Mould allergen Alt a 1 spiked with the micronutrient retinoic acid reduces Th2 response and ameliorates Alternaria allergy in BALB/c mice.

BACKGROUND: We investigated the biological function of the mould allergen Alt a 1 as a carrier of micronutrients, such as the vitamin A metabolite retinoic acid (RA) and the influence of RA binding on its allergenicity in vitro and in vivo. METHODS: Alt a 1-RA complex formation was analyzed in silico and in vitro. PBMCs from Alternaria-allergic donors were stimulated with Alt a 1 complexed with RA (holo-Alt a 1) or empty apo-Alt a 1 and analyzed for cytokine production and CD marker expression. Serum IgE-binding and crosslinking assays to apo- and holo-protein were correlated to B-cell epitope analysis. Female BALB/c mice already sensitized to Alt a 1 were intranasally treated with apo-Alt a 1, holo-Alt a 1 or RA alone before measuring anaphylactic response, serum antibody levels, splenic cytokines and CD marker expression. RESULTS: In silico docking calculations and in vitro assays showed that the extent of RA binding depended on the higher quaternary state of Alt a 1. Holo-Alt a 1 loaded with RA reduced IL-13 released from PBMCs and CD3+CD4+CRTh2 cells. Complexing Alt a 1 to RA masked its IgE B-cell epitopes and reduced its IgE-binding capacity. In a therapeutic mouse model of Alternaria allergy nasal application of holo-Alt a 1, but not of apo-Alt a 1, significantly impeded the anaphylactic response, impaired splenic antigen-presenting cells and induced IL-10 production. CONCLUSION: Holo-Alt a 1 binding to RA was able to alleviate Th2 immunity in vitro, modulate an ongoing Th2 response and prevent anaphylactic symptoms in vivo, presenting a novel option for improving allergen-specific immunotherapy in Alternaria allergy.

An EAACI review: Go green in health care and research. Practical suggestions for sustainability in clinical practice, laboratories, and scientific meetings.

Health care professionals (HCPs) and researchers in the health care sector dedicate their professional life to maintaining and optimizing the health of their patients. To achieve this, significant amounts of resources are used and currently it is estimated that the health care sector contributes to more than 4% of net greenhouse gas (GHG) emissions. GHG emissions adversely impact planetary health and consequently human health, as the two are intricately linked. There are many factors of health care that contribute to these emissions. Hospitals and research labs also use high amounts of consumables which require large amounts of raw materials and energy to produce. They are further responsible for polluting the environment via disposal of plastics, drug products, and other chemicals. To maintain and develop state-of-the-art best practices and treatments, medical experts exchange and update their knowledge on methods and technologies in the respective fields at highly specialized scientific meetings. These meetings necessitate thousands of attendants traveling around the globe. Therefore, while the goal of HCPs is to care for the individual, current practices have an enormous (indirect) impact on the health of the patients by their negative environmental impacts. There is an urgent need for HCPs and researchers to mitigate these detrimental effects. The installation of a sustainability-manager at health care facilities and research organizations to implement sustainable practices while still providing quality health care is desirable. Increased use of telemedicine, virtual/hybrid conferences and green chemistry have recently been observed. The benefits of these practices need to be evaluated and implemented as appropriate. With this manuscript, we aim to increase the awareness about the negative impacts of the health care system (including health care research) on planetary and human health. We suggest some easy and highly impactful steps and encourage health care professionals and research scientists of all hierarchical levels to immediately implement them in their professional as well as private life to counteract the health care sector's detrimental effects on the environment.

The One Health approach for allergic diseases and asthma.

The One Health approach is a collaborative and interdisciplinary strategy with focal point on human, animal, and environmental health interconnections. One Health can support the advanced management of allergic diseases and asthma, as complex, multifactorial diseases driven by interactions between the resilience response to the exposome. According to the One Health concept allergic diseases and asthma arising from exposures to a wide range of allergens, infectious agents and irritants (such as pollutants) occurring indoors and outdoors can be heavily influenced by environmental health (air, water, and soil quality) intermingled with animal health. These are currently heavily impacted by climate change, land use, urbanization, migration, overpopulation, and many more. Thus, a coordinated response to address the underlying factors that contribute to the development of allergic diseases and asthma needs to focus on the environment, human, and animal health altogether. Collaborative efforts across multiple sectors, including public health, veterinary medicine, environmental science, and community engagement are thus needed. A wide range of activities, including monitoring and surveillance of environmental and health data, targeted interventions to reduce exposures to allergens and irritants, and research on the underlying mechanisms that drive the development of allergic diseases and asthma are needed to move the field forward. In this consensus document elaborated by the European Academy of Allergy and Clinical Immunology (EAACI) and American Academy of Allergy, Asthma, and Immunology (AAAAI) under the practical allergy (PRACTALL) series, we provide insights into the One Heath approach aiming to provide a framework for addressing the complex and multifactorial nature of allergic diseases and asthma.

Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines update - III - Cow's milk allergens and mechanisms triggering immune activation.

Background: The immunopathogenesis of cow's milk protein allergy (CMPA) is based on different mechanisms related to immune recognition of protein epitopes, which are affected by industrial processing. Purpose: The purpose of this WAO DRACMA paper is to: (i) give a comprehensive overview of milk protein allergens, (ii) to review their immunogenicity and allergenicity in the context of industrial processing, and (iii) to review the milk-related immune mechanisms triggering IgE-mediated immediate type hypersensitivity reactions, mixed reactions and non-IgE mediated hypersensitivities. Results: The main cow's milk allergens - α-lactalbumin, ß-lactoglobulin, serum albumin, caseins, bovine serum albumins, and others - may determine allergic reactions through a range of mechanisms. All marketed milk and milk products have undergone industrial processing that involves heating, filtration, and defatting. Milk processing results in structural changes of immunomodulatory proteins, leads to a loss of lipophilic compounds in the matrix, and hence to a higher allergenicity of industrially processed milk products. Thereby, the tolerogenic capacity of raw farm milk, associated with the whey proteins α-lactalbumin and ß-lactoglobulin and their lipophilic ligands, is lost. Conclusion: The spectrum of immunopathogenic mechanisms underlying cow's milk allergy (CMA) is wide. Unprocessed, fresh cow's milk, like human breast milk, contains various tolerogenic factors that are impaired by industrial processing. Further studies focusing on the immunological consequences of milk processing are warranted to understand on a molecular basis to what extent processing procedures make single milk compounds into allergens.

Role of dietary fiber in promoting immune health-An EAACI position paper.

Microbial metabolism of specific dietary components, such as fiber, contributes to the sophisticated inter-kingdom dialogue in the gut that maintains a stable environment with important beneficial physiological, metabolic, and immunological effects on the host. Historical changes in fiber intake may be contributing to the increase of allergic and hypersensitivity disorders as fiber-derived metabolites are evolutionarily hardwired into the molecular circuitry governing immune cell decision-making processes. In this review, we highlight the importance of fiber as a dietary ingredient, its effects on the microbiome, its effects on immune regulation, the importance of appropriate timing of intervention to target any potential window of opportunity, and potential mechanisms for dietary fibers in the prevention and management of allergic diseases. In addition, we review the human studies examining fiber or prebiotic interventions on asthma and respiratory outcomes, allergic rhinitis, atopic dermatitis, and overall risk of atopic disorders. While exposures, interventions, and outcomes were too heterogeneous for meta-analysis, there is significant potential for using fiber in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health.

The extended farm effect: The milk protein ß-lactoglobulin in stable dust protects against allergies.

BACKGROUND: The allergy- and asthma-protective farm effect is mediated by numerous factors. Especially dust from cattle stables and raw cow's milk show beneficial properties, suggesting a bovine protein to be involved. As a major milk protein and member of the lipocalin family, ß-lactoglobulin (BLG) binds small, hydrophobic ligands and thereby modulates the immune response. Empty BLG promotes allergy development, whereas BLG in association with ligands shows allergy-preventive as well as allergy-reducing effects in vivo and in vitro. RESULTS: BLG has been identified as a major protein in stable dust (therein bound to zinc) as well as in the air around cattle stables. This association with zinc favors an allergy-protective immune profile. CONCLUSION: Its immune-modulating, allergy-protective characteristics together with its presence in raw cow's milk as well as in stable dust and ambient air render BLG an essential contributor to the farm effect.

Secretory protein beta-lactoglobulin in cattle stable dust may contribute to the allergy-protective farm effect.

BACKGROUND: Growing up on a cattle farm and consuming raw cow's milk protects against asthma and allergies. We expect a cattle-specific protein as active component in this farm effect. METHODS: Dust was collected from cattle and poultry stables and from mattresses of households. Urine was obtained from cattle, and ambient aerosols were sampled. Samples were analysed for BLG by SDS PAGE/immunoblot and mass spectrometry, and for association with metals by SEC-ICP-MS. PBMC of healthy donors were incubated with BLG +/- zinc, and proliferation and cytokines determined. BALB/c mice were pre-treated intranasally with stable dust extract containing BLG or depleted of BLG, and subsequent allergy response after sensitization was evaluated on antibody and symptom level. RESULTS: A major protein in dust from cattle farms and ambient air was identified as BLG. Urine from female and male cattle is a major source of BLG. In dust samples, BLG was associated with zinc. In vitro, zinc-BLG provoked significantly lower proliferation of CD4+ and CD8+ cells while inducing significantly higher levels of IFN-γ and IL-6 than the apo-BLG devoid of zinc. In vivo, pre-treatment of mice with dust extract containing BLG resulted in lower allergy symptom scores to BLG and unrelated Bet v 1 than pre-treatment with extract depleted of BLG. These in vitro and in vivo effects were independent of endotoxin. CONCLUSION: The lipocalin BLG is found in large amounts in cattle urine, accumulates in bovine dust samples and is aerosolized around farms. Its association with zinc favorably shapes the human cellular immune response towards Th1-cytokines in vitro. BLG together with zinc in stable dust protects mice from allergic sensitization. BLG with its associated ligands may in an innate manner contribute to the allergy-protective farm effect.

Climate change and global health: A call to more research and more action.

There is increasing understanding, globally, that climate change and increased pollution will have a profound and mostly harmful effect on human health. This review brings together international experts to describe both the direct (such as heat waves) and indirect (such as vector-borne disease incidence) health impacts of climate change. These impacts vary depending on vulnerability (i.e., existing diseases) and the international, economic, political, and environmental context. This unique review also expands on these issues to address a third category of potential longer-term impacts on global health: famine, population dislocation, and environmental justice and education. This scholarly resource explores these issues fully, linking them to global health in urban and rural settings in developed and developing countries. The review finishes with a practical discussion of action that health professionals around the world in our field can yet take.

Nutrient supplementation for prevention of viral respiratory tract infections in healthy subjects: A systematic review and meta-analysis.

It remains uncertain as to whether nutrient supplementation for the general population considered healthy could be useful in the prevention of RTIs, such as COVID-19. In this systematic review and meta-analysis, the evidence was evaluated for primary prevention of any viral respiratory tract infection (RTI) such as SARS-CoV-2, through supplementation of nutrients with a recognized role in immune function: multiple micronutrients, vitamin A, folic acid, vitamin B12, C, D, E, beta-carotene, zinc, iron and long-chain polyunsaturated fatty acids. The search produced 15,163 records of which 93 papers (based on 115 studies) met the inclusion criteria, resulting in 199,055 subjects (191,636 children and 7,419 adults) from 37 countries. Sixty-three studies were included in the meta-analyses, which was performed for children and adults separately. By stratifying the meta-analysis by world regions, only studies performed in Asia showed a significant but heterogeneous protective effect of zinc supplementation on RTIs (RR 0.86, 95% CI 0.7-0.96, I2  = 79.1%, p = .000). Vitamin D supplementation in adults significantly decreased the incidence of RTI (RR 0.89, 95% CI 0.79-0.99, p = .272), particularly in North America (RR 0.82 95% CI 0.68-0.97), but not in Europe or Oceania. Supplementation of nutrients in the general population has either no or at most a very limited effect on prevention of RTIs. Zinc supplementation appears protective for children in Asia, whilst vitamin D may protect adults in the USA and Canada. In 10/115 (8.7%) studies post-hoc analyses based on stratification for nutritional status was performed. In only one study zinc supplementation was found to be more effective in children with low zinc serum as compared to children with normal zinc serum levels.

One Health: EAACI Position Paper on coronaviruses at the human-animal interface, with a specific focus on comparative and zoonotic aspects of SARS-CoV-2.

The latest outbreak of a coronavirus disease in 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), evolved into a worldwide pandemic with massive effects on health, quality of life, and economy. Given the short period of time since the outbreak, there are several knowledge gaps on the comparative and zoonotic aspects of this new virus. Within the One Health concept, the current EAACI position paper dwells into the current knowledge on SARS-CoV-2's receptors, symptoms, transmission routes for human and animals living in close vicinity to each other, usefulness of animal models to study this disease and management options to avoid intra- and interspecies transmission. Similar pandemics might appear unexpectedly and more frequently in the near future due to climate change, consumption of exotic foods and drinks, globe-trotter travel possibilities, the growing world population, the decreasing production space, declining room for wildlife and free-ranging animals, and the changed lifestyle including living very close to animals. Therefore, both the society and the health authorities need to be aware and well prepared for similar future situations, and research needs to focus on prevention and fast development of treatment options (medications, vaccines).

Micronutritional supplementation with a holoBLG-based FSMP (food for special medical purposes)-lozenge alleviates allergic symptoms in BALB/c mice: Imitating the protective farm effect.

BACKGROUND: Previously, the protective farm effect was imitated using the whey protein beta-lactoglobulin (BLG) that is spiked with iron-flavonoid complexes. Here, we formulated for clinical translation a lozenge as food for special medical purposes (FSMP) using catechin-iron complexes as ligands for BLG. The lozenge was tested in vitro and in a therapeutical BALB/c mice model. METHODS: Binding of iron-catechin into BLG was confirmed by spectroscopy and docking calculations. Serum IgE binding of children allergic or tolerating milk was assessed to loaded (holo-) versus empty (apo-) BLG and for human mast cell degranulation. BLG and Bet v 1 double-sensitized mice were orally treated with the holoBLG or placebo lozenge, and immunologically analysed after systemic allergen challenge. Human PBMCs of pollen allergic subjects were flow cytometrically assessed after stimulation with apoBLG or holoBLG using catechin-iron complexes as ligands. RESULTS: One major IgE and T cell epitope were masked by catechin-iron complexes, which impaired IgE binding of milk-allergic children and degranulation of mast cells. In mice, only supplementation with the holoBLG lozenge reduced clinical reactivity to BLG and Bet v 1, promoted Tregs, and suppressed antigen presentation. In allergic subjects, stimulation of PBMCs with holoBLG led to a significant increase of intracellular iron in circulating CD14+ cells with significantly lower expression of HLADR and CD86 compared to their stimulation with apoBLG. CONCLUSION: The FSMP lozenge targeted antigen presenting cells and dampened immune activation in human immune cells and allergic mice in an antigen-non-specific manner, thereby conferring immune resilience against allergic symptoms.

Quality of life and asthma control in pregnant women with asthma.

BACKGROUND: Asthma is the most commonly occurring respiratory illness during pregnancy. Associations with complications of pregnancy and adverse perinatal outcome have been established. However, little is known about quality of life (QoL) in pregnant women with asthma and how it relates to asthma control particularly for Iran. OBJECTIVE: To determine the relationship between asthma related QoL and asthma control and severity. METHODS: We conducted a prospective study in pregnant women with asthma. We used the Asthma Control Questionnaire and the Asthma Quality of Life Questionnaire (AQLQ) and the guidelines of the Global Initiative for Asthma for assessment of asthma severity. RESULTS: Among 1603 pregnant women, 34 were diagnosed with asthma. Of these 13 had intermittent, 10 mild, 8 moderate and 3 severe persistent asthma. There was a significant decrease of QoL with poorer asthma control (p = 0.014). This decline could be due to limitations of activity in those with poorer asthma control, which is underlined by the significant decline of QoL with increasing asthma severity (p = 0.024). CONCLUSION: Although the majority of pregnant women with asthma had a favorable score in AQLQ, reduced QoL was related to increased asthma severity and poor asthma control. This underlines the importance of controlling asthma during pregnancy not only for the prevention of adverse pregnancy outcomes but also for the preservation of QoL.

Bovine Holo-Beta-Lactoglobulin Cross-Protects Against Pollen Allergies in an Innate Manner in BALB/c Mice: Potential Model for the Farm Effect.

The lipocalin beta-lactoglobulin (BLG) is a major protein compound in cow's milk, and we detected it in cattle stable dust. BLG may be a novel player in the farm protective effect against atopic sensitization and hayfever. In previous studies, we demonstrated that only the ligand-filled holo-form of BLG prevented sensitization to itself. Here, we investigated whether holo-BLG could, in an innate manner, also protect against allergic sensitization to unrelated birch pollen allergens using a murine model. BALB/c mice were nasally pretreated four times in biweekly intervals with holo-BLG containing quercetin-iron complexes as ligands, with empty apo-BLG, or were sham-treated. Subsequently, mice were intraperitoneally sensitized two times with apo-BLG or with the unrelated birch pollen allergen apo-Bet v 1, adjuvanted with aluminum hydroxide. After subsequent systemic challenge with BLG or Bet v 1, body temperature drop was monitored by anaphylaxis imaging. Specific antibodies in serum and cytokines of BLG- and Bet v 1-stimulated splenocytes were analyzed by ELISA. Additionally, human peripheral blood mononuclear cells of pollen allergic subjects were stimulated with apo- versus holo-BLG before assessment by FACS. Prophylactic treatment with the holo-BLG resulted in protection against allergic sensitization and clinical reactivity also to Bet v 1 in an unspecific manner. Pretreatment with holo-BLG resulted in significantly lower BLG-as well as Bet v 1-specific antibodies and impaired antigen-presentation with significantly lower numbers of CD11c+MHCII+ cells expressing CD86. Pretreatment with holo-BLG also reduced the release of Th2-associated cytokines from Splenocytes in BLG-sensitized mice. Similarly, in vitro stimulation of PBMCs from birch pollen allergic subjects with holo-BLG resulted in a relative decrease of CD3+CD4+ and CD4+CRTh2 cells, but not of CD4+CD25+CD127- Treg cells, compared to apo-BLG stimulation. In conclusion, prophylactic treatment with holo-BLG protected against allergy in an antigen-specific and -unspecific manner by decreasing antigen presentation, specific antibody production and abrogating a Th2-response. Holo-BLG therefore promotes immune resilience against pollen allergens in an innate manner and may thereby contribute to the farm protective effect against atopic sensitization.

Allergens and Adjuvants in Allergen Immunotherapy for Immune Activation, Tolerance, and Resilience.

Allergen immunotherapy (AIT) is the only setting in which a vaccine is applied in patients allergic exactly to the active principle in the vaccine. Therefore, AIT products need to be not only effective but also safe. In Europe, for subcutaneous AIT, this has been achieved by the allergoid strategy in which IgE epitopes are destroyed or masked. In addition, adjuvants physically precipitate the allergen at the injection site to prevent too rapid systemic distribution. The choice of adjuvant critically shapes the efficacy and type of immune response to the injected allergen. In contrast to TH2-promoting adjuvants, others clearly counteract allergy. Marketed products in Europe are formulated with aluminum hydroxide (alum) (66.7%), microcrystalline tyrosine (16.7%), calcium phosphate (11.1%), or the TH1 adjuvant monophosphoryl lipid A (5.6%). In contrast to the European practice, in the United States mostly nonadjuvanted extracts and no allergoids are used for subcutaneous AIT, highlighting not only a regulatory but maybe a "historic preference." Sublingual AIT in the form of drops or tablets is currently applied worldwide without adjuvants, usually with higher safety but lower patient adherence than subcutaneous AIT. This article will discuss how AIT and adjuvants modulate the immune response in the treated patient toward immune activation, modulation, or-with new developments in the pipeline-immune resilience.

Cow's milk protein ß-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells.

BACKGROUND: Beta-lactoglobulin (BLG) is a bovine lipocalin in milk with an innate defense function. The circumstances under which BLG is associated with tolerance of or allergy to milk are not understood. OBJECTIVE: Our aims were to assess the capacity of ligand-free apoBLG versus loaded BLG (holoBLG) to protect mice against allergy by using an iron-quercetin complex as an exemplary ligand and to study the molecular mechanisms of this protection. METHODS: Binding of iron-quercetin to BLG was modeled and confirmed by spectroscopy and docking calculations. Serum IgE binding to apoBLG and holoBLG in children allergic to milk and children tolerant of milk was assessed. Mice were intranasally treated with apoBLG versus holoBLG and analyzed immunologically after systemic challenge. Aryl hydrocarbon receptor (AhR) activation was evaluated with reporter cells and Cyp1A1 expression. Treated human PBMCs and human mast cells were assessed by fluorescence-activated cell sorting and degranulation, respectively. RESULTS: Modeling predicted masking of major IgE and T-cell epitopes of BLG by ligand binding. In line with this modeling, IgE binding in children allergic to milk was reduced toward holoBLG, which also impaired degranulation of mast cells. In mice, only treatments with holoBLG prevented allergic sensitization and anaphylaxis, while sustaining regulatory T cells. BLG facilitated quercetin-dependent AhR activation and, downstream of AhR, lung Cyp1A1 expression. HoloBLG shuttled iron into monocytic cells and impaired their antigen presentation. CONCLUSION: The cargo of holoBLG is decisive in preventing allergy in vivo. BLG without cargo acted as an allergen in vivo and further primed human mast cells for degranulation in an antigen-independent fashion. Our data provide a mechanistic explanation why the same proteins can act either as tolerogens or as allergens.

Formulations for Allergen Immunotherapy in Human and Veterinary Patients: New Candidates on the Horizon.

Allergen immunotherapy is currently the only causal treatment for allergic diseases in human beings and animals. It aims to re-direct the immune system into a tolerogenic or desensitized state. Requirements include clinical efficacy, safety, and schedules optimizing patient or owner compliance. To achieve these goals, specific allergens can be formulated with adjuvants that prolong tissue deposition and support uptake by antigen presenting cells, and/or provide a beneficial immunomodulatory action. Here, we depict adjuvant formulations being investigated for human and veterinary allergen immunotherapy.

Allergen immunotherapy in the current COVID-19 pandemic: A position paper of AeDA, ARIA, EAACI, DGAKI and GPA: Position paper of the German ARIA GroupA in cooperation with the Austrian ARIA GroupB, the Swiss ARIA GroupC, German Society for Applied Allergology (AEDA)D, German Society for Allergology and Clinical Immunology (DGAKI)E, Society for Pediatric Allergology (GPA)F in cooperation with AG Clinical Immunology, Allergology and Environmental Medicine of the DGHNO-KHCG and the European Academy of Allergy and Clinical Immunology (EAACI)H.

No abstract available.