Environmental pollutants and the immune response.

Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system. Xenobiotic receptors, including the aryl hydrocarbon receptor (AHR), sense and respond to a subset of environmental pollutants by activating the expression of detoxification enzymes to protect the body. However, chronic activation of the AHR leads to immunotoxicity. KEAP1-NRF2 is another important system that protects the body against environmental pollutants. KEAP1 is a sensor protein that detects environmental pollutants, leading to activation of the transcription factor NRF2. NRF2 protects the body from immunotoxicity by inducing the expression of genes involved in detoxification, antioxidant and anti-inflammatory activities. Intervening in these sensor-response systems could protect the body from the devastating immunotoxicity that can be induced by environmental pollutants.

From allergen genes to allergy vaccines.

IgE-mediated allergy is a hypersensitivity disease affecting more than 25% of the population. The structures of the most common allergens have been revealed through molecular cloning technology in the past two decades. On the basis of this knowledge of the sequences and three-dimensional structures of culprit allergens, investigators can now analyze the immune recognition of allergens and the mechanisms of allergic inflammation in allergic patients. Allergy vaccines have been constructed that are able to selectively target the aberrant immune responses in allergic patients via different pathways of the immune system. Here we review various types of allergy vaccines that have been developed based on allergen structures, results from their clinical application in allergic patients, and future strategies for allergen-specific immunotherapy and allergy prophylaxis.

From Amish farm dust to bacterial lysates: The long and winding road to protection from allergic disease.

Allergic diseases typically begin in early life and can impose a heavy burden on children and their families. Effective preventive measures are currently unavailable but may be ushered in by studies on the "farm effect", the strong protection from asthma and allergy found in children born and raised on traditional farms. Two decades of epidemiologic and immunologic research have demonstrated that this protection is provided by early and intense exposure to farm-associated microbes that target primarily innate immune pathways. Farm exposure also promotes timely maturation of the gut microbiome, which mediates a proportion of the protection conferred by the farm effect. Current research seeks to identify allergy-protective compounds from traditional farm environments, but standardization and regulation of such substances will likely prove challenging. On the other hand, studies in mouse models show that administration of standardized, pharmacological-grade lysates of human airway bacteria abrogates allergic lung inflammation by acting on multiple innate immune targets, including the airway epithelium/IL-33/ILC2 axis and dendritic cells whose Myd88/Trif-dependent tolerogenic reprogramming is sufficient for asthma protection in adoptive transfer models. To the extent that these bacterial lysates mimic the protective effects of natural exposure to microbe-rich environments, these agents might provide an effective tool for prevention of allergic disease.

The impact of outdoor pollution and extreme temperatures on asthma-related outcomes: A systematic review for the EAACI guidelines on environmental science for allergic diseases and asthma.

Air pollution is one of the biggest environmental threats for asthma. Its impact is augmented by climate change. To inform the recommendations of the EAACI Guidelines on the environmental science for allergic diseases and asthma, a systematic review (SR) evaluated the impact on asthma-related outcomes of short-term exposure to outdoor air pollutants (PM2.5, PM10, NO2, SO2, O3, and CO), heavy traffic, outdoor pesticides, and extreme temperatures. Additionally, the SR evaluated the impact of the efficacy of interventions reducing outdoor pollutants. The risk of bias was assessed using ROBINS-E tools and the certainty of the evidence by using GRADE. Short-term exposure to PM2.5, PM10, and NO2 probably increases the risk of asthma-related hospital admissions (HA) and emergency department (ED) visits (moderate certainty evidence). Exposure to heavy traffic may increase HA and deteriorate asthma control (low certainty evidence). Interventions reducing outdoor pollutants may reduce asthma exacerbations (low to very low certainty evidence). Exposure to fumigants may increase the risk of new-onset asthma in agricultural workers, while exposure to 1,3-dichloropropene may increase the risk of asthma-related ED visits (low certainty evidence). Heatwaves and cold spells may increase the risk of asthma-related ED visits and HA and asthma mortality (low certainty evidence).

[The impact of today's environment on allergies: can we take action?] / Incidence de l'environnement actuel sur les allergies : peut-on agir ?

Allergic diseases have risen sharply in recent decades. After some epidemiological data, we take a look at the various hypotheses explaining this allergy "epidemic". Changes in our environment, such as pollution, are a source of climate change and an increase in allergic diseases through inflammation of epithelial barriers. Allergy prevention, a public health emergency, relies on environmental actions at both individual and collective levels.

Extracellular vesicles of the probiotic bacteria E. coli O83 activate innate immunity and prevent allergy in mice.

BACKGROUND: E. coli O83 (Colinfant Newborn) is a Gram-negative (G-) probiotic bacterium used in the clinic. When administered orally, it reduces allergic sensitisation but not allergic asthma. Intranasal administration offers a non-invasive and convenient delivery method. This route bypasses the gastrointestinal tract and provides direct access to the airways, which are the target of asthma prevention. G- bacteria such as E. coli O83 release outer membrane vesicles (OMVs) to communicate with the environment. Here we investigate whether intranasally administered E. coli O83 OMVs (EcO83-OMVs) can reduce allergic airway inflammation in mice. METHODS: EcO83-OMVs were isolated by ultracentrifugation and characterised their number, morphology (shape and size), composition (proteins and lipopolysaccharide; LPS), recognition by innate receptors (using transfected HEK293 cells) and immunomodulatory potential (in naïve splenocytes and bone marrow-derived dendritic cells; BMDCs). Their allergy-preventive effect was investigated in a mouse model of ovalbumin-induced allergic airway inflammation. RESULTS: EcO83-OMVs are spherical nanoparticles with a size of about 110 nm. They contain LPS and protein cargo. We identified a total of 1120 proteins, 136 of which were enriched in OMVs compared to parent bacteria. Proteins from the flagellum dominated. OMVs activated the pattern recognition receptors TLR2/4/5 as well as NOD1 and NOD2. EcO83-OMVs induced the production of pro- and anti-inflammatory cytokines in splenocytes and BMDCs. Intranasal administration of EcO83-OMVs inhibited airway hyperresponsiveness, and decreased airway eosinophilia, Th2 cytokine production and mucus secretion. CONCLUSIONS: We demonstrate for the first time that intranasally administered OMVs from probiotic G- bacteria have an anti-allergic effect. Our study highlights the advantages of OMVs as a safe platform for the prophylactic treatment of allergy. Video Abstract.

Maternal fish oil and/or probiotics intervention: Allergic diseases in children up to two years old.

BACKGROUND: As n-3 long-chain polyunsaturated fatty acids and probiotics possess immunomodulatory properties, theoretically they could lower the risk of allergic diseases. But their effects remain controversial. We aimed to study the effects of fish oil and probiotics separately or in combination from early pregnancy onwards to lower the risk of allergic diseases in the infants. METHODS: In this double-blind trial, women (n = 439) in early pregnancies were randomized into four intervention groups: fish oil + placebo, probiotics + placebo, fish oil + probiotics, and placebo + placebo. Fish oil (1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid) and probiotic (Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each) supplements were provided for daily consumption from randomization up to 6 months postpartum. All analyses were adjusted with pet ownership. RESULTS: No difference between the infants in the four intervention groups were found regarding physician-diagnosed food allergy, atopic eczema, or atopy at the age of 12 or 24 months (all p > .05). The probiotic intervention was associated with lower odds of recurrent wheezing at 24 months (OR 0.39, 95% CI 0.18-0.84, p = .017), but not at 12 months. CONCLUSIONS: The use of fish oil and/or probiotics from early pregnancy onwards did not lower the odds of childhood allergic diseases or atopy, with the exception of the probiotic intervention which decreased the risk of recurrent wheezing when the infants were two years old. This suggests that the incidence of asthma could also decrease later in childhood and thus these outcomes need to be clarified in further investigations.

Quality of systematic reviews on timing of complementary feeding for early childhood allergy prevention.

BACKGROUND: Only rigorously prepared analyses can provide the highest level of evidence to inform decision-making. Several recent systematic reviews (SRs) examined the hypothesis that the early introduction of specific allergenic complementary foods (CFs) to infants may lead to a lower incidence of one or more allergic outcomes. However, the methodological rigour and quality of reporting of SRs in this area has not yet been systematically evaluated. METHODS: We comprehensively searched PubMed, Medline (Ovid), and Web of Science Core Collection on 13th January 2022, using a pre-specified and tested search syntax for SRs with RCT evidence on the early introduction of allergenic CFs as a means for allergy prevention in infants and children. We examined the quality and risk of bias (RoB) using AMSTAR-2 and ROBIS tools, examined adherence to the Preferred Reporting Items for SRs and Meta-Analyses (PRISMA), and checked whether certainty of the evidence was assessed. RESULTS: Twelve SRs were included. Application of both tools resulted in similar overall judgements in terms of direction and extent for nine of the 12 SRs. Nine SRs were found to be of critically low to low quality according to AMSTAR-2 and to be at high RoB according to ROBIS. One SR received a moderate quality rating (AMSTAR-2) and high RoB rating (ROBIS). However, for two SRs, judgements between AMSTAR-2 and ROBIS were at stark variance. Only two SRs fully adhered to the PRISMA checklist. Six SRs evaluated the certainty of the body of RCT evidence. Several SRs failed to consider unpublished studies either by an explicit a priori exclusion or by inadequate search strategies. CONCLUSIONS: Well-conducted SRs are important for decision-making and informing guideline development, the quality of their methodology should therefore be considered. The methodological rigour and the reporting quality of SRs on the timing of CF for allergy prevention must be improved. REGISTRATION: https://osf.io/7cs4b .

Hypovitaminosis D in infants: Evidence that increased intake of vitamin D reduces the incidence of allergic and respiratory disorders.

AIM: The study assessed the relationship between vitamin D status in infants and the presence of allergic and/or respiratory disorders. MATERIALS AND METHODS: The study cohort comprised 81 hospitalized infants presenting at the Pediatric Clinic, University Clinical Center Kragujevac, Serbia, between January 2011 and June 2016. RESULTS: The age of the infants ranged from 29 days to 12 months. All infants received prophylactic doses of vitamin D3 of 400 IU/daily until the end of the first year of life regardless of whether they are fed with adapted infant formula (n = 20) or breast milk (n = 37) or concurrently both (n = 24), up to the 5th month of life. The mean level of plasma 25(OH)D was 29.65 ng/mL. Hypovitaminosis D (mean serum level of 25(OH)D < 30 ng/mL) was found in n = 38 infants of which 6 presented with severe vitamin D deficiency (level below 10 ng/mL), 13 presented with vitamin D deficiency (level between 10 and 20 ng/mL) and 19 had vitamin D insufficiency (levels between 20 and 30 ng/mL). The median vitamin D serum level in infants with allergic disease (n = 16) was 32.35 ng/mL and in infants with respiratory disease (n = 65) 28.99 ng/mL. CONCLUSION: Daily vitamin D3 supplementation with 400 IU in infants until the end of the first year of life is too low to provide optimal defense against respiratory and/or allergic conditions.

Protection against allergies: Microbes, immunity, and the farming effect.

The prevalence of asthma and other allergic diseases has rapidly increased in "Westernized" countries over recent decades. This rapid increase suggests the involvement of environmental factors, behavioral changes or lifestyle, rather than genetic drift. It has become increasingly clear that the microbiome plays a key role in educating the host immune system and, thus, regulation of disease susceptibility. This review will focus on recent advances uncovering immunological and microbial mechanisms that protect against allergies, in particular, within the context of a farming environment. A whole body of epidemiological data disclosed the nature of the protective exposures in a farm. Current evidence points toward an important role of the host microbiome in setting an immunological equilibrium that determines progression toward, or protection against allergic diseases. Conclusive mechanistic insights on how microbial exposures prevent from developing allergic diseases in humans are still lacking but findings from experimental models reveal plausible immunological mechanisms. Gathering further knowledge on these mechanisms and confirming their relevance in humans is of great importance to develop preventive strategies for children at risk of developing allergies.

Early priming of asthma and respiratory allergies: Future aspects of prevention: A statement by the European Forum for Education and Research in Allergy and Airway Disease (EUFOREA) and the EAACI-Clemens von Pirquet Foundation.

In order to summarize recent research on the prevention of allergies-particularly asthma-and stimulate new activities for future initiatives, a virtual workshop sponsored by the EAACI Clemens von Pirquet foundation and EUFOREA was held in October 2021. The determinants of the "allergic march" as well as the key messages from intervention studies were reviewed by an international faculty of experts. Several unmet needs were identified, and a number of priorities for future studies were proposed.

Environmental influences on childhood allergies and asthma - The Farm effect.

Asthma and allergies are major health problems and exert an enormous socioeconomic burden. Besides genetic predisposition, environmental factors play a crucial role in the development of these diseases in childhood. Multiple worldwide epidemiological studies have shown that children growing up on farms are immune to allergic diseases and asthma. Farm-related exposures shape children's immune homeostasis, via mediators such as N-glycolylneuraminic acid or arabinogalactan, or by diverse environmental microbes. Moreover, nutritional factors, such as breastfeeding or farm milk and food diversity, inducing short-chain fatty acids-producing bacteria in the intestine, contribute to farm-related effects. All farm-related exposures induce an anti-inflammatory response of the innate immunity and increase the differentiation of regulatory T cells and T helper cell type 1. A better understanding of the components of the farm environment, that are protective to the development of allergy and asthma, and their underlying mechanisms, will help to develop new strategies for the prevention of allergy and asthma.

The Role of the Allergist in Coronavirus Disease 2019 Vaccine Allergy Safety: A Pilot Study on a "Hub-and-Spoke" Model for Population-Wide Allergy Service.

BACKGROUND: Hong Kong started its coronavirus disease 2019 (COVID-19) vaccination program in February 2021. A territory-wide Vaccine Allergy Safety (VAS) clinic was set up to assess individuals deemed at "higher risk" of COVID-19 vaccine-associated allergies. A novel "hub-and-spoke" model was piloted to tackle the overwhelming demand of services by allowing nonallergists to conduct assessment. OBJECTIVE: To evaluate the outcomes of the VAS hub-and-spoke model for allergy assessment. METHODS: Records of patients attending the VAS hub-and-spoke Clinics between March and August 2021 were reviewed (n = 2725). We studied the overall results between the Hub (allergist led) and Spoke (nonallergist led) Clinics. The Hub and the Hong Kong West Cluster Spoke Clinic were selected for subgroup analysis as they saw the largest number of patients (n = 1411). RESULTS: A total of 2725 patients were assessed under the VAS hub-and-spoke model. Overall, 2324 patients (85.3%) were recommended to proceed with vaccination. Allergists recommended significantly more patients for vaccination than nonallergists (odds ratio = 21.58; P < .001). Subgroup analysis revealed that 881 of 1055 (83.5%) patients received their first dose of COVID-19 vaccination safely after assessment. Among those recommended vaccination, more patients assessed by allergists received their first dose of vaccination (odds ratio = 4.18; P < .001). CONCLUSION: The hub-and-spoke model has proven to be successful for the vaccination campaign. This study has illustrated the crucial role of allergists in countering vaccine hesitancy. Results from the study revealed considerable differences in outcomes between allergist-led and nonallergist-led clinics. Precise reasons for these differences warrant further evaluation. We are hopeful that the hub-and-spoke model can be similarly adapted for other allergist-integrative services in the future.

Analysing the protection from respiratory tract infections and allergic diseases early in life by human milk components: the PRIMA birth cohort.

BACKGROUND: Many studies support the protective effect of breastfeeding on respiratory tract infections. Although infant formulas have been developed to provide adequate nutritional solutions, many components in human milk contributing to the protection of newborns and aiding immune development still need to be identified. In this paper we present the methodology of the "Protecting against Respiratory tract lnfections through human Milk Analysis" (PRIMA) cohort, which is an observational, prospective and multi-centre birth cohort aiming to identify novel functions of components in human milk that are protective against respiratory tract infections and allergic diseases early in life. METHODS: For the PRIMA human milk cohort we aim to recruit 1000 mother-child pairs in the first month postpartum. At one week, one, three, and six months after birth, fresh human milk samples will be collected and processed. In order to identify protective components, the level of pathogen specific antibodies, T cell composition, Human milk oligosaccharides, as well as extracellular vesicles (EVs) will be analysed, in the milk samples in relation to clinical data which are collected using two-weekly parental questionnaires. The primary outcome of this study is the number of parent-reported medically attended respiratory infections. Secondary outcomes that will be measured are physician diagnosed (respiratory) infections and allergies during the first year of life. DISCUSSION: The PRIMA human milk cohort will be a large prospective healthy birth cohort in which we will use an integrated, multidisciplinary approach to identify the longitudinal effect human milk components that play a role in preventing (respiratory) infections and allergies during the first year of life. Ultimately, we believe that this study will provide novel insights into immunomodulatory components in human milk. This may allow for optimizing formula feeding for all non-breastfed infants.

Effective Ways to Prevent Allergic Diseases: Where Do We Stand?

Since allergic diseases are of great public health relevance, effective primary prevention strategies are urgently needed. This chapter gives an overview of existing primary prevention programs on environmental exposures and dietary strategies based on epidemiological studies which have defined risk- and protective factors for the development of allergic diseases.The allergy protective effect mediated by growing up on a traditional farm environment is well studied. But the exact underlying mechanisms have still not been fully clarified and have not yet led to concrete prevention strategies. The beneficial effect of avoiding cigarette smoke exposure, indoor moisture and molds in pregnancy and childhood on the development of asthma is well documented. Whereas the avoidance of house dust mite exposure is not recommended to prevent eczema or allergy. Dietary supplementation with vitamins, pre- and probiotics in pregnant woman and their offspring is not harmful but evidence for the prevention of allergic diseases is still lacking. Fish oil consumption was shown to be asthma protective. The early introduction of peanuts and egg protein to prevent peanut and egg allergy in children with atopic dermatitis is promising. Further studies are needed to increase the overall evidence in allergy prevention. Most studies lack methodological standards such as randomization and blinding. More evidence is in demand on the potential beneficial impact of multifaceted interventional studies. The future of allergy prevention strategies might be based on individual risk assessment. Therefore, research in the immunological and molecular basis of allergic diseases needs to be promoted.

Epigenetic Mechanisms in Allergy Development and Prevention.

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

Choking, allergic reactions, and pickiness: A qualitative study of maternal perceived threats and risk avoidance strategies during complementary feeding.

An infant's early eating experiences influence later growth and health. However, motivators for mothers' complementary feeding decisions for their infants, such as the process of introducing solid foods, remains unclear. This qualitative study identified maternal perceived threats surrounding complementary feeding and strategies mothers use to mitigate perceived threats of adverse feeding-related health outcomes for their infants. Twenty-seven mothers participated in private, semi-structured interviews. Inductive and deductive qualitative content analysis revealed three primary themes of maternal perceived threats: a) choking, b) allergic reaction, and c) pickiness. Within each primary theme were sub-themes that further delineated the perceived threats and outlined specific and focused complementary feeding practices (CFPs) mothers used for each type of perceived threat. Findings suggest mothers have difficulty with estimating the likelihood and severity of risks and rely on elevated threat perception to guide their feeding decisions. CFPs used to prevent perceived threats were disproportionate to risks, and, at times, actually introduced additional, alternative risks.

Recommendations were made for diagnosis and management of allergic reactions to COVID-19 vaccines.

SOURCE CITATION: Greenhawt M, Abrams EM, Shaker M, et al. The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach. J Allergy Clin Immunol Pract. 2021;9:3546-67. 34153517.