The Immunobiology and Treatment of Food Allergy.

IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper T cell (TH2) adaptive immune response. While the processes governing this loss of tolerance are incompletely understood, several host-related and environmental factors impacting the risk of IgE-FA development have been identified. Mounting evidence supports the role of an impaired epithelial barrier in the development of IgE-FA, with exposure of allergens through damaged skin and gut epithelium leading to the aberrant production of alarmins and activation of TH2-type allergic inflammation. The treatment of IgE-FA has historically been avoidance with acute management of allergic reactions, but advances in allergen-specific immunotherapy and the development of biologics and other novel therapeutics are rapidly changing the landscape of food allergy treatment. Here, we discuss the pathogenesis and immunobiology of IgE-FA in addition to its diagnosis, prognosis, and treatment.

Mechanisms of climate change and related air pollution on the immune system leading to allergic disease and asthma.

Climate change is considered the greatest threat to global health. Greenhouse gases as well as global surface temperatures have increased causing more frequent and intense heat and cold waves, wildfires, floods, drought, altered rainfall patterns, hurricanes, thunderstorms, air pollution, and windstorms. These extreme weather events have direct and indirect effects on the immune system, leading to allergic disease due to exposure to pollen, molds, and other environmental pollutants. In this review, we will focus on immune mechanisms associated with allergy and asthma-related health risks induced by climate change events. We will review current understanding of the molecular and cellular mechanisms by which the changing environment mediates these effects.

Climate change and public health: The effects of global warming on the risk of allergies and autoimmune diseases: The effects of global warming on the risk of allergies and autoimmune diseases.

Global climate change and extreme weather events are associated with epigenetic modifications in immune cells, leading to the possible increased risk and prevalence of allergies and autoimmune diseases.

Impact of climate change on immune responses and barrier defense.

Climate change is not just jeopardizing the health of our planet but is also increasingly affecting our immune health. There is an expanding body of evidence that climate-related exposures such as air pollution, heat, wildfires, extreme weather events, and biodiversity loss significantly disrupt the functioning of the human immune system. These exposures manifest in a broad range of stimuli, including antigens, allergens, heat stress, pollutants, microbiota changes, and other toxic substances. Such exposures pose a direct and indirect threat to our body's primary line of defense, the epithelial barrier, affecting its physical integrity and functional efficacy. Furthermore, these climate-related environmental stressors can hyperstimulate the innate immune system and influence adaptive immunity-notably, in terms of developing and preserving immune tolerance. The loss or failure of immune tolerance can instigate a wide spectrum of noncommunicable diseases such as autoimmune conditions, allergy, respiratory illnesses, metabolic diseases, obesity, and others. As new evidence unfolds, there is a need for additional research in climate change and immunology that covers diverse environments in different global settings and uses modern biologic and epidemiologic tools.

Effect of air pollution on asthma.

Asthma is a chronic inflammatory airway disease characterized by respiratory symptoms, variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Exposure to air pollution has been linked to an increased risk of asthma development and exacerbation. This review aims to comprehensively summarize recent data on the impact of air pollution on asthma development and exacerbation. Specifically, we reviewed the effects of air pollution on the pathogenic pathways of asthma, including type 2 and non-type 2 inflammatory responses, and airway epithelial barrier dysfunction. Air pollution promotes the release of epithelial cytokines, driving TH2 responses, and induces oxidative stress and the production of proinflammatory cytokines. The enhanced type 2 inflammation, furthered by air pollution-induced dysfunction of the airway epithelial barrier, may be associated with the exacerbation of asthma. Disruption of the TH17/regulatory T cell balance by air pollutants is also related to asthma exacerbation. As the effects of air pollution exposure may accumulate over time, with potentially stronger impacts in the development of asthma during certain sensitive life periods, we also reviewed the effects of air pollution on asthma across the lifespan. Future research is needed to better characterize the sensitive period contributing to the development of air pollution-induced asthma and to map air pollution-associated epigenetic biomarkers contributing to the epigenetic ages onto asthma-related genes.

Effects of extreme weather on health in underserved communities.

Increased fossil fuel use has increased carbon dioxide concentrations leading to global warming and climate change with increased frequency and intensity of extreme weather events such as thunderstorms, wildfires, droughts, and heat waves. These changes increase the risk of adverse health effects for all human beings. However, these experiences do not affect everyone equally. Underserved communities, including people of color, the elderly, people living with chronic conditions, and socioeconomically disadvantaged groups, have greater vulnerability to the impacts of climate change. These vulnerabilities are a result of multiple factors such as disparities in health care, lower educational status, and systemic racism. These social inequities are exacerbated by extreme weather events, which act as threat multipliers increasing disparities in health outcomes. It is clear that without human action, these global temperatures will continue to increase to unbearable levels creating an existential crisis. There is now global consensus that climate change is caused by anthropogenic activity and that actions to mitigate and adapt to climate change are urgently needed. The 2015 Paris Accord was the first truly global commitment that set goals to limit further warming. It also aimed to implement equity in action, founded on the principle of common but differentiated responsibilities. Meeting these goals requires individual, community, organizational, national, and global cooperation. Health care professionals, often in the frontline with firsthand knowledge of the health impacts of climate change, can play a key role in advocating for just and equitable climate change adaptation and mitigation policies.

Health-based strategies for overcoming barriers to climate change adaptation and mitigation.

Climate change poses an unequivocal threat to the respiratory health of current and future generations. Human activities-largely through the release of greenhouse gases-are driving rising global temperatures. Without a concerted effort to mitigate greenhouse gas emissions or adapt to the effects of a changing climate, each increment of warming increases the risk of climate hazards (eg, heat waves, floods, and droughts) that that can adversely affect allergy and immunologic diseases. For instance, wildfires, which release large quantities of particulate matter with a diameter of less than 2.5 µm (an air pollutant), occur with greater intensity, frequency, and duration in a hotter climate. This increases the risk of associated respiratory outcomes such as allergy and asthma. Fortunately, many mitigation and adaptation strategies can be applied to limit the impacts of global warming. Adaptation strategies, ranging from promotions of behavioral changes to infrastructural improvements, have been effectively deployed to increase resilience and alleviate adverse health effects. Mitigation strategies aimed at reducing greenhouse gas emissions can not only address the problem at the source but also provide numerous direct health cobenefits. Although it is possible to limit the impacts of climate change, urgent and sustained action must be taken now. The health and scientific community can play a key role in promoting and implementing climate action to ensure a more sustainable and healthy future.

Acute and chronic impacts of heat stress on planetary health.

Heat waves are increasing in intensity, frequency, and duration causing significant heat stress in all living organisms. Heat stress has multiple negative effects on plants affecting photosynthesis, respiration, growth, development, and reproduction. It also impacts animals leading to physiological and behavioral alterations, such as reduced caloric intake, increased water intake, and decreased reproduction and growth. In humans, epidemiological studies have shown that heat waves are associated with increased morbidity and mortality. There are many biological effects of heat stress (structural changes, enzyme function disruption, damage through reactive oxygen or nitrogen species). While plants and animals can mitigate some of these effects through adaptive mechanisms such as the generation of heat shock proteins, antioxidants, stress granules, and others, these mechanisms may likely be inadequate with further global warming. This review summarizes the effects of heat stress on plants and animals and the adaptative mechanisms that have evolved to counteract this stress.

Mechanisms of gut epithelial barrier impairment caused by food emulsifiers polysorbate 20 and polysorbate 80.

BACKGROUND: The rising prevalence of many chronic diseases related to gut barrier dysfunction coincides with the increased global usage of dietary emulsifiers in recent decades. We therefore investigated the effect of the frequently used food emulsifiers on cytotoxicity, barrier function, transcriptome alterations, and protein expression in gastrointestinal epithelial cells. METHODS: Human intestinal organoids originating from induced pluripotent stem cells, colon organoid organ-on-a-chip, and liquid-liquid interface cells were cultured in the presence of two common emulsifiers: polysorbate 20 (P20) and polysorbate 80 (P80). The cytotoxicity, transepithelial electrical resistance (TEER), and paracellular-flux were measured. Immunofluorescence staining of epithelial tight-junctions (TJ), RNA-seq transcriptome, and targeted proteomics were performed. RESULTS: Cells showed lysis in response to P20 and P80 exposure starting at a 0.1% (v/v) concentration across all models. Epithelial barrier disruption correlated with decreased TEER, increased paracellular-flux and irregular TJ immunostaining. RNA-seq and targeted proteomics analyses demonstrated upregulation of cell development, signaling, proliferation, apoptosis, inflammatory response, and response to stress at 0.05%, a concentration lower than direct cell toxicity. A proinflammatory response was characterized by the secretion of several cytokines and chemokines, interaction with their receptors, and PI3K-Akt and MAPK signaling pathways. CXCL5, CXCL10, and VEGFA were upregulated in response to P20 and CXCL1, CXCL8 (IL-8), CXCL10, LIF in response to P80. CONCLUSIONS: The present study provides direct evidence on the detrimental effects of food emulsifiers P20 and P80 on intestinal epithelial integrity. The underlying mechanism of epithelial barrier disruption was cell death at concentrations between 1% and 0.1%. Even at concentrations lower than 0.1%, these polysorbates induced a proinflammatory response suggesting a detrimental effect on gastrointestinal health.

Child-focused climate change and health content in medical schools and pediatric residencies.

Anthropogenic climate change-driven primarily by the combustion of fossil fuels that form greenhouse gases-has numerous consequences that impact health, including extreme weather events of accelerating frequency and intensity (e.g., wildfires, thunderstorms, droughts, and heat waves), mental health sequelae of displacement from these events, and the increase in aeroallergens and other pollutants. Children are especially vulnerable to climate-related exposures given that they are still developing, encounter higher exposures compared to adults, and are at risk of losing many healthy future years of life. In order to better meet the needs of generations of children born into a world affected by climate change, medical trainees must develop their knowledge of the relationships between climate change and children's health-with a focus on applying that information in clinical practice. This review provides an overview of salient climate change and children's health topics that medical school and pediatric residency training curricula should cover. In addition, it highlights the strengths and limitations of existing medical school and residency climate change and pediatric health curricula. IMPACT: Provides insight into the current climate change and pediatric health curricular opportunities for medical trainees in North America at both the medical school and residency levels. Condenses climate change and pediatric health material relevant to trainees to help readers optimize curricula at their institutions.

The Role of Climate Change in Asthma.

Human activity and increased use of fossil fuels have led to climate change. These changes are adversely affecting human health, including increasing the risk of developing asthma. Global temperatures are predicted to increase in the future. In 2019, asthma affected an estimated 262 million people and caused 455,000 deaths. These rates are expected to increase. Climate change by intensifying climate events such as drought, flooding, wildfires, sand storms, and thunderstorms has led to increases in air pollution, pollen season length, pollen and mold concentration, and allergenicity of pollen. These effects bear implications for the onset, exacerbation, and management of childhood asthma and are increasing health inequities. Global efforts to mitigate the effects of climate change are urgently needed with the goal of limiting global warming to between 1.5 and 2.0 °C of preindustrial times as per the 2015 Paris Agreement. Clinicians need to take an active role in these efforts in order to prevent further increases in asthma prevalence. There is a role for clinician advocacy in both the clinical setting as well as in local, regional, and national settings to install measures to control and curb the escalating disease burden of childhood asthma in the setting of climate change.

Food allergy, mechanisms, diagnosis and treatment: Innovation through a multi-targeted approach.

The incidence of food allergy (FA) has continued to rise over the last several decades, posing significant burdens on health and quality of life. Significant strides into the advancement of FA diagnosis, prevention, and treatment have been made in recent years. In an effort to lower reliance on resource-intensive food challenges, the field has continued work toward the development of highly sensitive and specific assays capable of high-throughput analysis to assist in the diagnosis FA. In looking toward early infancy as a critical period in the development of allergy or acquisition of tolerance, evidence has increasingly suggested that early intervention via the early introduction of food allergens and maintenance of skin barrier function may decrease the risk of FA. As such, large-scale investigations are underway evaluating infant feeding and the impact of emollient and steroid use in infants with dry skin for the prevention of allergy. On the other end of the spectrum, the past few years have been witness to an explosive increase in clinical trials of novel and innovative therapeutic strategies aimed at the treatment of FA in those whom the disease has already manifested. A milestone in the field, 2020 marked the approval of the first drug, oral peanut allergen, for the indication of peanut allergy. With a foundation of promising data supporting the safety and efficacy of single- and multi-allergen oral immunotherapy, current efforts have turned toward the use of probiotics, biologic agents, and modified allergens to optimize and improve upon existing paradigms. Through these advancements, the field hopes to gain footing in the ongoing battle against FA.

Phase 2, randomized multi oral immunotherapy with omalizumab 'real life' study.

BACKGROUND: Oral immunotherapy (OIT) is frequently discontinued due to adverse events (AEs) and current data suggests that lowering OIT doses can minimize severity and frequency of AEs. However, the minimum daily dose that can enable desensitization and induce immune responses in multi-food OIT (mOIT) is unknown. METHODS: Participants aged 2-25 years with multi-food allergies were pretreated with fixed-dose omalizumab (150 mg, 3 doses, every 4 weeks), and randomized 1:1 to receive mOIT to a total maintenance dose of either 300 or 1200 mg total protein, (total dose includes at least two and up to a max of five allergens) and then transitioned to real-food protein equivalents after 18 weeks of treatment. The primary endpoint was the proportion of subjects with increases in IgG4/IgE ratio of at least 2 allergens by ≥25% from baseline after 18 weeks of therapy. The primary efficacy and safety analyses were done in the intention-to-treat population. RESULTS: Sixty participants were enrolled across two sites. Seventy percent of participants in both arms showed changes in sIgG4/sIgE ratio in at least 2 allergens with no difference between the treatment groups (OR [95% CI] = 1.00 [0.29, 3.49]). Overall, there were no differences in AEs between the 300 and 1200 mg groups (19% vs. 17%, p = .69), respectively. CONCLUSIONS: Our data suggest that plasma marker changes are induced early, even at a total protein dose of 300 mg inclusive of multiple allergens when mOIT is combined with fixed-dose omalizumab. Identification of optimal mOIT dosing with adjunct omalizumab is needed for the long-term success of OIT. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03181009).

Early intervention and prevention of allergic diseases.

Food allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well-developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of (1) an intact epidermal barrier to prevent epicutaneous antigen presentation, (2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and (3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA.

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.

Improving planetary health is integral to improving children's health-a call to action.

IMPACT: This article summarizes the adverse effects of climate and environmental change on children's health. We call for policy change, education, and advocacy to halt further deterioration of planetary health and for specific measures to prevent the negative effects of climate and environmental change on children's health. We offer an agenda for research, policy change, and healthcare practices to improve the resilience of pediatric populations in the face of climate change.

Food allergy across the globe.

The prevalence of food allergy (FA) is increasing in some areas of the globe, highlighting the need for better strategies for prevention, diagnosis, and therapy. In the last few decades, we have made great strides in understanding the causes and mechanisms underlying FAs, prompting guideline updates. Earlier guidelines recommended avoidance of common food allergens during pregnancy and lactation and delaying the introduction of allergenic foods in children aged between 1 and 3 years. Recent guidelines for allergy prevention recommend consumption of a healthy and diverse diet without eliminating or increasing the consumption of allergenic foods during pregnancy or breast-feeding. Early introduction of allergenic foods is recommended by most guidelines for allergy prevention after a period of exclusive breast-feedng (6 months [World Health Organization] or 4 months [European Academy of Allergy and Clinical Immunology]). New diagnostics for FA have been developed with varied availability of these tests in different countries. Finally, the first oral immunotherapy drug for FA was approved by the US Food and Drug Administration and European Medicines Agency in 2020. In this review, we will address the global prevalence of FA, our current understanding of the causes of FA, and the latest guidelines for preventing, diagnosing, and treating FA. We will also discuss similarities and differences between FA guidelines.

Vaccines and allergic reactions: The past, the current COVID-19 pandemic, and future perspectives.

Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.

COVID-19 pandemic: Practical considerations on the organization of an allergy clinic-An EAACI/ARIA Position Paper.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has evolved into a pandemic infectious disease transmitted by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Allergists and other healthcare providers (HCPs) in the field of allergies and associated airway diseases are on the front line, taking care of patients potentially infected with SARS-CoV-2. Hence, strategies and practices to minimize risks of infection for both HCPs and treated patients have to be developed and followed by allergy clinics. METHOD: The scientific information on COVID-19 was analysed by a literature search in MEDLINE, PubMed, the National and International Guidelines from the European Academy of Allergy and Clinical Immunology (EAACI), the Cochrane Library, and the internet. RESULTS: Based on the diagnostic and treatment standards developed by EAACI, on international information regarding COVID-19, on guidelines of the World Health Organization (WHO) and other international organizations, and on previous experience, a panel of experts including clinicians, psychologists, IT experts, and basic scientists along with EAACI and the "Allergic Rhinitis and its Impact on Asthma (ARIA)" initiative have developed recommendations for the optimal management of allergy clinics during the current COVID-19 pandemic. These recommendations are grouped into nine sections on different relevant aspects for the care of patients with allergies. CONCLUSIONS: This international Position Paper provides recommendations on operational plans and procedures to maintain high standards in the daily clinical care of allergic patients while ensuring the necessary safety measures in the current COVID-19 pandemic.

Maternal gestational mercury exposure in relation to cord blood T cell alterations and placental gene expression signatures.

The immunotoxic impacts of mercury during early life is poorly understood. We investigated the associations between gestational mercury exposure and frequency of cord blood T cells as well as placental gene expression. Frequency of natural Treg cells was positively associated with prenatal and postpartum mercury toenail concentrations. Frequency of NKT and activated naïve Th cells was positively associated with prenatal toenail mercury concentrations and number of maternal silver-mercury dental amalgams, respectively. Placental gene expression analyses revealed distinct gene signatures associated with mercury exposure. Decreased placental expression of a histone demethylase, KDM4DL, was associated with both higher prenatal and postpartum maternal toenail mercury levels among male infants and remained statistically significant after adjustment for fish and seafood consumption. The results suggest that gestational exposure to mercury concentrations contribute to alterations in both T cells and gene expression in placenta at birth. These alterations may inform mechanisms of mercury immunotoxicity.