. Compared to children without allergic sensitization, 11 (92%) plasma metabolites and 8 (80%) urinary metabolites were found to be significantly different in children with IgE and food sensitization respectively. There were significant correlations between the plasma 3-hydroxybutyric acid and excreted volumes of the hydroxy acids, which were strongly correlated to plasma leucine and valine levels. Urine N-phenylacetylglycine, a microbial-host co-metabolite, was strongly correlated with total serum and food allergen-specific IgE levels. Plasma pyruvate and urine valine, leucine, and isoleucine degradation metabolisms were significantly associated with allergic sensitization for childhood asthma. In conclusion, blood and urine metabolome reflect different metabolic pathways in allergic reactions. Plasma pyruvate metabolism to acetic acid appears to be associated with serum IgE production, whereas urine branched-chain amino acid metabolism primarily reflects food allergic reactions against allergies. [ABSTRACT FROM AUTHOR]

The improvement of the knowledge of the pathophysiological mechanisms underlying the tolerance and sensitization to food antigens has recently led to a radical change in the clinical approach to food allergies. Epidemiological studies show a global increase in the prevalence of food allergy all over the world and manifestations of food allergy appear increasingly frequent also in elderly subjects. Environmental and nutritional changes have partly changed the epidemiology of allergic reactions to foods and new food allergic syndromes have emerged in recent years. The deepening of the study of the intestinal microbiota has highlighted important mechanisms of immunological adaptation of the mucosal immune system to food antigens, leading to a revolution in the concept of immunological tolerance. As a consequence, new prevention models and innovative therapeutic strategies aimed at a personalized approach to the patient affected by food allergy are emerging. This review focuses on these new perspectives and their practical implications in the management of food allergy, providing an updated view of this complex pathology. [ABSTRACT FROM AUTHOR]

Prenatal smoking exposure and early-life respiratory infections are major determinants of asthma during childhood. We investigate the factors influencing allergic sensitization (AS), asthma, and lung function in children and the balance between individual and environmental characteristics at different life stages. 1714 children aged 7-16 years and living in southern Italy were investigated using a parental questionnaire, skin prick tests, and spirometry. We found 41.0% AS prevalence: among children without parental history of asthma, male sex, maternal smoking during pregnancy (MatSmoke), and acute respiratory diseases in the first two years of life (ARD2Y) were significant risk factors for AS. MatSmoke was associated (OR = 1.79) with ARD2Y, and this association was influenced by sex. ARD2Y was, in turn, a significant risk factor (OR = 8.53) for childhood current asthma, along with AS (OR up to 3.03) and rhinoconjuctivitis (OR = 3.59). Forced mid-expiratory flow (FEF 25-75% ) was negatively affected by ARD2Y, with a sex-related effect. Thus, males exposed to MatSmoke had significantly lower FEF 25-75% than unexposed males. Despite the difficulty of discriminating among the complex interactions underlying the development of allergic respiratory diseases, ARD2Y appears to strongly influence both asthma and lung function during childhood. In turn, ARD2Y is influenced by prenatal exposure to tobacco smoke with a sex-dependent effect.

In contrast with Th1 immune responses against pathogenic viruses and bacteria, the incipient events that generate Th2 responses remain less understood. One difficulty in the identification of universal operating principles stems from the diversity of entities against which cellular and molecular Th2 responses are produced. Such responses are launched against harmful macroscopic parasites and noxious substances, such as venoms, but also against largely innocuous allergens. This suggests that the established understanding about sense and recognition applied to Th1 responses may not be translatable to Th2 responses. This review will discuss processes and signals known to occur in Th2 responses, particularly in the context of food allergy. We propose that perturbations of homeostasis at barrier sites induced by external or internal subverters, which can activate or lower the threshold activation of the immune system, are the major requirement for allergic sensitization. Innate signals produced in the tissue under these conditions equip dendritic cells with a program that forms an adaptive Th2 response. [ABSTRACT FROM AUTHOR]

Exposure to air pollution is associated with increased morbidity from cardiovascular diseases, lung cancer, respiratory and allergic diseases. The aim of this study was to investigate allergic diseases in 111 traffic wardens compared to a control group of 101 administrative employees. All participating subjects underwent a physical examination, in which a complete medical history was taken and a dedicated allergological questionnaire administered. Spirometry, Specific IgE dosage (RAST) and skin prick tests (SPT) were done. Diagnostic investigations such as the nasal cytology, a specific nasal provocation test and rhinomanometry were also performed. Statistical analyses were performed using STATA version 11. The percentage of subjects with a diagnosis of allergy was higher in the exposed workers than in the controls. As regards the clinical tests, the positivity was higher for the group of exposed subjects. Among the exposed workers, those who worked on foot or motorcycle had a higher positivity in clinical trials compared to the traffic wardens who used the car. Our study showed a higher percentage of allergic subjects in the group of workers exposed to outdoor pollutants than in the controls. These results suggest that allergological tests should be included in the health surveillance protocols for workers exposed to outdoor pollutants.