Air pollutants contribute to epithelial barrier dysfunction and allergic diseases.

Air pollution is a global problem associated with various health conditions, causing elevated rates of morbidity and mortality. Major sources of air pollutants include industrial emissions, traffic-related pollutants, and household biomass combustion, in addition to indoor pollutants from chemicals and tobacco. Various types of air pollutants originate from both human activities and natural sources. These include particulate matter, pollen, greenhouse gases, and other harmful gases. Air pollution is linked to allergic diseases, including atopic dermatitis, allergic rhinitis, allergic conjunctivitis, food allergy, and bronchial asthma. These pollutants lead to epithelial barrier dysfunction, dysbiosis, and immune dysregulation. In addition, climate change and global warming may contribute to the exacerbation and the development of allergic diseases related to air pollutants. Epigenetic changes associated with air pollutants have also been connected to the onset of allergic diseases. Furthermore, these changes can be passed down through subsequent generations, causing a higher prevalence of allergic diseases in offspring. Modulation of the aryl hydrocarbon receptor could be a valuable strategy for alleviating air pollutant-induced epidermal barrier dysfunction and atopic dermatitis. A more effective approach to preventing allergic diseases triggered by air pollutants is to reduce exposure to them. Implementing public policies aimed at safeguarding individuals from air pollutant exposure may prove to be the most efficient solution. A pressing need exists for global policy initiatives that prioritize efforts to reduce the production of air pollutants.

Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Endotypes of atopic dermatitis and food allergy.

Atopic dermatitis (AD) and food allergy (FA) are strongly associated, with one-third of children with AD developing concomitant FA. Epithelial barrier dysfunction is important in both conditions. Genetic factors, such as filaggrin mutations and IL-4 receptor alpha chain polymorphisms, are linked to increased risk. In addition, several environmental exposures lead to reduced filaggrin and contribute to skin barrier dysfunction. Staphylococcus aureus colonization appears to contribute to AD and FA, as well as activating the type 2 immune response. Comprehensive multiomic studies using skin tape stripping have identified distinct atopic endotypes with unique characteristics of the stratum corneum lipids, proteins, S aureus abundance, and type 2 cytokine expression. Our new understanding of AD and FA presents an area of opportunity to move toward improved diagnosis and prevention of atopy.

Staphylococcus aureus causes aberrant epidermal lipid composition and skin barrier dysfunction.

BACKGROUND: Staphylococcus (S) aureus colonization is known to cause skin barrier disruption in atopic dermatitis (AD) patients. However, it has not been studied how S. aureus induces aberrant epidermal lipid composition and skin barrier dysfunction. METHODS: Skin tape strips (STS) and swabs were obtained from 24 children with AD (6.0 ± 4.4 years) and 16 healthy children (7.0 ± 4.5 years). Lipidomic analysis of STS samples was performed by mass spectrometry. Skin levels of methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA) were evaluated. The effects of MSSA and MRSA were evaluated in primary human keratinocytes (HEKs) and organotypic skin cultures. RESULTS: AD and organotypic skin colonized with MRSA significantly increased the proportion of lipid species with nonhydroxy fatty acid sphingosine ceramide with palmitic acid ([N-16:0 NS-CER], sphingomyelins [16:0-18:0 SM]), and lysophosphatidylcholines [16:0-18:0 LPC], but significantly reduced the proportion of corresponding very long-chain fatty acids (VLCFAs) species (C22-28) compared to the skin without S. aureus colonization. Significantly increased transepidermal water loss (TEWL) was found in MRSA-colonized AD skin. S. aureus indirectly through interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and IL-33 inhibited expression of fatty acid elongase enzymes (ELOVL3 and ELOVL4) in HEKs. ELOVL inhibition was more pronounced by MRSA and resulted in TEWL increase in organotypic skin. CONCLUSION: Aberrant skin lipid profiles and barrier dysfunction are associated with S. aureus colonization in AD patients. These effects are attributed to the inhibition of ELOVLs by S. aureus-induced IL-1ß, TNF-α, IL-6, and IL-33 seen in keratinocyte models and are more prominent in MRSA than MSSA.

Physical influences on the skin barrier and pathogenesis of allergy.

PURPOSE OF REVIEW: As the incidence of allergic conditions has increased in recent decades, the effects of climate change have been implicated. There is also increased knowledge on the effects of other physical influences, such as scratching and Staphylococcus aureus . The skin barrier is the first line of defense to the external environment, so understanding the ways that these factors influence skin barrier dysfunction is important. RECENT FINDINGS: Although the impact on environmental exposures has been well studied in asthma and other allergic disorders, there is now more literature on the effects of temperature, air pollution, and detergents on the skin barrier. Factors that cause skin barrier dysfunction include extreme temperatures, air pollution (including greenhouse gases and particulate matter), wildfire smoke, pollen, scratching, S. aureus, and detergents. SUMMARY: Understanding the ways that external insults affect the skin barrier is important to further understand the mechanisms in order to inform the medical community on treatment and prevention measures for atopic conditions.

The impact of temperature on the skin barrier and atopic dermatitis.

Climate change is a global threat to public health and causes or worsens various diseases including atopic dermatitis (AD), allergic, infectious, cardiovascular diseases, physical injuries, and mental disorders. The incidence of allergy, such as AD, has increased over the past several decades, and environmental factors such as climate change have been implicated as a potential mechanism. A substantial amount of literature has been published on the impact of climate factors, including cold and hot temperatures, on the skin barrier and AD. Studies in several countries have found a greater incidence of AD in children born in the colder seasons of fall and winter. The effect of cold and warm temperatures on itch, skin flares, increased outpatient visits, skin barrier dysfunction, development of AD, and asthma exacerbations have been reported. Understanding mechanisms by which changes in temperature influence allergies is critical to the development of measures for the prevention and treatment of allergic disorders, such as AD and asthma. Low and high temperatures induce the production of proinflammatory cytokines and lipid mediators such as interleukin-1ß, thymic stromal lymphopoietin, and prostaglandin E2, and cause itch and flares by activation of TRPVs such as TRPV1, TRPV3, and TRPV4. TRPV antagonists may attenuate temperature-mediated itch, skin barrier dysfunction, and exacerbation of AD.

Transient receptor potential vanilloid 1 plays a major role in low temperature-mediated skin barrier dysfunction.

BACKGROUND: Children born in the fall and winter are at increased risk for developing atopic dermatitis and food allergy. Because these seasons are associated with low temperatures, we hypothesized that exposure to low temperatures may compromise keratinocyte differentiation and contribute to skin barrier dysfunction. OBJECTIVE: We examined whether low temperature causes skin barrier dysfunction. METHODS: Primary human epidermal keratinocytes (HEK) were differentiated in 1.3 mmol CaCl2 media and cultured at different temperatures. The cells were transfected with transient receptor potential cation channel subfamily V member 1 (TRPV1) or STAT3 small interfering RNA (siRNA) to examine the effects of these gene targets in HEK exposed to low temperature. Gene expression of TRPV1, epidermal barrier proteins, and keratinocyte-derived cytokines were evaluated. Organotypic skin equivalents were generated using HEK transfected with control or TRPV1 siRNA and grown at 25°C or 37°C. Transepidermal water loss (TEWL) and levels of epidermal barrier proteins were evaluated. RESULTS: Filaggrin (FLG) and loricrin (LOR) expression, but not keratin (KRT)-1 and KRT-10 expression, was downregulated in HEK incubated at 25°C, while TRPV1 silencing increased intracellular Ca2+ influx (keratinocyte differentiation signal) and enhanced the expression of epidermal differentiation proteins. IL-1ß and thymic stromal lymphopoietin induced by low temperature inhibited FLG expression in keratinocytes through the TRPV1/STAT3 pathway. Moreover, low temperature-mediated inhibition of FLG and LOR was recovered, and TEWL was decreased in organotypic skin transfected with TRPV1 siRNA. CONCLUSION: TRPV1 is critical in low temperature-mediated skin barrier dysfunction. Low temperature exposure induced thymic stromal lymphopoietin, an alarmin implicated in epicutaneous allergen sensitization.

The SunBEAm birth cohort: Protocol design.

Background: Food allergy (FA) and atopic dermatitis (AD) are common conditions that often present in the first year of life. Identification of underlying mechanisms and environmental determinants of FA and AD is essential to develop and implement effective prevention and treatment strategies. Objectives: We sought to describe the design of the Systems Biology of Early Atopy (SunBEAm) birth cohort. Methods: Funded by the National Institute of Allergy and Infectious Diseases (NIAID) and administered through the Consortium for Food Allergy Research (CoFAR), SunBEAm is a US population-based, multicenter birth cohort that enrolls pregnant mothers, fathers, and their newborns and follows them to 3 years. Questionnaire and biosampling strategies were developed to apply a systems biology approach to identify environmental, immunologic, and multiomic determinants of AD, FA, and other allergic outcomes. Results: Enrollment is currently underway. On the basis of an estimated FA prevalence of 6%, the enrollment goal is 2500 infants. AD is defined on the basis of questionnaire and assessment, and FA is defined by an algorithm combining history and testing. Although any FA will be recorded, we focus on the diagnosis of egg, milk, and peanut at 5 months, adding wheat, soy, cashew, hazelnut, walnut, codfish, shrimp, and sesame starting at 12 months. Sampling includes blood, hair, stool, dust, water, tape strips, skin swabs, nasal secretions, nasal swabs, saliva, urine, functional aspects of the skin, and maternal breast milk and vaginal swabs. Conclusions: The SunBEAm birth cohort will provide a rich repository of data and specimens to interrogate mechanisms and determinants of early allergic outcomes, with an emphasis on FA, AD, and systems biology.

Origin of Allergy From In Utero Exposures to the Postnatal Environment.

As the incidence of atopic conditions continues to increase, emphasis has been placed on understanding the origin of allergy with hope that prevention measures can be achieved. The perinatal environment is important for this understanding, given that both the immune system and microbiome start forming prenatally. Maternal exposure can greatly impact on fetal health. Additionally, the dysfunctional epithelial barrier is influential in allowing allergens and irritants to penetrate the skin or mucosa, leading to the release of proinflammatory cytokines and mediators to drive type 2 tissue inflammation and the onset of allergy. There are numerous factors related to skin, airway, and gut epithelial barriers dysfunction, and genetic predispositions are also present. Comprehensive birth cohort studies and further mechanistic studies will be keys to understanding the origin of allergy.