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Air pollution and IgE sensitization in 4 European birth cohorts-the MeDALL project.
Melén, E, Standl, M, Gehring, U, Altug, H, Antó, JM, Berdel, D, Bergström, A, Bousquet, J, Heinrich, J, Koppelman, GH, et al
The Journal of allergy and clinical immunology. 2021;(2):713-722
Abstract
BACKGROUND Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. OBJECTIVE Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. METHODS A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 μm, less than 10 μm, and between 2.5 and 10 μm; PM2.5 absorbance (a measurement of the blackness of PM2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). RESULTS Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-μg/m3 increase in NO2 exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen Phleum pratense 1 (Phl p 1) and the cat allergen Felis domesticus 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-μg/m3 increase in exposure). CONCLUSION Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants.
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Free Amino Acids in Human Milk: A Potential Role for Glutamine and Glutamate in the Protection Against Neonatal Allergies and Infections.
van Sadelhoff, JHJ, Wiertsema, SP, Garssen, J, Hogenkamp, A
Frontiers in immunology. 2020;:1007
Abstract
Breastfeeding is indicated to support neonatal immune development and to protect against neonatal infections and allergies. Human milk composition is widely studied in relation to these unique abilities, which has led to the identification of various immunomodulating components in human milk, including various bioactive proteins. In addition to proteins, human milk contains free amino acids (FAAs), which have not been well-studied. Of those, the FAAs glutamate and glutamine are by far the most abundant. Levels of these FAAs in human milk sharply increase during the first months of lactation, in contrast to most other FAAs. These unique dynamics are globally consistent, suggesting that their levels in human milk are tightly regulated throughout lactation and, consequently, that they might have specific roles in the developing neonate. Interestingly, free glutamine and glutamate are reported to exhibit immunomodulating capacities, indicating that these FAAs could contribute to neonatal immune development and to the unique protective effects of breastfeeding. This review describes the current understanding of the FAA composition in human milk. Moreover, it provides an overview of the effects of free glutamine and glutamate on immune parameters relevant for allergic sensitization and infections in early life. The data reviewed provide rationale to study the role of free glutamine and glutamate in human milk in the protection against neonatal allergies and infections.
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Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy.
Hausmann, O, Daha, M, Longo, N, Knol, E, Müller, I, Northrup, H, Brockow, K
Molecular genetics and metabolism. 2019;(1-2):84-91
Abstract
OBJECTIVE To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.
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Factors influencing the infant gut microbiome at age 3-6 months: Findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART).
Sordillo, JE, Zhou, Y, McGeachie, MJ, Ziniti, J, Lange, N, Laranjo, N, Savage, JR, Carey, V, O'Connor, G, Sandel, M, et al
The Journal of allergy and clinical immunology. 2017;(2):482-491.e14
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Abstract
BACKGROUND The gut microbiome in infancy influences immune system maturation, and may have an important impact on allergic disease risk. OBJECTIVE We sought to determine how prenatal and early life factors impact the gut microbiome in a relatively large, ethnically diverse study population of infants at age 3 to 6 months, who were enrolled in Vitamin D Antenatal Asthma Reduction Trial, a clinical trial of vitamin D supplementation in pregnancy to prevent asthma and allergies in offspring. METHODS We performed 16S rRNA gene sequencing on 333 infants' stool samples. Microbial diversity was computed using the Shannon index. Factor analysis applied to the top 25 most abundant taxa revealed 4 underlying bacterial coabundance groups; the first dominated by Firmicutes (Lachnospiraceae/Clostridiales), the second by Proteobacteria (Klebsiella/Enterobacter), the third by Bacteriodetes, and the fourth by Veillonella. Scores for coabundance groups were used as outcomes in regression models, with prenatal/birth and demographic characteristics as independent predictors. Multivariate analysis, using all microbial community members, was also conducted. RESULTS White race/ethnicity was associated with lower diversity but higher Bacteroidetes coabundance scores. C-section birth was associated with higher diversity, but decreased Bacteroidetes coabundance scores. Firmicutes scores were higher for infants born by C-section. Breast-fed infants had lower proportions of Clostridiales. Cord blood vitamin D was linked to increased Lachnobacterium, but decreased Lactococcus. CONCLUSIONS The findings presented here suggest that race, mode of delivery, breast-feeding, and cord blood vitamin D levels are associated with infant gut microbiome composition, with possible long-term implications for immune system modulation and asthma/allergic disease incidence.
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Effect of Maternal Dietary Patterns during Pregnancy on Self-Reported Allergic Diseases in the First 3 Years of Life: Results from the GUSTO Study.
Loo, EXL, Ong, L, Goh, A, Chia, AR, Teoh, OH, Colega, MT, Chan, YH, Saw, SM, Kwek, K, Gluckman, PD, et al
International archives of allergy and immunology. 2017;(2):105-113
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Abstract
BACKGROUND Maternal diet during pregnancy has been suggested to be an important early-life exposure that influences immune tolerance and the development of allergic diseases in offspring. METHODS We examined the relationship between maternal dietary patterns assessed using 24-h recalls and food diaries at 26-28 weeks of pregnancy and the subsequent development of allergic outcomes in the offspring in the Growing Up in Singapore towards Healthy Outcomes (GUSTO) birth cohort. Exploratory factor analysis was used to characterize maternal dietary patterns during pregnancy. During repeated visits in the first 36 months of life, questionnaires were administered to ascertain allergic symptoms, namely, eczema, rhinitis, and wheeze. At ages 18 and 36 months, we administered skin-prick testing to inhalant and food allergens. RESULTS Of the 3 maternal dietary patterns that emerged, the seafood and noodles pattern was associated with a reduced risk of developing allergen sensitization at both 18 months (odds ratio [95% confidence interval]: 0.7 [0.5-0.9]) and 36 months (0.7 [0.6-0.9]) after adjustment for a family history of allergy, and ethnicity, sex, and maternal education levels. No associations between the patterns vegetables, fruit, and white rice or pasta, cheese, and processed meat were observed with any of the allergic outcomes in the first 18 and 36 months of life. CONCLUSION Maternal diet during pregnancy can influence the subsequent development of allergic outcomes in offspring.
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Low-grade disease activity in early life precedes childhood asthma and allergy.
Chawes, BL
Danish medical journal. 2016;(8)
Abstract
Asthma and allergies are today the most common chronic diseases in children and the leading causes of school absences, chronic medication usage, emergency department visits and hospitalizations, which affect all members of the family and represent a significant societal and scientific challenge. These highly prevalent disorders are thought to originate from immune distortion in early childhood, but the etiology and heterogeneity of the disease mechanisms are not understood, which hampers preventive initiatives and makes treatment inadequate. The objective of this thesis is to investigate the presence of an early life disease activity prior to clinical symptoms to understand the anteceding pathophysiological steps towards childhood asthma and allergy. The thesis is built on seven studies from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) birth cohort examining biomarkers of disease activity in 411 asymptomatic neonates in cord blood (I-II), urine (III), exhaled breath (IV-V) and infant lung function (VI-VII) in relation to the subsequent development of asthma and allergy during the first seven years of life. In papers I-II, we studied cord blood chemokines and 25(OH)-vitamin D, which represent a proxy of the inborn immature immune system, the intrauterine milieu, and the maternal immune health during pregnancy. High levels of the Th2-related chemokine CCL22 and high CCL22/CXCL11 ratio were positively correlated with total IgE level during preschool age (II). This suggests an inborn Th2 skewing of the immune system in healthy newborns subsequently developing elevated total IgE antibodies, which is considered to increase the risk of asthma and allergies later in life. Additionally, deficient cord blood 25(OH)-vitamin D levels were associated with a 2.7-fold increased risk of recurrent wheeze at age 0-7 years (I). Together, these findings support the concept that early life immune programming in the pre-symptomatic era plays an essential role for promotion of or protection against asthma and allergies. Therefore, preventive initiatives to restore immune health, such as vitamin D supplementation, should be directed to the fetus and the earliest postnatal life. The eosinophil granulocyte has a major role in the allergic inflammatory cascade and eosinophilia is considered a hallmark of many allergic phenotypes. In paper III, we examined neonatal urinary biomarkers including eosinophil protein X (u-EPX), which is contained in the eosinophil granules. Elevated u-EPX in asymptomatic neonates was associated with development of allergic sensitization and nasal eosinophilia, but not with wheezing or asthma (III). These findings suggest the presence of an ongoing low-grade disease process in early life characterized by eosinophil activation prior to appearance of allergy-related conditions. In papers IV-V, we investigated perinatal and genetic predictors of neonatal fractional exhaled nitric oxide (FeNO) and the relationship between neonatal FeNO and wheezing later in child-hood. The a priori selected determinants encompassed asthma genetic risk variants, anthropometrics, demographics, socioeconomics, parental asthma and allergy, maternal smoking, paracetamol and antibiotic usage during pregnancy, and neonatal bacterial airway colonization. Among those, only the DENND1B risk allele and paternal history of asthma and allergy were associated with increased FeNO values (V) suggesting that raised FeNO in neonatal life is primarily an inherited trait. The neonatal FeNO levels were widely dispersed (1-67 ppb) and children with values in the upper quartile were at increased risk of recurrent wheezing in early childhood, but not persistent wheezing, reduced lung function or allergy-related endpoints (IV). This suggests that elevated neonatal FeNO represents an early asymptomatic low-grade disease process other than congenitally small airway calibre contributing to a transient wheezing phenotype. Reduced lung function in neonates is associated with wheezing and asthma proneness, but it is unknown if such host factor also confers a risk of acute bronchiolitis, which is considered an index event of asthma persisting into school age. In paper VI, we investigated neonatal forced flow, volume, and responsiveness to methacholine in relation to occurrence of acute severe bronchiolitis at age 0-2 years. Children developing bronchiolitis had a 2.5-fold increased bronchial responsiveness as neonates (VI) suggesting a preexisting joint propensity of the airways to react adversely to common respiratory viruses and to develop asthma. This finding proposes airway hyperresponsiveness as yet another marker of low-grade disease activity among asymptomatic neonates on a trajectory towards childhood asthma. In paper VII, we examined whether neonates with impaired pulmonary capacity also had signs of systemic inflammation prior to clinical symptoms. Reduced FEV0.5 was significantly associated with elevated serum hs-CRP and other blood inflammatory markers (VII) suggesting presence of systemic low-grade inflammation from the beginning of life. Chronic low-grade inflammation is a common nominator of virtually all the major non-communicable welfare diseases (NCDs) of modernity whereof asthma and allergies are the earliest debuting disorders. The novel finding of systemic low-grade inflammation among neonates at increased risk of asthma and allergy, therefore implies that exploring the origins of asthma and allergy may also unravel disease mechanisms involved in other NCDs. In conclusion, the series of papers presented in this thesis (I-VII) evidence the presence of a pre-symptomatic disease process measurable in several body compartments, which supports the notion of low-grade disease activity in early life as a generic trait among neonates developing asthma and allergy. This hypothesis piggybacking on single biomarker assessments could be enforced and refined by applying novel global omics approaches. In particular, metabolomic analyses of serum, urine, and airway lining fluid from neonates as well as neonatal VOC profiling of exhaled breath may facilitate a broader understanding of the early low-grade disease activity preceding clinical symptoms. Disentangling the introductory pathophysiological mechanisms and underlying endotypes of disease is paramount for generating successful preventive measures to alleviate the major global burden of asthma, allergy, and other NCDs of modern time.
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Childhood allergies and asthma: New insights on environmental exposures and local immunity at the lung barrier.
Smits, HH, van der Vlugt, LE, von Mutius, E, Hiemstra, PS
Current opinion in immunology. 2016;:41-47
Abstract
While certain bacteria and respiratory viruses promote local inflammation and disease onset, a more diverse colonization of the different species in the (gut) microbiome may be linked to more regulatory responses and protection against asthma and allergies. These processes are also influenced in part by food intake, both targeting the composition of the gut microbiome and influencing the immune system via metabolites. Early life environmental microbial exposure also contributes to protection against asthma and allergy and is linked with an early activation of the innate immune system and the development of regulatory immune responses. Although greater mechanistic insight is needed, it is tempting to speculate that part of the environmental effect can be explained by modulation of the microbiome composition at mucosal surfaces, epithelial barrier function and/or local immunity. A review of the latest studies is provided.
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Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders.
Theoharides, TC, Tsilioni, I, Patel, AB, Doyle, R
Translational psychiatry. 2016;(6):e844
Abstract
Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1β), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFβ induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.
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Soluble CD14, α-and β-defensins in breast milk: association with the emergence of allergy in a high-risk population.
Savilahti, EM, Kukkonen, AK, Kuitunen, M, Savilahti, E
Innate immunity. 2015;(3):332-7
Abstract
As innate immunity factors in breast milk (BM) modulate infants' immune responses, we investigated whether soluble CD14 (sCD14) and defensin levels in BM are associated with the emergence of allergy in childhood. The randomly selected group of 260 mother-child pairs belonged to a randomized, double-blind placebo-controlled trial where 1223 mothers with fetuses at high risk for allergy received for the 4 last wk of pregnancy a mixture of probiotics, or placebo; after birth, the child received the treatment for 6 mo. Children were followed for the emergence of sensitization and allergic symptoms for 5 yr. IgE-mediated allergic disorder was diagnosed in 80 children by the age of 5 yr. Levels of sCD14, human neutrophil peptide (HNP) 1-3 and β-defensin 2 (HBD2) in colostrum and in BM 3 mo post-partum were measured with ELISA. BM sCD14 levels decreased from 0 to 3 mo. HNP1-3 and HBD2 were detected in colostrum, but not in BM 3 mo post-partum. High sCD14 levels in BM 3 mo post-partum were associated with children developing an IgE-mediated allergic disorder by the age of 5 yr. BM HNP1-3, HBD2 or sCD14 levels were not associated with probiotics treatment. Our results suggest that sCD14 in BM influences the emergence of allergy in children with atopic heredity.
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Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood.
Gunaratne, AW, Makrides, M, Collins, CT
The Cochrane database of systematic reviews. 2015;(7):CD010085
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BACKGROUND Allergies have become more prevalent globally over the last 20 years. Dietary consumption of n-3 (or omega 3) long chain polyunsaturated fatty acids (LCPUFA) has declined over the same period of time. This, together with the known role of n-3 LCPUFA in inhibiting inflammation, has resulted in speculation that n-3 LCPUFA may prevent allergy development. Dietary n-3 fatty acids supplements may change the developing immune system of the newborn before allergic responses are established, particularly for those with a genetic predisposition to the production of the immunoglobulin E (IgE) antibody. Individuals with IgE-mediated allergies have both the signs and symptoms of the allergic disease and a positive skin prick test (SPT) to the allergen. OBJECTIVES To assess the effect of n-3 LCPUFA supplementation in pregnant and/or breastfeeding women on allergy outcomes (food allergy, atopic dermatitis (eczema), allergic rhinitis (hay fever) and asthma/wheeze) in their children. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 August 2014), PubMed (1966 to 01 August 2014), CINAHL via EBSCOhost (1984 to 01 August 2014), Scopus (1995 to 01 August 2014), Web of Knowledge (1864 to 01 August 2014) and ClinicalTrials.gov (01 August 2014) and reference lists of retrieved studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) evaluating the effect of n-3 LCPUFA supplementation of pregnant and/or lactating women (compared with placebo or no treatment) on allergy outcomes of the infants or children. Trials using a cross-over design and trials examining biochemical outcomes only were not eligible for inclusion. DATA COLLECTION AND ANALYSIS Two review authors independently assessed eligibility and trial quality and performed data extraction. Where the review authors were also investigators on trials selected, an independent reviewer assessed trial quality and performed data extraction. MAIN RESULTS Eight trials involving 3366 women and their 3175 children were included in the review. In these trials, women were supplemented with n-3 LCPUFA during pregnancy (five trials), lactation (two trials) or both pregnancy and lactation (one trial). All trials randomly allocated women to either a n-3 LCPUFA supplement or a control group. The risk of bias varied across the eight included trials in this review with only two trials with a low risk of selection, performance and attrition bias.N-3 LCPUFA supplementation showed a clear reduction in the primary outcome of any allergy (medically diagnosed IgE mediated) in children aged 12 to 36 months (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.98; two RCTs; 823 children), but not beyond 36 months (RR 0.86, 95% CI 0.61 to 1.20; one RCT, 706 children). For any allergy (medically diagnosed IgE mediated and/or parental report), no clear differences were seen in children either at 12 to 36 months (RR 0.89, 95% CI 0.71 to 1.11; two RCTs, 823 children) or beyond 36 months of age (RR 0.96, 95% CI 0.84 to 1.09; three RCTs, 1765 children).For the secondary outcomes of specific allergies there were no clear differences for food allergies at 12 to 36 months and beyond 36 months, but a clear reduction was seen for children in their first 12 months with n-3 LCPUFA (both for medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report). There was a clear reduction in medically diagnosed IgE-mediated eczema with n-3 LCPUFA for children 12 to 36 months of age, but not at any other time point for both medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report. No clear differences for allergic rhinitis or asthma/wheeze were seen at any time point for both medically diagnosed IgE mediated, and medically diagnosed IgE mediated and/or parental report.There was a clear reduction in children's sensitisation to egg and sensitisation to any allergen between 12 to 36 months of age when mothers were supplemented with n-3 LCPUFA.In terms of safety for the mother and child, n-3 LCPUFA supplementation during pregnancy did not show increased risk of postpartum haemorrhage or early childhood infections. AUTHORS' CONCLUSIONS Overall, there is limited evidence to support maternal n-3 LCPUFA supplementation during pregnancy and/or lactation for reducing allergic disease in children. Few differences in childhood allergic disease were seen between women who were supplemented with n-3 LCPUFA and those who were not.