Epicutaneous Sensitization Research Articles

Maternal High-Fat Diet Exacerbates Epicutaneous Sensitization and Oral Challenge-Induced Food Allergy to Ovalbumin in Offspring Mice.

Dietary factors have been associated with an increased prevalence of food allergy (FA). However, little is known about how an unhealthy diet in early life affects FA reactions in offspring. The objective of this study is to provide a scientific foundation for developing and promoting healthy dietary patterns in early life. In this study, we found that maternal high-fat diet (HFD) during pregnancy and lactation exacerbates FA (HFD-FA) in offspring mice, leading to increased serum levels of mast cell protease 1. First, we studied the systemic immunity of the HFD-FA mice and observed elevated levels of proinflammatory cytokines (IL-4, IL-6, and IL-1β) and a reduced frequency of Treg cells in splenocytes. Additionally, the HFD-FA mice showed increased gut permeability, accumulation of intestinal mast cells, and a decrease in the Treg cell frequency in the mesenteric lymph nodes. Furthermore, our findings also indicated a reduction in gut microbial diversity and abundance in HFD-FA mice. Importantly, lipid metabolism profiling revealed unique lipid profiles in the HFD-FA mice, with significant upregulation of triglycerides and downregulation of sphingolipids. Taken together, our results suggest that maternal HFD alters intestinal homeostasis and increases FA susceptibility in offspring mice.

Mechanisms for initiation of food allergy by skin pre-disposed to atopic dermatitis.

Food allergy can be life-threatening and often develops early in life. In infants and children, loss-of-function mutations in skin barrier genes associate with food allergy. In a mouse model with skin barrier mutations (Flakey Tail, FT+/- mice), topical epicutaneous sensitization to a food allergen peanut extract (PNE), an environmental allergen Alternaria alternata (Alt) and a detergent induce food allergy and then an oral PNE-challenge induces anaphylaxis. Exposures to these allergens and detergents can occur for infants and children in a household setting. From the clinical and preclinical studies of neonates and children with skin barrier mutations, early oral exposure to allergenic foods before skin sensitization may induce tolerance to food allergens and thus protect against development of food allergy. In the FT+/- mice, oral food allergen prior to skin sensitization induce tolerance to food allergens. However, when the skin of FT+/- pups are exposed to a ubiquitous environmental allergen at the time of oral consumption of food allergens, this blocks the induction of tolerance to the food allergen and the mice can then be skin sensitized with the food allergen. The development of food allergy in neonatal FT+/- mice is mediated by altered skin responses to allergens with increases in skin expression of interleukin 33, oncostatin M and amphiregulin. The development of neonate food allergy is enhanced when born to an allergic mother, but it is inhibited by maternal supplementation with α-tocopherol. Moreover, preclinical studies suggest that food allergen skin sensitization can occur before manifestation of clinical features of atopic dermatitis. Thus, these parameters may impact design of clinical studies for food allergy, when stratifying individuals by loss of skin barrier function or maternal atopy before offspring development of atopic dermatitis.

IL-4 acts on skin-derived dendritic cells to promote the TH2 response to cutaneous sensitization and the development of allergic skin inflammation

Atopic dermatitis is characterized by scratching and a TH2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells. We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation. DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4+ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA. Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. Invitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive TH2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4-/- mice and CD11c-CreIl4rflox/- mice, which lack IL-4Rα expression in DCs (DCΔ/Δll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DCΔ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls. Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for TH2 polarization and drive allergic skin inflammation.

Skin Predictive Biomarkers for the Development of Atopic Dermatitis and Food Allergy in Infants.

The pathogenesis of atopic dermatitis (AD) is multifactorial, involving a dynamic interplay between genetic susceptibility, skin-barrier dysfunction, microbiome alterations, and immune dysregulation, whereas food allergy (FA) arises from the interplay of transcutaneous sensitization to food allergens and failure in the induction of oral tolerance. Skin epicutaneous sensitization is commonly involved in the development of AD and FA. Although clinical trials have been conducted to prevent AD or FA by applications of emollients on the skin after birth, the results are not consistent. For more effective preventive strategies, reliable biomarkers are required to identify high-risk individuals. Skin tape stripping (STS) is a non-invasive technique for identifying these biomarkers in the skin. By analyzing the stratum corneum collected via STS, researchers can gain molecular or cellular insights into the early pathogenesis and potential progression of AD and FA. This review aims to elucidate the critical aspects of AD and FA, underlying their pathogenesis, early manifestations, and STS's potential as a tool for identifying predictive non-invasive biomarkers in infants prior to onset of clinical disease.

Basophils are important for development of allergic skin inflammation

Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis. We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation. Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR. Basophils were important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic TH2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive TH2 polarization of naive T cells. Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.

Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency

Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD). We sought to understand the mechanisms of eczema in DOCK8 deficiency. Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus. Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by Saureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8-/- mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8-/- and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to Saureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells. Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to Saureus to drive eczema in DOCK8 deficiency.

Practical issues of using emollients for the prevention of exacerbations of atopic dermatitis during the flowering season: expert resolution

In February 2023, a meeting of the Council of Experts was held, attended by leading specialists in the fields of allergology, pediatrics and dermatology. The Working Group discussed the problem of sensitization to pollen allergens in patients with atopic dermatitis and exacerbation of the disease during the pollination season of plants, as well as the formation of epicutaneous sensitization through a damaged epidermal barrier. The experts comprehensively considered the criteria that a modern emollient used for the care of atopic dermatitis patients’ skin should meet, discussed the role of moisturizers in preventing seasonal exacerbations of atopic dermatitis based on previously conducted research, and developed unified recommendations on the principles of managing this type of patients. Suggestions were made for further informational and organizational measures aimed at expanding the knowledge of patients and medical specialists about the problem of epicutaneous sensitization to aeroallergens in atopic dermatitis patients, their role in the development of seasonal exacerbations of atopic dermatitis, and the possibility of their prevention using modern emollients.

Comparison of immune responses and intestinal flora in epicutaneously sensitized BALB/c or C57BL/6 mouse models of food allergy

Cutaneous exposure to food allergens through a disrupted skin barrier is recognized as an important cause of food allergy, and the cutaneous sensitized mouse model has been established to investigate relevant allergic disorders. However, the role of different genetic backgrounds of mice on immune responses to food allergens upon epicutaneous sensitization is largely unknown. In this study, two strains of mice, i.e., the BALB/c and C57BL/6 mice, were epicutaneously sensitized with ovalbumin on atopic dermatitis (AD)-like skin lesions, followed by intragastric challenge to induce IgE-mediated food allergy. Allergic outcomes were measured as clinical signs, specific antibodies and cytokines, and immune cell subpopulations, as well as changes in intestinal barrier function and gut microbiota. Results showed that both strains of mice exhibited typical food-allergic symptoms with a Th2-skewed response. The C57BL/6 mice, rather than the BALB/c mice, were fitter for establishing an epicutaneously sensitized model of food allergy since a stronger Th2-biased response and severer disruptions in the intestinal barrier and gut homeostasis were observed. This study provides knowledge for selecting an appropriate mouse model to study food-allergic responses associated with AD-like skin lesions and highlights the role of genetic variations in the immune mechanism underlying pathogenesis of food allergy.

Study the involvement of Langerin in mediating epicutaneous sensitization of atopic dermatitis-like mouse model

Objective: To explore the role of Langerin in mediating epicutaneous sensitization of atopic dermatitis (AD) in mouse model. Methods: Mice were topically treated with calcipotriol (MC903) plus ovalbumin (OVA) on the ears to establish AD mouse models, and mice were divided into wild-type control group, wild-type AD group, Langerin knockout control group, and Langerin knockout AD group. Changes of lesion were daily observed. Infiltration of inflammatory cells, mRNA expression of Tslp, Il4, Il13, Il17a, and Il22, levels of serum total IgE, OVA-specific IgE (sIgE), OVA sIgG1 and OVA sIgG2a, proportion of regulatory T (Treg) cells in cervical draining lymph nodes were evaluated at the end of model preparation. Results: Skin tumidness and thickness, dermal inflammatory cells infiltration, the mRNA expression levels of Tslp, Il4, Il13, Il17a and Il22 in wild-type AD groups were higher than those in wild-type control groups, with (1.80±0.66, 1.64±0.25, 1.71±0.54, 2.41±0.23, 2.49±0.32) and (0.53±0.45, 0.85±0.29, 0.73±0.50, 0.72±0.25, 0.56±0.29), respectively (all P<0.05). In addition, the levels of serum total IgE, OVA sIgE and OVA sIgG1 in wild-type AD groups were higher than those in wild-type control groups, with [(1 216.00±572.70) ng/ml, (597.00±538.30) ng/ml, 1.59±0.09] and [(24.22±35.04) ng/ml, (20.01±41.71) ng/ml, 1.16±0.03], respectively (all P<0.05). In Langerin knockout mice, compared to wild-type mice, skin erythema, skin tumidness, epidermal thickening, inflammatory cell infiltration were more obvious; the mRNA expression levels of Tslp, Il4, Il13, Il17a and Il22 were upregulated with (8.19±6.44, 2.53±0.69, 2.82±0.73, 3.94±1.32, 3.80±1.43) (all P<0.05); the levels of serum total IgE, OVA sIgE and OVA sIgG1 were significantly increased with (2 508.00±657.10) ng/ml, (1 808.00±470.70) ng/ml, (1.73±0.09) (all P<0.05); the number of CD4+CD25+CD127-Treg cells were decreased significantly with (13.25±0.96)% and (15.31±1.47)%, respectively (P<0.05). Conclusion: Langerin is involved in mediating epicutaneous sensitization of the AD mouse model and plays a negative immunoregulatory role.

Epicutaneous Sensitization to the Phytocannabinoid β-Caryophyllene Induces Pruritic Inflammation.

In recent years, there has been increased accessibility to cannabis for recreational and medicinal use. Incidentally, there has been an increase in reports describing allergic reactions to cannabis including exacerbation of underlying asthma. Recently, multiple protein allergens were discovered in cannabis, yet these fail to explain allergic sensitization in many patients, particularly urticaria and angioedema. Cannabis has a rich chemical profile including cannabinoids and terpenes that possess immunomodulatory potential. We examined whether major cannabinoids of cannabis such as cannabidiol (CBD) and the bicyclic sesquiterpene beta-caryophyllene (β-CP) act as contact sensitizers. The repeated topical application of mice skin with β-CP at 10 mg/mL (50 µL) induced an itch response and dermatitis at 2 weeks in mice, which were sustained for the period of study. Histopathological analysis of skin tissues revealed significant edema and desquamation for β-CP at 10 mg/mL. For CBD and β-CP, we observed a dose-dependent increase in epidermal thickening with profound thickening observed for β-CP at 10 mg/mL. Significant trafficking of CD11b cells was observed in various compartments of the skin in response to treatment with β-CP in a concentration-dependent manner. Mast cell trafficking was restricted to β-CP (10 mg/mL). Mouse proteome profiler cytokine/chemokine array revealed upregulation of complement C5/5a (anaphylatoxin), soluble intracellular adhesion molecule-1 (sICAM-1) and IL-1 receptor antagonist (IL-1RA) in animals dosed with β-CP (10 mg/mL). Moreover, we observed a dose-dependent increase in serum IgE in animals dosed with β-CP. Treatment with β-CP (10 mg/mL) significantly reduced filaggrin expression, an indicator of barrier disruption. In contrast, treatment with CBD at all concentrations failed to evoke scratching and dermatitis in mice and did not result in increased serum IgE. Further, skin tissues were devoid of any remarkable features, although at 10 mg/mL CBD we did observe the accumulation of dermal CD11b cells in skin tissue sections. We also observed increased filaggrin staining in mice repeatedly dosed with CBD (10 mg/mL). Collectively, our studies indicate that repeated exposure to high concentrations of β-CP can induce dermatitis-like pathological outcomes in mice.

Indoor aeroallergens from American cockroaches and mites initiate atopic march via cutaneous contact in a murine model.

The progression of allergic diseases from atopic dermatitis in childhood to other allergic conditions such as asthma in later life is often referred to as the atopic march. In order to study the relationship between cutaneous sensitization by aeroallergen and atopic march, we established a mouse model to test the hypothesis using American cockroaches and house dust mites as the model allergens. Mice were sensitized via skin with native cockroach extract (CraA) or recombinant Per a 2 and Der p 2 proteins without adjuvant. Each mouse was subjected to a total of three 1-week patching sensitizations with a 2-week interval in between each application. The resulting immunological variables in sera, scratching behavior, airway hyperresponsiveness (AHR), and pathology of skin lesions and nasal mucosa were evaluated. In mice, application of CraA, rPer a 2, and rDer p 2 aeroallergens through skin patching induced significantly high levels of both total IgE and specific IgEs. The epicutaneous sensitization after a subsequent allergen challenge showed a significant increase in scratch bouts, AHR, epidermal thickness, and eosinophil counts in the skin compared with the control mice. In addition, stimulation of murine splenocytes with allergens increased higher levels of Th2 cytokines, anti-inflammatory cytokines, and chemokines excretion. Our study provides evidence supporting that epicutaneous sensitization to aeroallergens also led to nasal and airway symptoms comparable to atopic march as described in humans. We hope this new allergy model will be useful in the development of new preventive and therapeutic strategies aimed at stopping the atopic march.

Practical issues of using emollients for the prevention of exacerbations of atopic dermatitis during the flowering season: expert resolution

In February 2023, a meeting of the Council of Experts was held, attended by leading specialists in the fields of allergology, pediatrics and dermatology. The working group discussed the problem of sensitization to pollen allergens in patients with atopic dermatitis (AD) and exacerbation of the disease during the pollination season of plants, as well as the formation of epicutaneous sensitization through a damaged epidermal barrier. The experts comprehensively considered the criteria that a modern emollient used for the care of AD patients' skin should meet, discussed the role of moisturizers in preventing seasonal exacerbations of AD based on previously conducted research, and developed unified recommendations on the principles of managing this type of patients. Suggestions were made for further informational and organizational measures aimed at expanding the knowledge of patients and medical specialists about the problem of epicutaneous sensitization to aeroallergens in AD patients, their role in the development of seasonal exacerbations of AD, and the possibility of their prevention using modern emollients.

Staphylococcus aureus δ-toxin present on skin promotes the development of food allergy in a murine model.

Patients with food allergy often suffer from atopic dermatitis, in which Staphylococcus aureus colonization is frequently observed. Staphylococcus aureus δ-toxin activates mast cells and promotes T helper 2 type skin inflammation in the tape-stripped murine skin. However, the physiological effects of δ-toxin present on the steady-state skin remain unknown. We aimed to investigate whether δ-toxin present on the steady-state skin impacts the development of food allergy. The non-tape-stripped skins of wild-type, KitW-sh/W-sh, or ST2-deficient mice were treated with ovalbumin (OVA) with or without δ-toxin before intragastric administration of OVA. The frequency of diarrhea, numbers of jejunum or skin mast cells, and serum levels of OVA-specific IgE were measured. Conventional dendritic cell 2 (cDC2) in skin and lymph nodes (LN) were analyzed. The cytokine levels in the skin tissues or culture supernatants of δ-toxin-stimulated murine keratinocytes were measured. Anti-IL-1α antibody-pretreated mice were analyzed. Stimulation with δ-toxin induced the release of IL-1α, but not IL-33, in murine keratinocytes. Epicutaneous treatment with OVA and δ-toxin induced the local production of IL-1α. This treatment induced the translocation of OVA-loaded cDC2 from skin to draining LN and OVA-specific IgE production, independently of mast cells and ST2. This resulted in OVA-administered food allergic responses. In these models, pretreatment with anti-IL-1α antibody inhibited the cDC2 activation and OVA-specific IgE production, thereby dampening food allergic responses. Even without tape stripping, δ-toxin present on skin enhances epicutaneous sensitization to food allergen in an IL-1α-dependent manner, thereby promoting the development of food allergy.

Thymic stromal lymphopoietin rather than IL-33 drives food allergy after epicutaneous sensitization to food allergen

A major route of sensitization to food allergen is through an impaired skin barrier. IL-33 and thymic stromal lymphopoietin (TSLP) have both been implicated in epicutaneous sensitization and food allergy, albeit in different murine models. We assessed the respective contributions of TSLP and IL-33 to the development of atopic dermatitis (AD) and subsequent food allergy in TSLP and IL-33 receptor (ST2)-deficient mice using an AD model that does not require tape stripping. TSLP receptor (TSLPR)-/-, ST2-/-, and BALB/cJ control mice were exposed to 3 weekly epicutaneous skin patches of one of saline, ovalbumin (OVA), or a combination of OVA and Aspergillus fumigatus (ASP), followed by repeated intragastric OVA challenges and development of food allergy. ASP and/or OVA patched, but not OVA-alone patched, BALB/cJ mice developed an AD-like skin phenotype. However, epicutaneous OVA sensitization occurred in OVA patched mice and was decreased in ST2-/- mice, resulting in lower intestinal mast cell degranulation and accumulation, as well as OVA-induced diarrhea occurrences on intragastric OVA challenges. In TSLPR-/- mice, intestinal mast cell accumulation was abrogated, and no diarrhea was observed. AD was significantly milder in OVA+ ASP patched TSLPR-/- mice compared to wild type and ST2-/- mice. Accordingly, intestinal mast cell accumulation and degranulation were impaired in OVA+ ASP patched TSLPR-/- mice compared to wild type and ST2-/- mice, protecting TSLPR-/- mice from developing allergic diarrhea. Epicutaneous sensitization to food allergen and development of food allergy can occur without skin inflammation and is partly mediated by TSLP, suggesting that prophylactic targeting of TSLP may be useful in mitigating the development of AD and food allergy early in life in at-risk infants.

Epicutaneous Sensitization and Food Allergy: Preventive Strategies Targeting Skin Barrier Repair-Facts and Challenges.

Food allergy represents a growing public health and socio-economic problem with an increasing prevalence over the last two decades. Despite its substantial impact on the quality of life, current treatment options for food allergy are limited to strict allergen avoidance and emergency management, creating an urgent need for effective preventive strategies. Advances in the understanding of the food allergy pathogenesis allow to develop more precise approaches targeting specific pathophysiological pathways. Recently, the skin has become an important target for food allergy prevention strategies, as it has been hypothesized that allergen exposure through the impaired skin barrier might induce an immune response resulting in subsequent development of food allergy. This review aims to discuss current evidence supporting this complex interplay between the skin barrier dysfunction and food allergy by highlighting the crucial role of epicutaneous sensitization in the causality pathway leading to food allergen sensitization and progression to clinical food allergy. We also summarize recently studied prophylactic and therapeutic interventions targeting the skin barrier repair as an emerging food allergy prevention strategy and discuss current evidence controversies and future challenges. Further studies are needed before these promising strategies can be routinely implemented as prevention advice for the general population.

A Murine Model of Food Allergy by Epicutaneous Adjuvant-Free Allergen Sensitization Followed by Oral Allergen Challenge Combined with Aspirin for Enhanced Detection of Hypersensitivity Manifestations and Immunotherapy Monitoring.

Food allergy is one of the major existing health problems, but no effective treatment is available. In the current work, a murine model that closely mimics pathogenesis of human food allergy and its quantifiable diagnostic parameter design, even for mild hypersensitivity reactions, were established. BALB/c mice were epicutaneously sensitized with 1 mg chicken egg ovomucoid (OVM) or cow's milk casein, free of adjuvants, five times a week for two consecutive weeks. Eleven days later, allergen-specific IgG1 and IgE in serum were measured by ELISA. On day 25, 20 mg OVM or 12 mg α-casein was administered orally, and allergic reactions such as the fall in rectal temperature, symptom scores during 90-120 min, serum mast cell protease-1 and cytokine levels were monitored. The detection of mild allergic reactions due to adjuvant-free allergen sensitization and oral allergen challenge routes was amplified by the combination of oral allergen and aspirin administration simultaneously or aspirin administration within 15-30 min before an allergen challenge. Quantification of the maximum symptom score and the frequency of symptoms during the monitoring period improved evaluation accuracy of food allergy signals. Based on these results, efficacy of casein oral immunotherapy for cow's milk allergies, which are generally difficult to detect, was monitored adequately.

The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice

Atopic dermatitis (AD) is characterized by TH2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The TH2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity. We sought to investigate whether the IL-4Rα R576 polymorphism is associated with AD severity and exaggerates allergic skin inflammation in mice. Nighttime itching interfering with sleep, Rajka-Langeland, and Eczema Area and Severity Index scores were used to assess AD severity. Allergic skin inflammation following epicutaneous sensitization of mice 1 or 2 IL-4Rα R576 alleles (QR and RR) and IL-4Rα Q576 (QQ) controls was assessed by flow cytometric analysis of cells and quantitative RT-PCR analysis of cytokines in skin. The frequency of nighttime itching in 190 asthmatic inner-city children with AD, as well as Rajka-Langeland and Eczema Area and Severity Index scores in 1116 White patients with AD enrolled in the Atopic Dermatitis Research Network, was higher in subjects with the IL-4Rα R576 polymorphism compared with those without, with statistical significance for the Rajka-Langeland score. Following epicutaneous sensitization of mice with ovalbumin or house dust mite, skin infiltration by CD4+ cells and eosinophils, cutaneous expression of Il4 and Il13, transepidermal water loss, antigen-specific IgE antibody levels, and IL-13 secretion by antigen-stimulated splenocytes were significantly higher in RR and QR mice compared with QQ controls. Bone marrow radiation chimeras demonstrated that both hematopoietic cells and stromal cells contribute to the mutants' exaggerated allergic skin inflammation. The IL-4Rα R576 polymorphism predisposes to more severe AD and increases allergic skin inflammation in mice.

Context-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march

Atopic diseases, including atopic dermatitis (AD) and asthma, affect a large proportion of the population, with increasing prevalence worldwide. AD often precedes the development of asthma, known as the atopic march. Allergen sensitization developed through the barrier-defective skin of AD has been recognized to be a critical step leading to asthma, in which thymic stromal lymphopoietin (TSLP) was previously shown to be critical. In this study, using a laser-assistant microporation system to disrupt targeted skin layers for generating micropores at a precise anatomic depth of mouse skin, we model allergen exposure superficially or deeply in the skin, leading to epicutaneous sensitization or dermacutaneous sensitization that is associated with a different cytokine microenvironment. Our work shows a differential requirement for TSLP in these two contexts, and identifies an important function for IL-1β, which is independent of TSLP, in promoting allergen sensitization and subsequent allergic asthma.

Single-dose AAV vector gene immunotherapy to treat food allergy

Immunotherapies for patients with food allergy have shown some success in limiting allergic responses. However, these approaches require lengthy protocols with repeated allergen dosing and patients can relapse following discontinuation of treatment. The purpose of this study was to test if a single dose of an adeno-associated virus (AAV) vector can safely prevent and treat egg allergy in a mouse model. AAV vectors expressing ovalbumin (OVA) under an ubiquitous or liver-specific promoter were injected prior to or after epicutaneous sensitization with OVA. Mice treated with either AAV8-OVA vector were completely protected from allergy sensitization. These animals had a significant reduction in anaphylaxis mediated by a reduction in OVA-specific IgE titers. In mice with established OVA allergy, allergic responses were mitigated only in mice treated with an AAV8-OVA vector expressing OVA from an ubiquitous promoter. In conclusion, an AAV vector with a liver-specific promoter was more effective for allergy prevention, but higher OVA levels were necessary for reducing symptoms in preexisting allergy. Overall, our AAV gene immunotherapy resulted in an expansion of OVA-specific FoxP3+ CD4+ T cells, an increase in the regulatory cytokine IL-10, and a reduction in the IgE promoting cytokine IL-13.

Scallop aquaculture has a potential risk of natto-induced hypersensitivity reactions in a local area of northern Japan

BackgroundFermented soybean (natto)-induced hypersensitivity reactions (natto allergy) are rare and can result in late-onset anaphylaxis. The allergen in natto is considered to be poly-γ-glutamic acid (PGA), and marine sports are a risk factor for natto allergy due to epicutaneous sensitization to PGA from cnidarian stings. However, no research on natto allergy in fishery workers has yet been performed. MethodsWe conducted a chart review of inpatients diagnosed with anaphylaxis due to natto at Hokkaido Prefectural Haboro Hospital between April 1, 2009, and August 31, 2020. We also administered self-report questionnaires about food hypersensitivity reactions to Japanese fishery workers, including members of the Kitarumoi Fishery Cooperative Association and part-time workers in this area, from February 1 to May 31, 2021. ResultsWe found six inpatients (29 inpatients with food-induced anaphylaxis among approximately 11,000 community-dwelling residents) with late-onset anaphylaxis due to natto; all were involved in scallop aquaculture. The questionnaires revealed that 27 participants had natto allergy. We divided the fishery workers into a scallop aquaculture (Scallop) group (n = 211) and other fishery group (n = 106). The Scallop group was significantly associated with natto allergy after adjustments for confounders (OR: 5.73, 95% CI: 1.46–22.56) by logistic regression analysis. In the Scallop group, older age, experience in repairing nets, and a longer length of work experience were significantly related to participants with natto allergy (n = 23), but not participants without natto allergy (n = 181). ConclusionsOur results indicated an association between scallop aquaculture and natto allergy.