Egg-sensitised infants have elevated CD4+ effector memory T regulatory cells from birth.

BACKGROUND: IgE-mediated sensitisation to egg is common in infants. In some cases, the processes leading to egg sensitisation are established in early life, even before introduction to solid foods. The underlying mechanisms remain poorly understood. METHODS: We performed detailed immune cell phenotyping of peripheral blood mononuclear cells and determined in vitro cytokine responses following allergen specific and non-specific immune stimulation. To determine if unique immune profiles were linked to early-life egg sensitisation, we compared 92 infants at 4-6 months of age, with (EggCAP+, n = 41) and without (EggCAP-, n = 51) early egg sensitisation. Additionally, 47 cord blood samples were analysed. For a subset of participants (n = 39), matching cord blood mononuclear cells were assessed by flow cytometry to establish the impact of IgE sensitisation on immune developmental trajectories. RESULTS: EggCAP+ infants were found to exhibit a unique immune phenotype characterised by increased levels of circulating CD4+ T regulatory cells (Treg), CD4+ effector memory (EM) Treg and increased expression of the IgE receptor, FcεR1, on basophils. The increased CD4+ EM Treg profiles were already present in cord blood samples from EggCAP+ infants. A general Th2-skewing of the immune system was observed based on increased IL-13 production following phytohemagglutinin stimulation and by comparing immune developmental trajectories, EggCAP+ infants displayed an expansion of basophils and reduced levels of CD4- T cells compared to EggCAP- infants. CONCLUSIONS: Immunological profiles associated with egg sensitisation are detectable in infant circulation at 4-6 months of age and at birth. Understanding the immune mechanisms underlying early-life sensitisation could provide important insights for future food allergy prevention strategies.

PKCζ activation promotes maturation of cord blood T cells towards a Th1 IFN-γ propensity.

A significant number of babies present transiently with low protein kinase C zeta (PKCζ) levels in cord blood T cells (CBTC), associated with reduced ability to transition from a neonatal Th2 to a mature Th1 cytokine bias, leading to a higher risk of developing allergic sensitisation, compared to neonates whose T cells have 'normal' PKCζ levels. However, the importance of PKCζ signalling in regulating their differentiation from a Th2 to a Th1 cytokine phenotype propensity remains undefined. To define the role of PKCζ signalling in the regulation of CBTC differentiation from a Th2 to a Th1cytokine phenotype we have developed a neonatal T cell maturation model which enables the cells to develop to CD45RA- /CD45RO+ T cells while maintaining the Th2 immature cytokine bias, despite having normal levels of PKCζ. The immature cells were treated with phytohaemagglutinin, but in addition with phorbol 12-myristate 13-acetate (PMA), an agonist which does not activate PKCζ. This was compared to development in CBTC in which the cells were transfected to express constitutively active PKCζ. The lack of PKCζ activation by PMA was monitored by western blot for phospho-PKCζ and translocation from cell cytosol to the membrane by confocal microscopy. The findings demonstrate that PMA fails to activate PKCζ in CBTC. The data show that CBTC matured under the influence of the PKC stimulator, PMA, maintain a Th2 cytokine bias, characterised by robust IL-4 and minimal interferon gamma production (IFN-γ), and lack of expression of transcriptional factor, T-bet. This was also reflected in the production of a range of other Th2/Th1 cytokines. Interestingly, introduction of a constitutively active PKCζ mutant into CBTC promoted development towards a Th1 profile with high IFN-γ production. The findings demonstrate that PKCζ signalling is essential for the immature neonatal T cells to transition from a Th2 to a Th1 cytokine production bias.

Epigenomic variability is associated with age-specific naïve CD4 T cell response to activation in infants and adolescents.

Childhood is a critical period of immune development. During this time, naïve CD4 (nCD4) T cells undergo programmed cell differentiation, mediated by epigenetic changes, in response to external stimuli leading to a baseline homeostatic state that may determine lifelong disease risk. However, the ontogeny of epigenetic signatures associated with CD4 T cell activation during key developmental periods are yet to be described. We investigated genome-wide DNA methylation (DNAm) changes associated with nCD4 T activation following 72 h culture in media+anti-CD3/CD28 beads in healthy infants (aged 12 months, n = 18) and adolescents (aged 10-15 years, n = 15). We integrated these data with transcriptomic and cytokine profiling from the same samples. nCD4 T cells from both age groups show similar extensive epigenetic reprogramming following activation, with the majority of genes involved in the T cell receptor signaling pathway associated with differential methylation. Additionally, we identified differentially methylated probes showing age-specific responses, that is, responses in only infants or adolescents, including within a cluster of T cell receptor (TCR) genes. These encoded several TCR alpha joining (TRAJ), and TCR alpha variable (TRAV) genes. Cytokine data analysis following stimulation revealed enhanced release of IFN-γ, IL-2 and IL-10, in nCD4 T cells from adolescents compared with infants. Overlapping differential methylation and cytokine responses identified four probes potentially underpinning these age-specific responses. We show that DNAm in nCD4T cells in response to activation is dynamic in infancy and adolescence, with additional evidence for age-specific effects potentially driving variation in cytokine responses between these ages.

Feasibility and safety of introducing cashew nut spread in infant diets-A randomized trial.

BACKGROUND: To reduce peanut allergy prevalence, infant feeding guidelines now recommend introducing peanuts in an age-appropriate form (such as peanut butter) as part of complementary feeding. However, due to a lack of randomized trial evidence, most infant feeding and food allergy prevention guidelines do not include tree nuts. The aims of this trial were to determine safety and feasibility of dosage consumption recommendations for infant cashew nut spread introduction. METHODS: This is a parallel, three-arm (1:1:1 allocation), single-blinded (outcome assessors), randomized controlled trial. General population term infants were randomized at 6-8 months of age to either a one teaspoon (Intervention 1 n = 59) or increasing dosage regime of one teaspoon at 6-7 months, two teaspoons at 8-9 months, and three teaspoons from 10 months of age onwards (Intervention 2 n = 67) cashew nut spread, both three times per week, or no specific advice on cashew introduction (Control n = 70). At 1 year of age, food challenge proven IgE-mediated cashew nut allergy was assessed. RESULTS: Compliance in Intervention 1 (92%) was higher than Intervention 2 (79%), p = .04. Only one infant had delayed (at 5 h) facial swelling and eczema flare to cashew introduction at 6.5 months, but no cashew allergy at 1 year. Only one infant (Control) had cashew allergy at 1 year, and this infant had not been introduced to cashew prior to 12 months of age. CONCLUSION: Regular infant consumption of one teaspoon of cashew nut spread three times per week from 6 to 8 months of age was found to be feasible and safe.

Increasing emergency department visits for anaphylaxis in very early childhood: A canary in the coal mine.

AIM: The incidence of anaphylaxis is increasing globally in tandem with changing environmental and lifestyle factors. There is very limited data on very early childhood presentations. We aim to assess changes in rates, characteristics and management of infant anaphylaxis in a paediatric ED over a 15-year period. METHODS: We conducted a retrospective study of children <2 years of age who presented with verified anaphylaxis comparing cases in years 2003-2007 with those in 2013-2017. Standardised information was collected on demographics, clinical presentation, management and triggers. RESULTS: Manually confirmed anaphylaxis rates in <2 year olds increased from 3.6 to 6.2 per 104 population (OR 1.7, 95% CI: 1.3-2.7; p < 0.001) with the greatest increase in <1 year olds. Anaphylaxis severity increased between 2003-2007 and 2013-2017 (OR 2.3, 95% CI: 1.2-4.3; p = 0.018). Failure to administer adrenaline was reduced in 2013-2017 (p = 0.007). Food was the leading anaphylaxis trigger (97.85%). CONCLUSION: This is the first study to suggest an increase in the incidence and severity of ED anaphylaxis presentations in children aged <2 years. Increased awareness of specific characteristics in this age group is required to facilitate timely recognition and optimal management. Further large-scale studies are warranted to understand underlying environmental drivers and find prevention strategies to reduce the burden of disease.

Perinatal Women's Perspectives of, and Engagement in, Digital Emotional Well-Being Training: Mixed Methods Study.

BACKGROUND: Psychological distress in the early postpartum period can have long-lasting deleterious effects on a mother's well-being and negatively affect her infant's development. Intervention approaches based in contemplative practices such as mindfulness and loving-kindness and compassion are intended to alleviate distress and cultivate well-being and can be delivered effectively as digital mental health interventions (DMHIs). OBJECTIVE: To understand the feasibility of engaging perinatal women in digital interventions, this study aimed to document participants' experiences in the Mums Minds Matter (MMM) study, a pilot randomized controlled trial comparing mindfulness, loving-kindness and compassion, and progressive muscle relaxation training delivered in a digital format and undertaken during pregnancy. To assess the different stages of engagement during and after the intervention, we adapted the connect, attend, participate, enact (CAPE) framework that is based on the idea that individuals go through different stages of engagement before they are able to enact change. METHODS: The MMM study was nested within a longitudinal birth cohort, The ORIGINS Project. We aimed to recruit 25 participants per randomization arm. Data were collected sequentially during the intervention through regular web-based surveys over 8 weeks, with opportunities to provide regular feedback. In the postintervention phase, qualitative data were collected through purposive sampling. RESULTS: Of 310 eligible women, 84 (27.1% [connect rate]) enrolled to participate in MMM. Of the remaining 226 women who did not proceed to randomization, 223 (98.7%) failed to complete the baseline surveys and timed out of eligibility (after 30 weeks' gestation), and 3 (1.3%) displayed high psychological distress scores. Across all program groups, 17 (20% [attend rate]) of the 84 participants actively opted out, although more may have disengaged from the intervention but did not withdraw. The main reasons for withdrawal were busy life and other priorities. In this study, we assessed active engagement and ongoing skills use (participate and enact) through postintervention interviews. We undertook 15 participant interviews, conducted 1 month to 3 months after the intervention. Our results provide insights into participant barriers and enablers as well as app changes, such as the ability to choose topics, daily reminders, case studies, and diversity in sounds. Implementing a DMHI that is brief, includes frequent prompts or nudges, and is easily accessible is a key strategy to target perinatal women. CONCLUSIONS: Our research will enable future app designs that are sufficiently nuanced to maximize the uptake, engagement, and application of mental health skills and contemplative practices in the perinatal period. Providing convenient access to engaging and effective prevention programs is critical and should be part of prenatal self-care. Our research underscores the appeal and feasibility of digital intervention approaches based in contemplative practices for perinatal women. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) 12620000672954p; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000672954p. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/19803.

Associations between the human immune system and gut microbiome with neurodevelopment in the first 5 years of life: A systematic scoping review.

The aim of this review was to map the literature assessing associations between maternal or infant immune or gut microbiome biomarkers and child neurodevelopmental outcomes within the first 5 years of life. We conducted a PRISMA-ScR compliant review of peer-reviewed, English-language journal articles. Studies reporting gut microbiome or immune system biomarkers and child neurodevelopmental outcomes prior to 5 years were eligible. Sixty-nine of 23,495 retrieved studies were included. Of these, 18 reported on the maternal immune system, 40 on the infant immune system, and 13 on the infant gut microbiome. No studies examined the maternal microbiome, and only one study examined biomarkers from both the immune system and the gut microbiome. Additionally, only one study included both maternal and infant biomarkers. Neurodevelopmental outcomes were assessed from 6 days to 5 years. Associations between biomarkers and neurodevelopmental outcomes were largely nonsignificant and small in effect size. While the immune system and gut microbiome are thought to have interactive impacts on the developing brain, there remains a paucity of published studies that report biomarkers from both systems and associations with child development outcomes. Heterogeneity of research designs and methodologies may also contribute to inconsistent findings. Future studies should integrate data across biological systems to generate novel insights into the biological underpinnings of early development.

Anti-Müllerian hormone concentration is associated with central adiposity and reproductive hormones in expectant fathers.

OBJECTIVE: The role of the anti-Müllerian hormone (AMH) as an indicator of physical and reproductive health in men is unclear. We assessed the relationships between AMH and follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and metabolic parameters, in a cohort of expectant fathers. DESIGN: ORIGINS Project prospective cohort study. SETTING: Community-dwelling men. PARTICIPANTS: Partners of pregnant women attending antenatal appointments. MAIN OUTCOME MEASURES: Serum AMH, FSH, LH, testosterone, and metabolic parameters. RESULTS: In 485 expectant fathers, median age 33 years, median AMH was 40 pmol/L (quartiles 29, 56). AMH was inversely correlated with FSH, age, and body mass index (BMI) (correlation coefficients: -.32, -.24, and -.17 respectively). The age association was nonlinear, with peak AMH between 20 and 30 years, a decline thereafter, and somewhat steady levels after 45 years. The inverse association of AMH with FSH was log-linear and independent of age and BMI (ß: -.07, SE: 0.01, p < .001). AMH was inversely correlated with waist circumference and directly associated with sex hormone-binding globulin. Testosterone was moderately correlated with AMH (correlation coefficient: .09, ß: .011, SE: 0.004, p = .014): this association was mediated by an inverse relationship with BMI (mediated proportion 0.49, p < .001). CONCLUSIONS: In reproductively active men, lower AMH is a biomarker for advancing age, and for poorer metabolic and reproductive health. The inverse association between AMH and FSH is independent of age and BMI, whereas the association of AMH and testosterone is mediated via BMI. The utility of AMH to predict reproductive and cardiometabolic outcomes in men warrants further investigation.

Exiting the Anthropocene: Achieving personal and planetary health in the 21st century.

Planetary health provides a perspective of ecological interdependence that connects the health and vitality of individuals, communities, and Earth's natural systems. It includes the social, political, and economic ecosystems that influence both individuals and whole societies. In an era of interconnected grand challenges threatening health of all systems at all scales, planetary health provides a framework for cross-sectoral collaboration and unified systems approaches to solutions. The field of allergy is at the forefront of these efforts. Allergic conditions are a sentinel measure of environmental impact on human health in early life-illuminating how ecological changes affect immune development and predispose to a wider range of inflammatory noncommunicable diseases (NCDs). This shows how adverse macroscale ecology in the Anthropocene penetrates to the molecular level of personal and microscale ecology, including the microbial systems at the foundations of all ecosystems. It provides the basis for more integrated efforts to address widespread environmental degradation and adverse effects of maladaptive urbanization, food systems, lifestyle behaviors, and socioeconomic disadvantage. Nature-based solutions and efforts to improve nature-relatedness are crucial for restoring symbiosis, balance, and mutualism in every sense, recognizing that both personal lifestyle choices and collective structural actions are needed in tandem. Ultimately, meaningful ecological approaches will depend on placing greater emphasis on psychological and cultural dimensions such as mindfulness, values, and moral wisdom to ensure a sustainable and resilient future.

Understanding Engagement in Digital Mental Health and Well-being Programs for Women in the Perinatal Period: Systematic Review Without Meta-analysis.

BACKGROUND: Pregnancy and the postnatal period can be a time of increased psychological distress, which can be detrimental to both the mother and the developing child. Digital interventions are cost-effective and accessible tools to support positive mental health in women during the perinatal period. Although studies report efficacy, a key concern regarding web-based interventions is the lack of engagement leading to drop out, lack of participation, or reduced potential intervention benefits. OBJECTIVE: This systematic review aimed to understand the reporting and levels of engagement in studies of digital psychological mental health or well-being interventions administered during the perinatal period. Specific objectives were to understand how studies report engagement across 4 domains specified in the Connect, Attend, Participate, and Enact (CAPE) model, make recommendations on best practices to report engagement in digital mental health interventions (DMHIs), and understand levels of engagement in intervention studies in this area. To maximize the utility of this systematic review, we intended to develop practical tools for public health use: to develop a logic model to reference the theory of change, evaluate the studies using the CAPE framework, and develop a guide for future data collection to enable consistent reporting in digital interventions. METHODS: This systematic review used the Cochrane Synthesis Without Meta-analysis reporting guidelines. This study aimed to identify studies reporting DMHIs delivered during the perinatal period in women with subclinical mood symptoms. A systematic database search was used to identify relevant papers using the Ovid Platform for MEDLINE, PsycINFO, EMBASE, Scopus, Web of Science, and Medical Subject Headings on Demand for all English-language articles published in the past 10 years. RESULTS: Searches generated a database of 3473 potentially eligible studies, with a final selection of 16 (0.46%) studies grouped by study design. Participant engagement was evaluated using the CAPE framework and comparable variables were described. All studies reported at least one engagement metric. However, the measures used were inconsistent, which may have contributed to the wide-ranging results. There was insufficient reporting for enactment (ie, participants' real-world use of intervention skills), with only 38% (6/16) of studies clearly recording longer-term practice through postintervention interviews. The logic model proposes ways of conceptualizing and reporting engagement details in DMHIs more consistently in the future. CONCLUSIONS: The perinatal period is the optimal time to intervene with strength-based digital tools to build positive mental health. Despite the growing number of studies on digital interventions, few robustly explore engagement, and there is limited evidence of long-term skill use beyond the intervention period. Our results indicate variability in the reporting of both short- and long-term participant engagement behaviors, and we recommend the adoption of standardized reporting metrics in future digital interventions. TRIAL REGISTRATION: PROSPERO CRD42020162283; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=162283.

Longitudinal egg-specific regulatory T- and B-cell development: Insights from primary prevention clinical trials examining the timing of egg introduction.

BACKGROUND: Egg allergy affects almost 1 in 10 Australian infants. Early egg introduction has been associated with a reduced risk in developing egg allergy; however, the immune mechanisms underlying this protection remain unclear. OBJECTIVE: To examine the role of regulatory immune cells in tolerance induction during early egg introduction. METHODS: Cryopreserved peripheral blood mononuclear cells (PBMC) were obtained from infants from 2 randomized controlled trials of early introduction of egg for the primary prevention of egg allergy; BEAT (at 12 months, n = 42) and STEP (at 5 months n = 82; 12 months n = 82) study cohorts. In vitro ovalbumin-stimulated PBMC were analyzed by flow cytometry for presence of ovalbumin-specific regulatory T cells, using activation markers, FoxP3, and IL-10 expression. Ovalbumin-specific regulatory B cells were identified by co-expression of fluorescence-conjugated ovalbumin and IL-10. RESULTS: Specific, age-dependent expansion of ovalbumin-specific regulatory T cells was only observed in infants who (a) had early egg introduction and (b) did not have egg allergy at 12 months. This expansion was blunted or impaired in children who did not undergo early egg introduction and in those with clinical egg allergy at 12 months. Infants with egg allergy at 12 months of age also had reduced frequency of ovalbumin-specific regulatory B cells compared to egg-tolerant infants. CONCLUSION: Early egg introduction and clinical tolerance to egg were associated with expansion of ovalbumin-specific T and B regulatory cells, which may be an important developmental process for tolerance acquisition to food allergens.

Maternal Late-Pregnancy Serum Unmetabolized Folic Acid Concentrations Are Not Associated with Infant Allergic Disease: A Prospective Cohort Study.

BACKGROUND: The increase in childhood allergic disease in recent decades has coincided with increased folic acid intakes during pregnancy. Circulating unmetabolized folic acid (UMFA) has been proposed as a biomarker of excessive folic acid intake. OBJECTIVE: We aimed to determine if late-pregnancy serum UMFA and total folate concentrations were associated with allergic disease risk in the offspring at 1 y of age in a population at high risk of allergy. METHODS: The cohort consisted of 561 mother-infant pairs from Western Australia. To be eligible the infant had to have a first-degree relative (mother, father, or sibling) with a history of medically diagnosed allergic disease. Maternal venous blood was collected between 36 and 40 wk of gestation. Serum UMFA was measured by LC-tandem MS. Serum total folate was determined using a microbiological method with chloramphenicol-resistant Lactobacillus rhamnosus as the test organism, and was collected between 36 and 40 wk of gestation. UMFA concentrations were measured by tandem MS using stable isotope dilution; folate concentrations were determined using the microbiological method with standardized kits. Infant allergic disease outcomes of medically diagnosed eczema, steroid-treated eczema, atopic eczema, IgE-mediated food allergy, allergen sensitization, and medically diagnosed wheeze were assessed at 1 y of age. RESULTS: Median (IQR) concentrations for UMFA and serum folate were 1.6 (0.6-4.7) and 53.2 (32.6-74.5) nmol/L, respectively. Of the infants, 34.6% had medically diagnosed eczema, 26.4% allergen sensitization, and 14.9% had an IgE-mediated food allergy. In both adjusted and unadjusted models there was little evidence of association between UMFA or serum folate and any of the infant allergy outcomes. CONCLUSIONS: In this cohort of children at high risk of allergic disease there was no association between maternal UMFA or serum folate concentrations measured in late pregnancy and allergic disease outcomes at 1 y of age.

Lower Cord Blood IL-17 and IL-25, but Not Other Epithelial Cell-Derived Cytokines Are Associated with Atopic Dermatitis in Infancy.

BACKGROUND: There is a growing need for early biomarkers that may predict the development of atopic dermatitis (AD). As alterations in skin barrier may be a primary event in disease pathogenesis, epithelial cell (EC) cytokines expression patterns may be a potential biomarker in early life to target allergy preventive strategies towards "at-risk" infants. OBJECTIVES: The aim of this longitudinal investigation was to examine from birth over the course of infancy levels of the EC cytokines: thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, IL-25, and IL-17 in infants at high-risk of AD due to maternal atopy. METHOD: We collected (n = 31) cord blood samples from atopic mothers and followed up their infants at 4-6 and 12 months of age for collection of peripheral venous blood samples and diagnosis of AD. TSLP concentration was measured by ELISA after acetone precipitation of the samples. IL-33, IL-25, and IL-17 levels were measured by Luminex. RESULTS: Seven infants who developed AD had lower levels of IL-25 and IL-17 at birth compared to the 24 infants who did not develop AD by 12 months of age. CONCLUSIONS: Lower cord blood levels of IL-17 and IL-25, but not other EC cytokines, were associated with the onset of AD during infancy. Our results highlight that the in-utero period appears critical, and potential maternal influences on cord blood EC-derived cytokine concentrations requires further exploration.

Developmental Origins of Health and Disease (DOHaD): The importance of life-course and transgenerational approaches.

With well-established evidence that early life conditions have a profound influence on lifespan and health-span, new interventional birth cohorts are examining ways to optimise health potential of individuals and communities. These are aimed at going beyond preventing disease, to the conditions that facilitate flourishing from an early age. Covering diverse domains, local community projects, such as The ORIGINS Project, are taking a broader approach to the protective and buffering factors that enhance resilience and reduce allostatic load, such as building nature relatedness, interpersonal relationships, mindfulness, and positive emotions. Such cohorts aim to address how 'upstream' approaches will have flow on effects to the 'historical' risk targets (such as poor nutrition, physical inactivity, and stress) by influencing these core behaviours through better relationships with self, community, and the environment. In addition to scientific pursuit, interventional cohorts can contribute to solutions ineverycommunity - nourishing individuals and communities towards positive change.

A role for early oral exposure to house dust mite allergens through breast milk in IgE-mediated food allergy susceptibility.

BACKGROUND: Successful prevention of food allergy requires the identification of the factors adversely affecting the capacity to develop oral tolerance to food antigen in early life. OBJECTIVES: This study sought to determine whether oral exposure to Dermatophagoides pteronyssinus through breast milk affects gut mucosal immunity with long-term effects on IgE-mediated food allergy susceptibility. METHODS: Gut immunity was explored in 2-week-old mice breast-fed by mothers exposed to D pteronyssinus, protease-inactivated D pteronyssinus, or to PBS during lactation. We further analyzed oral tolerance to a bystander food allergen, ovalbumin (OVA). In a proof-of-concept study, Der p 1 and OVA levels were determined in 100 human breast milk samples and the association with prevalence of IgE-mediated egg allergy at 1 year was assessed. RESULTS: Increased permeability, IL-33 levels, type 2 innate lymphoid cell activation, and Th2 cell differentiation were found in gut mucosa of mice nursed by mothers exposed to D pteronyssinus compared with PBS. This pro-Th2 gut mucosal environment inhibited the induction of antigen-specific FoxP3 regulatory T cells and the prevention of food allergy by OVA exposure through breast milk. In contrast, protease-inactivated D pteronyssinus had no effect on offspring gut mucosal immunity. Based on the presence of Der p 1 and/or OVA in human breast milk, we identified groups of lactating mothers, which mirror the ones found in mice to be responsible for different egg allergy risk. CONCLUSIONS: This study highlights an unpredicted potential risk factor for the development of food allergy, that is, D pteronyssinus allergens in breast milk, which disrupt gut immune homeostasis and prevents oral tolerance induction to bystander food antigen through their protease activity.

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.

BACKGROUND: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 µg, daily epicutaneous peanut protein; DBV712 250 µg). OBJECTIVE: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. METHODS: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 µg, subjects who had received DBV712 250 µg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. RESULTS: Of 213 eligible subjects who had received DBV712 250 µg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). CONCLUSIONS: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

A world of inflammation: the need for ecological solutions that co-benefit people, place and planet.

The ecology of the early environment - including microbial diversity, nutrition, nature, social interactions and the totality of exposures in the wider "exposome" - have life-long implications for all aspects of health and resilience. In particular, the emergence of "microbiome science" provides new evidence for vital relationships between biodiversity and health at every level. New perspectives of ecological interdependence connect personal and planetary health; the human health crisis cannot be separated from the social, political and economic "ecosystems" otherwise driving dysbiosis (from its etymological root, "life in distress") at every level. Adverse changes in macroscale ecology - of food systems, lifestyle behaviours, socioeconomic disadvantage and environmental degradation - all impact the microbial systems sitting at the foundations of all ecosystems. In particular, changes in the function and composition of the human-associated microbiome have been implicated in the mounting global burden of noncommunicable diseases (NCDs), exacerbating inflammation and metabolic dysregulation through multiple pathways across the lifespan. This "dysbiotic drift" (adverse shifts in ecology at all scales) underscores the need for ecological approaches aimed at restoring symbiosis, balance and mutualism. While there is promise with supplement-based strategies (e.g. probiotics, prebiotics), it is essential to focus on upstream factors implicated in dysbiosis, including the health of wider environments, lifestyle, nature relatedness, and the social policies and practices which can facilitate or inhibit dysbiotic drift. This also calls for ambitious integrative approaches which not only define these interconnections, but also capitalize on them to create novel, collaborative and mutualistic solutions to our vast interdependent global challenges.

L'écologie de l'environnement précoce - comprenant diversité microbienne, nutrition, nature, interactions sociales et totalité des expositions du large « exposome ¼ - a des implications tout au long de la vie pour tous les aspects de la santé et de la résilience. En particulier, l'émergence de « la science du microbiome ¼ fournit de nouvelles preuves pour les relations vitales entre biodiversité et santé à tous les niveaux. De nouvelles perspectives d'interdépendance écologique connectent la santé personnelle et planétaire ; la crise de la santé humaine ne peut être séparée des écosystèmes économique, politique et social à moins de mener à la dysbiose (de son origine étymologique « vie en péril ¼) à tous les niveaux. Les changements indésirables de l'écologie à grande échelle - systèmes alimentaires, comportement de style de vie, désavantages socio-économiques et dégradation environnementale - impactent tous les systèmes microbiens siégeant à la base de tous les écosystèmes. En particulier, les changements de fonction et de composition du microbiome associé à l'homme ont été impliqués dans l'augmentation de la charge globale des maladies non transmissibles (NCDs), exacerbant l'inflammation et la dérégulation du métabolisme à travers de multiples voies au cours de la vie. Cette « dérive de dysbiose ¼ (dérives indésirables de l'écologie à tous les niveaux) sous-estime le besoin des approches écologiques objectivant la restauration symbiose, balance et mutualisme. Alors que des stratégies supplémentaires sont prometteuses (ex : probiotiques, prébiotiques), il est essentiel de focaliser sur des facteurs en amont impliqués dans la dysbiose, comprenant : santé d'environnements plus larges, style de vie, nature de la parenté, et pratiques sociales, qui peuvent faciliter ou inhiber la dérive de dysbiose. Ceci appel aussi des approches qui ne définissent pas seulement ces interconnections mais aussi capitalisent sur elles pur créer des solutions nouvelles, collaboratives et mutualistes pour nos vastes défis globaux interdépendants.

La ecología del medio ambiente temprano -incluida la diversidad microbiana, la nutrición, la naturaleza, las interacciones sociales y la totalidad de las exposiciones en toda la amplitud del "exposoma"- tiene implicaciones de por vida para todos los aspectos de la salud y la resiliencia. En particular, el surgimiento de la "ciencia del microbioma" proporciona nueva evidencia de las relaciones vitales entre la biodiversidad y la salud en todos los niveles. Nuevas perspectivas de interdependencia ecológica conectan la salud personal y planetaria; la crisis de la salud humana no puede separarse de los "ecosistemas" sociales, políticos y económicos que de otro modo conducen a la disbiosis (de su raíz etimológica, "vida alterada") en todos los niveles. Los cambios adversos en la ecología a macroescala (de los sistemas alimentarios, los comportamientos de estilo de vida, las desventajas socioeconómicas y la degradación ambiental) tienen un impacto en los sistemas microbianos que se encuentran en los cimientos de todos los ecosistemas. En particular, los cambios en la función y composición del microbioma asociado a los seres humanos se han visto implicados en la creciente carga mundial de enfermedades no transmisibles (ENT), que exacerban la inflamación y la disregulación metabólica a través de múltiples vías a lo largo de la vida. Esta "deriva disbiótica" (cambios adversos en la ecología a todas las escalas) subraya la necesidad de enfoques ecológicos destinados a restaurar la simbiosis, el equilibrio y el mutualismo. Si bien es prometedor con las estrategias basadas en suplementos (por ejemplo, probióticos, prebióticos), es esencial centrarse en los factores anteriores implicados en la disbiosis, incluida la salud de entornos más amplios, el estilo de vida, la relación con la naturaleza y las políticas y prácticas sociales que pueden facilitar o inhibir la deriva disbiótica. Esto también requiere enfoques integradores ambiciosos que no solo definan estas interconexiones, sino que también las aprovechen para crear soluciones novedosas, colaborativas y mutualistas para nuestros vastos desafíos globales interdependientes.

A ecologia do ambiente inicial - incluindo diversidade microbiana, nutrição, natureza, interações sociais e a totalidade das exposições no "exposome" mais amplo - tem implicações ao longo da vida para todos os aspectos da saúde e resiliência. Em particular, o surgimento da "ciência do microbioma" fornece novas evidências para relações vitais entre a biodiversidade e a saúde em todos os níveis. Novas perspectivas de interdependência ecológica conectam a saúde pessoal e planetária; a crise da saúde humana não pode ser separada dos "ecossistemas" social, político e econômico, levando à disbiose (de sua raiz etimológica, "vida em perigo") em todos os níveis. Mudanças adversas na ecologia da macroescala - de sistemas alimentares, hábitos de vida, desvantagem socioeconômica e degradação ambiental - impactam os sistemas microbianos que estão na base de todos os ecossistemas. Em particular, as mudanças na função e na composição do microbioma associado ao ser humano têm sido implicadas no aumento da carga global de doenças não comunicáveis (DNCs), exacerbando a inflamação e a desregulação metabólica por meio de várias vias ao longo da vida. Esta "deriva disbiótica" (mudanças adversas na ecologia em todas as escalas) ressalta a necessidade de abordagens ecológicas destinadas a restaurar a simbiose, o equilíbrio e o mutualismo. Embora as estratégias baseadas em suplementos (por exemplo, probióticos, prebióticos) sejam uma grande promessa, é essencial focar nos fatores desencadeadores relacionados à disbiose, incluindo a saúde de forma geral, estilo de vida, relacionamento com a natureza e as políticas e práticas sociais que podem facilitar ou inibir a deriva disbiótica. Isso também exige abordagens integrativas ambiciosas que não apenas definam essas interconexões, mas também as capitalizem para criar soluções novas, colaborativas e mutualísticas para nossos desafios globais vastos e interdependentes.

Cord Blood T Cells Expressing High and Low PKCζ Levels Develop into Cells with a Propensity to Display Th1 and Th9 Cytokine Profiles, Respectively.

Low Protein Kinase C zeta (PKCζ) levels in cord blood T cells (CBTC) have been shown to correlate with the development of allergic sensitization in childhood. However, little is known about the mechanisms responsible. We have examined the relationship between the expression of different levels of PKCζ in CBTC and their development into mature T cell cytokine producers that relate to allergy or anti-allergy promoting cells. Maturation of naïve CBTC was initiated with anti-CD3/-CD28 antibodies and recombinant human interleukin-2 (rhIL-2). To stimulate lymphocyte proliferation and cytokine production the cells were treated with Phytohaemagglutinin (PHA) and Phorbol myristate acetate (PMA). Irrespective of the PKCζ levels expressed, immature CBTC showed no difference in lymphocyte proliferation and the production of T helper 2 (Th2) cytokine interleukin-4 (IL-4) and Th1 cytokine, interferon-gamma (IFN-γ), and influenced neither their maturation from CD45RA+ to CD45RO+ cells nor cell viability/apoptosis. However, upon maturation the low PKCζ expressing cells produced low levels of the Th1 cytokines, IFN-γ, IL-2 and tumour necrosis factor-alpha (TNF), no changes to levels of the Th2 cytokines, IL-4, IL-5 and IL-13, and an increase in the Th9 cytokine, IL-9. Other cytokines, lymphotoxin-α (LT-α), IL-10, IL-17, IL-21, IL-22 and Transforming growth factor-beta (TGF-ß) were not significantly different. The findings support the view that low CBTC PKCζ levels relate to the increased risk of developing allergic diseases.

Characterization of the Transient Deficiency of PKC Isozyme Levels in Immature Cord Blood T Cells and Its Connection to Anti-Allergic Cytokine Profiles of the Matured Cells.

Cord blood T cells (CBTC) from a proportion of newborns express low/deficient levels of some protein kinase C (PKC) isozymes, with low levels of PKCζ correlating with increased risk of developing allergy and associated decrease in interferon-gamma (IFN-γ) producing T cells. Interestingly, these lower levels of PKCζ were increased/normalized by supplementing women during pregnancy with n-3 polyunsaturated fatty acids. However, at present, we have little understanding of the transient nature of the deficiency in the neonate and how PKCζ relates to other PKC isozymes and whether their levels influence maturation into IFN-γ producing T cells. There is also no information on PKCζ isozyme levels in the T cell subpopulations, CD4+ and CD8+ cells. These issues were addressed in the present study using a classical culture model of neonatal T cell maturation, initiated with phytohaemagglutinin (PHA) and recombinant human interleukin-2 (rhIL-2). Of the isozymes evaluated, PKCζ, ß2, δ, µ, ε, θ and λ/ι were low in CBTCs. The PKC isozyme deficiencies were also found in the CD4+ and CD8+ T cell subset levels of the PKC isozymes correlated between the two subpopulations. Examination of changes in the PKC isozymes in these deficient cells following addition of maturation signals showed a significant increase in expression within the first few hours for PKCζ, ß2 and µ, and 1-2 days for PKCδ, ε, θ and λ/ι. Only CBTC PKCζ isozyme levels correlated with cytokine production, with a positive correlation with IFN-γ, interleukin (IL)-2 and tumour necrosis factor-alpha (TNF), and a negative association with IL-9 and IL-10. The findings reinforce the specificity in using CBTC PKCζ levels as a biomarker for risk of allergy development and identify a period in which this can be potentially 'corrected' after birth.

In infants with sufficient vitamin D status at birth, vitamin D supplementation does not impact immune development.

BACKGROUND: Low vitamin D levels have been associated with allergic diseases. Vitamin D has potent immunomodulatory properties, but the mechanisms remain unclear. We have investigated the effect of oral vitamin D supplementation on circulating immune cell phenotypes in infants. METHOD: A double-blinded randomised controlled trial was conducted to investigate the effect of oral vitamin D supplementation (400 IU/d) on eczema and immune development. A subset of 78 infants was included in this analysis. Phenotypic analysis of immune cell subsets was performed using flow cytometry. RESULTS: Vitamin D supplementation resulted in median 25(OH)D levels of 80.5 vs 59.5 nmol/L in the placebo group at 3 months of age (P = .002) and 87.5 vs 77 nmol/L at 6 months of age (P = .08). We observed significant changes in immune cell composition from birth (cord blood) to 6 months of age. Vitamin D supplementation did not impact these changes, nor did immune cell composition correlate with plasma 25(OH)D levels. Through exploratory analysis, we identified possible associations with eczema development and increased abundance of naïve CD4- T cells at birth, as well as associations with basophils, iNKT and central memory CD4+ T cells, and altered expression patterns of IgE receptor (FcεR1) on monocytes and dendritic cells with eczema at 6 months. CONCLUSIONS: Vitamin D supplementation in infants who were vitamin D sufficient at birth did not affect developmental changes in immune cells during the first 6 months of life. However, immune cell profiles at birth and at 6 months of age were associated with early life eczema.