MrgprA3+ Primary Sensory Neurons Mediate Acute Allergic Itch Responses in Atopic Dermatitis Model Mice.

Itch is a prominent symptom of atopic dermatitis (AD). However, the underlying mechanism remains complex and has not yet been fully elucidated. Mas-related G protein-coupled receptor A3 (MrgprA3) has emerged attention as a marker of primary sensory neurons that specifically transmit itch signals; however, its involvement in AD-related itch has not been extensively explored. In this study, we developed an AD itch mouse model by repeatedly applying house dust mite (HDM) extract to barrier-impaired skin via a special diet. To clarify the role of MrgprA3+ neurons in itch behavior in our AD model, we adopted a toxin receptor-mediated cell knockout strategy using transgenic mice in which the diphtheria toxin receptor (DTR) gene was placed under the control of the Mrgpra3 promoter. When the HDM extract was repeatedly applied to the face and back skin of special diet-fed mice, the mice exhibited AD-like dry and eczematous skin lesions accompanied by three types of itch-related behaviors:1) spontaneous scratching, 2) acute scratching after antigen challenge, and 3) light touch-evoked scratching. Upon diphtheria toxin administration, substantial depletion of DTR+/MrgprA3+ neurons was observed in the dorsal root ganglion. Ablation of MrgprA3+ neurons suppressed acute itch responses after HDM application, whereas spontaneous and touch-evoked itch behaviors remained unaffected. Our findings unequivocally demonstrate that in our AD model, MrgprA3+ primary sensory neurons mediate acute allergic itch responses, whereas these neurons are not involved in spontaneous itch or alloknesis.

The Effect of a TLR3 Agonist on Airway Allergic Inflammation and Viral Infection in Immunoproteasome-Deficient Mice.

Allergic asthma is characterized by increased type 2 inflammation, including eosinophils. Subjects with allergic asthma have recurrent symptoms due to their constant exposure to environmental allergens, such as house dust mite (HDM), which can be further exacerbated by respiratory infections like rhinovirus. The immunoproteasome (IP) is a proteolytic machinery that is induced by inflammatory mediators during virus infection, but the role of the IP in airway allergic inflammation during rhinovirus infection remains unknown. Wild-type (WT) and IP knockout (KO) mice were challenged with HDM. At 48 h after the last HDM challenge, mice were infected with rhinovirus 1B (RV-A1B) for 24 h. After HDM and RV-A1B treatment, IP KO (vs. WT) mice had significantly more lung eosinophils and neutrophils, as well as a significantly higher viral load, but less IFN-beta expression, compared to WT mice. A TLR3 agonist polyinosinic-polycytidylic acid (Poly I:C) treatment after RV-A1B infection in HDM-challenged IP KO mice significantly increased IFN-beta expression and reduced viral load, with a minimal effect on the number of inflammatory cells. Our data suggest that immunoproteasome is an important mechanism functioning to prevent excessive inflammation and viral infection in allergen-exposed mice, and that Poly I:C could be therapeutically effective in enhancing the antiviral response and lessening the viral burden in lungs with IP deficiency.

The impact of adverse reactions on adherence to sublingual immunotherapy for Japanese cedar pollinosis and house dust mite allergy in Japan.

BACKGROUND: Allergen immunotherapy is the only treatment that can achieve remission for allergic diseases. AIMS/OBJECTIVES: To investigate the three-year adherence to sublingual immunotherapy for Japanese cedar pollinosis and house dust mite allergy at a clinic in Japan and identify factors that influence adherence and severe adverse reactions. MATERIAL AND METHODS: In total, 174 patients aged 12 years or older who started sublingual immunotherapy for Japanese cedar pollinosis (n = 72), house dust mite allergy (n = 55), or both (n = 47) between May 2017 and June 2018. Patient age, sex, type of pharmacotherapy used, adverse reactions, blood test results, and duration of continuous treatment were investigated. RESULTS: The three-year treatment continuation rate was 40.8%. Adverse reaction rates were 12.6% for cedar pollinosis and 40.2% for house dust mite allergy. Patients with dose reductions due to severe reactions had lower first-year continuation rates. In the MITICURE® group, patients with severe reactions had significantly higher serum total IgE levels. Severe reactions were more common in MITICURE® patients with seven or more positive antigen types. CONCLUSIONS AND SIGNIFICANCE: Severe adverse reactions reduced early adherence.

Serum amyloid A1 induced dysfunction of airway macrophages via CD36 pathway in allergic airway inflammation.

Previous studies showed that serum amyloid A (SAA) and macrophages were associated with allergic airway inflammation. However, the interaction between SAA1 and macrophages in allergic airway inflammation remains to be further elucidated. In this study, the levels of SAA1 were measured in nasal tissues from patients with eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), house dust mite (HDM)-treated BEAS-2B cells and the tissues of mice of HDM-induced allergic airway inflammation. Human monocytes-derived macrophages and mouse bone marrow-derived macrophages (BMDMs) were exposed to SAA1, and CCL17 and the other M1/M2-related factors were evaluated using RT-PCR and/or ELISA. To test the effects of SAA1-treated BMDMs on chemotaxis and differentiation of CD4+ T cells, number of migrated cells and the levels of Th1 and Th2 were measured using flow cytometry. SAA1 receptors were examined in BMDMs and lung macrophages of model mice. CD36 neutralizing antibody was applied to explore the mechanisms of SAA1 in regulating BMDMs using RT-PCR and/or ELISA. We found that SAA1 was expressed in epithelial cells, and was increased in the nasal tissues of patients with eosinophilic CRSwNP and HDM-treated BEAS-2B- cells as well as the bronchoalveolar lavage fluid and lung tissues of mice exposed to HDM. We also found that the level of CCL17 was increased in M2 macrophages, more CD4+ T cells were recruited and proportion of Th2 was increased after the treatment of SAA1. The treatment of CD36 neutralizing antibody decreased CCL17 level in SAA1-treated M2 BMDMs. In summary, our results showed that SAA1 was increased in allergic airway inflammation, and the administration of SAA1 upregulated the expression of CCL17 in M2 macrophages via CD36 and promoted the chemotaxis of CD4+ T cells and differentiation of Th2. It may provide a new therapeutic strategy that could mediate allergic airway inflammation via suppressing SAA1 to reduce recruitment of CD4+ T cells and activation of Th2.

IgE plasma cells are transcriptionally and functionally distinct from other isotypes.

Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)-producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (<3 weeks) and long-lived IgE PCs accumulate in the bone marrow (BM) with prolonged exposure (>7 weeks). IgE PCs had distinct surface and gene expression profiles in these different tissues compared with other Ig isotypes. IgE BMPCs up-regulated genes associated with prosurvival and BM homing, whereas IgE dLN PCs expressed genes associated with recent class switching and differentiation. IgE PCs also exhibited higher expression of endoplasmic reticulum (ER) stress and protein coding genes and higher antibody secretion rate when compared with IgG1. Overall, this study highlights the unique developmental path and transcriptional signature of short-lived and long-lived IgE PCs.

Intermittent ozone inhalation during house dust mite-induced sensitization primes for adverse asthma phenotype.

The ability of air pollution to induce acute exacerbation of asthma is well documented. However, the ability of ozone (O3), the most reactive gaseous component of air pollution, to function as a modulator during sensitization is not well established. C57BL/6 J male mice were intranasally sensitized to house dust mite (HDM) (40 µg/kg) for 3 weeks on alternate days in parallel with once-a-week O3 exposure (1 ppm). Mice were euthanized 24 h following the last HDM challenge. Lung lavage, histology, lung function (both forced oscillation and forced expiration-based), immune cell profiling, inflammation (pulmonary and systemic), and immunoglobulin production were assessed. Compared to HDM alone, HDM + O3 leads to a significant increase in peribronchial inflammation (p < 0.01), perivascular inflammation (p < 0.001) and methacholine-provoked large airway hyperreactivity (p < 0.05). Serum total IgG and IgE and HDM-specific IgG1 were 3-5 times greater in HDM + O3 co-exposure compared to PBS and O3-exposed groups. An increase in activated/mature lung total and monocyte-derived dendritic cells (p < 0.05) as well as T-activated, and T memory lymphocyte subset numbers (p < 0.05) were noted in the HDM + O3 group compared to HDM alone group. Concurrent O3 inhalation and HDM sensitization also caused significantly greater (p < 0.05) lung tissue interleukin-17 pathway gene expression and mediator levels in the serum. Redox imbalance was manifested by impaired lung antioxidant defense and increased oxidants. O3 inhalation during allergic sensitization coalesces in generating a significantly worse TH17 asthmatic phenotype.

The storage mite Tyrophagus putrescentiae induces greater lung inflammation than house dust mites in mice.

Exposure to storage mite (SM) and house dust mite (HDM) allergens is a risk factor for sensitization and asthma development; however, the related immune responses and their pathology have not been fully investigated. The HDMs Dermatophagoides farinae and Dermatophagoides pteronyssinus and SM Tyrophagus putrescentiae are potent allergens that induce asthma. Most SM-related studies have focused on the allergic reactions of individuals by measuring their immunoglobulin (Ig)E expression. Considering the limited research on this topic, the present study aims to investigate the differences in the immune responses induced by HDMs and SMs and histologically analyze lung tissues in a mouse asthma model to understand the differential effects of HDM and SM. The results revealed that all mite species induced airway inflammation. Mice challenged with T. putrescentiae had the highest airway resistance and total cell, eosinophil, and neutrophil counts in the bronchoalveolar lavage fluid (BALF). The SM-sensitized groups showed more severe lesions and mucus hypersecretions than the HDM-sensitized groups. Although the degree of HDM and SM exposure was the same, the damage to the respiratory lung tissue was more severe in SM-exposed mice, which resulted in excessive mucin secretion and increased fibrosis. Furthermore, these findings suggest that SM sensitization induces a more significant hypersensitivity response in mucosal immunity than HDM sensitization in asthma models.

TCF-1 and TOX regulate the memory formation of intestinal group 2 innate lymphoid cells in asthma.

Immune memory has been expanded to group 2 innate lymphoid cells (ILC2s), but the cellular and molecular bases remain incompletely understood. Based on house dust mite (HDM)-induced mice asthma models and human samples, we applied flow cytometry, parabiosis, in vivo imaging and adoptive transplantation to confirm the persistence, migration and function of CD45+lineage-CD90.2+NK1.1-NKp46-ST2-KLRG1+IL-17RB+ memory-like ILC2s (ml-ILC2s). Regulated by CCR9/CCL25 and S1P signaling, ml-ILC2s reside in the lamina propria of small intestines (siLP) in asthma remission, and subsequently move to airway upon re-encountering antigens or alarmins. Furthermore, ml-ILC2s possess properties of longevity, potential of rapid proliferation and producing IL-13, and display transcriptional characteristics with up-regulation of Tox and Tcf-7. ml-ILC2s transplantation restore the asthmatic changes abrogated by Tox and Tcf7 knockdown. Our data identify siLP ml-ILC2s as a memory-like subset, which promotes asthma relapse. Targeting TCF-1 and TOX might be promising for preventing asthma recurrence.

Preventive and Therapeutic Effects of Lactiplantibacillus plantarum HD02 and MD159 through Mast Cell Degranulation Inhibition in Mouse Models of Atopic Dermatitis.

As the relationship between the gut microbiome and allergies becomes better understood, targeted strategies to prevent and treat allergies through gut microbiome modulation are being increasingly developed. In the study presented herein, we screened various probiotics for their ability to inhibit mast cell degranulation and identified Lactiplatibacillus plantarum HD02 and MD159 as effective candidates. The two strains significantly attenuated vascular permeability induced by mast cell degranulation in a passive cutaneous anaphylaxis (PCA) model and, in the MC903-induced murine atopic dermatitis (AD) model, demonstrated comparable preventive effects against allergies, reducing blood levels of MCPT-1 (mast cell protease-1) and total IgE. In the house dust mite (HDM)-induced murine AD model, both L. plantarum HD02 and MD159 showed therapeutic effects, with L. plantarum HD02 demonstrating superior efficacy. Nevertheless, L. plantarum MD159 better suppressed transepidermal water loss (TEWL). Furthermore, L. plantarum HD02 and MD159 significantly increased the number of splenic Foxp3+ regulatory T cells, with L. plantarum MD159 having a more pronounced effect. However, only L. plantarum HD02 achieved a reduction in immune cells in the draining lymph nodes. Our findings highlight L. plantarum HD02 and MD159 as promising candidates for the prevention and treatment of allergies, demonstrating significant efficacy in suppressing mast cell degranulation, reducing the number of allergy biomarkers, and modulating immune responses in experimental models of AD. Their distinct mechanisms of action suggest potential complementary roles in addressing allergic diseases, underscoring their therapeutic promise in clinical applications.

[LONGITUDINAL EVALUATION OF EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN PEDIATRIC PERENNIAL ALLERGIC RHINITIS USING LABORATORY EXAMINATIONS AND IN VIVO BIOMARKERS].

OBJECTIVE: The purpose of this study was to evaluate the efficacy of sublingual immunotherapy (SLIT) with house dust mite (HDM) on pediatric perennial allergic rhinitis (AR) based on longitudinal assessment of nasal symptoms, laboratory examination, and in vivo biomarkers. METHOD: The subjects included 40 children with perennial AR who had SLIT with HDM for 2 years. Nasal symptoms, medications, skin prick tests, nasal provocation tests, and peripheral blood tests were evaluated before, 6 months, one year and two years after the onset of SLIT. RESULTS: Total nasal symptom scores, prick test wheal diameter, and peripheral blood eosinophil count decreased in 6 months. Total nasal symptom scores continued to decrease from 6 months to 2 years. Symptom-medication scores and nasal provocation test responses decreased in 1 year. Symptom-medication scores continued to decline from 1 to 2 years. Medication scores and nasal eosinophilia decreased in 2 years. Serum specific IgE to HDM slightly increased transiently and decreased in 2 years. The severity of symptoms and specific IgE to HDM at the baseline, and changes of symptoms and specific IgE to HDM during the first six months and first one year of SLIT were correlated with improvement in symptom scores over two years of SLUT. TNSS at baseline was correlated with that at second year. CONCLUSION: Longitudinal assessment of symptoms, allergen specific IgE, and in vivo biomarkers showed the effectiveness of SLIT. Symptom scores and allergen specific IgE may also be early predictive factors of SLIT efficacy in children with AR.

Comparison of Immune Checkpoint Molecule Expression in Different Years of House Dust Mite Subcutaneous Immunotherapy on CD4+ T and Treg Cells in Children with Allergic Rhinitis.

Background: Allergen-specific immunotherapy, a unique inducer of tolerance, may result in T cell exhaution. Aims: To investigate how the duration of house dust mite (HDM) subcutaneous immunotherapy (SCIT) affects the expression of major immune checkpoint (ICP) molecules on the surface of CD4+ T-helper and regulatory T (Treg) cells. Study Design: Cross-sectional study. Methods: We enrolled 28 children with HDM-induced allergic rhinitis (AR) and six controls. The study participants were divided into six groups: one group each of patients in their first, second, and third years of HDM-SCIT; one group each comprising those in the first year following HDM-SCIT and those on pharmacotherapy; and the control group. The expression of ICPs on CD4+ T and Treg cells was determined using flow cytometry, and plasma levels of soluble ICPs were estimated by ELISA. Results: Our results revealed a significant increase in the expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3) on CD4+ T cells during the second and third years of SCIT, respectively. Additionally, a strong correlation was observed between the expression of CTLA-4 and T cell immunoglobulin and mucin domain containing molecule-3 in CD4+ T cells. Furthermore, we observed a significant correlation between the expressions of programmed cell death protein-1, CTLA-4, T cell Immunoreceptor with Immunoglobulin and Immunoreceptor Tyrosine-Based Inhibitory Motif domain, and LAG-3 on both CD4+ T and Treg cells. A robust correlation was observed between the plasma levels of soluble ICPs. Conclusion: HDM-SCIT induces CD4+ T cell exhaution, which may contribute to tolerance induction in children with AR.

Interleukin-33-activated basophils promote asthma by regulating Th2 cell entry into lung tissue.

Asthma is characterized by lung eosinophilia, remodeling, and mucus plugging, controlled by adaptive Th2 effector cells secreting IL-4, IL-5, and IL-13. Inhaled house dust mite (HDM) causes the release of barrier epithelial cytokines that activate various innate immune cells like DCs and basophils that can promote Th2 adaptive immunity directly or indirectly. Here, we show that basophils play a crucial role in the development of type 2 immunity and eosinophilic inflammation, mucus production, and bronchial hyperreactivity in response to HDM inhalation in C57Bl/6 mice. Interestingly, conditional depletion of basophils during sensitization did not reduce Th2 priming or asthma inception, whereas depletion during allergen challenge did. During the challenge of sensitized mice, basophil-intrinsic IL-33/ST2 signaling, and not FcεRI engagement, promoted basophil IL-4 production and subsequent Th2 cell recruitment to the lungs via vascular integrin expression. Basophil-intrinsic loss of the ubiquitin modifying molecule Tnfaip3, involved in dampening IL-33 signaling, enhanced key asthma features. Thus, IL-33-activated basophils are gatekeepers that boost allergic airway inflammation by controlling Th2 tissue entry.

Chicoric acid acts as an ALOX15 inhibitor to prevent ferroptosis in asthma.

BACKGROUND: Chicoric acid (CA) is a crucial immunologically active compound found in chicory and echinacea, possessing a range of biological activities. Ferroptosis, a type of iron-dependent cell death induced by lipid peroxidation, plays a key role in the development and advancement of asthma. Targeting ferroptosis could be a potential therapeutic strategy for treating asthma. PURPOSE: The purpose of this study was to explore the screening of ALOX15, a pivotal target of ferroptosis in asthma, and potential therapeutic agents, as well as to investigate the promising potential of CA as an ALOX15 inhibitor for modulating ferroptosis in asthma. METHODS: Through high-throughput data processing of bronchial epithelial RNA from asthma patients using bioinformatics and machine learning, the key target of ferroptosis in asthma, ALOX15, was identified. An inhibitor of ALOX15 was then obtained through high-throughput molecular docking and molecular dynamics simulation tests. In vitro experiments were conducted using a 16HBE cell model induced by house dust mite (HDM) and lipopolysaccharide (LPS), which were treated with the ALOX15 inhibitor (PD146176), CA treatment, or ALOX15 knockdown. In vivo experiments were also carried out using a mouse model induced by HDM and LPS. RESULTS: The composite model of ALOX15 and CA in molecular dynamics simulations shows good stability and flexibility. Network pharmacological analysis reveals that CA regulates ferroptosis through ALOX15 in treating asthma. In vitro studies show that ALOX15 is highly expressed in HDM and LPS treatments, while CA inhibits HDM and LPS-induced ferroptosis in 16HBE cells by reducing ALOX15 expression. Knockdown of ALOX15 has the opposite effect. Metabolomics analysis identifies key compounds associated with ferroptosis, including L-Targinine, eicosapentaenoic acid, 16-hydroxy hexadecanoic acid, and succinic acid. In vivo experiments demonstrate that CA suppresses ALOX15 expression, inhibits ferroptosis, and improves asthma symptoms in mice. CONCLUSION: Our research initially identified CA as a promising asthma treatment that effectively blocks ferroptosis by specifically targeting ALOX15. This study not only highlights CA as a potential therapeutic agent for asthma but also introduces novel targets and treatment options for this condition, along with innovative approaches for utilizing natural compounds to target diseases associated with ferroptosis.

Biological Sex Is an Effect Modifier of Allergen-Mediated Alteration of the Lung Proteome.

Asthma exhibits a distinct sex bias in the disease prevalence, severity, and response to therapy. However, sex-related differences in alterations of the lung proteome mediated by aeroallergens critical in asthma, such as house dust mites (HDM), remain unknown. In this study, we define sex-related differences in the lung proteome using an HDM-challenged mouse model by 1D LC-MS/MS. Sex-disaggregated data analysis showed that 406 proteins were uniquely altered in females, 273 proteins were uniquely altered in males, and 414 proteins were altered in both females and males in response to HDM. In a linear mixed model analysis, sex modified the HDM exposure effect for 163 proteins, i.e., a significant sex:exposure interaction was identified in 84 proteins in females and 35 proteins in males. Of these, 12 proteins showed a significant sex effect in both female and male lungs. We further selected 3 proteins Tjp1, Lamtor1, and G3BP2 for independent confirmation studies. Our findings detail the sex-specific lung proteome in response to an aeroallergen critical in asthma and demonstrate that sex is a significant effect modifier of HDM response. These results will serve as a valuable resource for delineating sex-specific mechanisms in aeroallergen-driven responses in asthma research.

Local receptor-interacting protein kinase 2 inhibition mitigates house dust mite-induced asthma.

BACKGROUND: House dust mite is the most frequent trigger of allergic asthma, with innate and adaptive immune mechanisms playing critical roles in outcomes. We recently identified the nucleotide-binding oligomerisation domain 1 (NOD1)/receptor-interacting serine/threonine protein kinase 2 (RIPK2) signalling pathway as a relevant contributor to murine house dust mite-induced asthma. This study aimed to evaluate the effectiveness of a pharmacological RIPK2 inhibitor administered locally as a preventive and therapeutic approach using a house dust mite-induced asthma model in wild-type and humanised NOD1 mice harbouring an asthma-associated risk allele, and its relevance using air-liquid interface epithelial cultures from asthma patients. METHODS: A RIPK2 inhibitor was administered intranasally either preventively or therapeutically in a murine house dust mite-induced asthma model. Airway hyperresponsiveness, bronchoalveolar lavage composition, cytokine/chemokine expression and mucus production were evaluated, as well as the effect of the inhibitor on precision-cut lung slices. Furthermore, the inhibitor was tested on air-liquid interface epithelial cultures from asthma patients and controls. RESULTS: While local preventive administration of the RIPK2 inhibitor reduced airway hyperresponsiveness, eosinophilia, mucus production, T-helper type 2 cytokines and interleukin 33 (IL-33) in wild-type mice, its therapeutic administration failed to reduce the above parameters, except IL-33. By contrast, therapeutic RIPK2 inhibition mitigated all asthma features in humanised NOD1 mice. Results in precision-cut lung slices emphasised an early role of thymic stromal lymphopoietin and IL-33 in the NOD1-dependent response to house dust mite, and a late effect of NOD1 signalling on IL-13 effector response. RIPK2 inhibitor downregulated thymic stromal lymphopoietin and chemokines in house dust mite-stimulated epithelial cultures from asthma patients. CONCLUSION: These data support that local interference of the NOD1 signalling pathway through RIPK2 inhibition may represent a new therapeutic approach in house dust mite-induced asthma.

Effect of photobiomodulation in an experimental in vitro model of asthma-Copd overlap.

The objective of the study was to evaluate the effect of photobiomodulation (PBM) with laser on the inflammatory process in an experimental in vitro model of ACO. The groups were: (1) human bronchial epithelial cells (BEAS-2B); (2) BEAS-2B cells treated with dexamethasone; (3) BEAS-2B cells irradiated with laser; (4) BEAS-2B cells stimulated with cigarette smoke extract (CSE) + House Dust Mite (HDM); (5) BEAS-2B cells stimulated with CSE + HDM and treated with dexamethasone; (6) BEAS-2B cells incubated with CSE + HDM and irradiated with laser. After 24 h, cytokines were quantified. There was a reduction in TNF-α, IL-1ß, IL-6, IL-4, IL-5, IL-13, IL-17, IL-21, IL-23, and an increase in IL-10 and IFN-γ in cells from the laser-irradiated ACO group compared to only ACO group. With these results, we can suggest that photobiomodulation acts in the modulation of inflammation observed in ACO, and may be a treatment option.

Coke oven emissions exacerbate allergic asthma by promoting ferroptosis in airway epithelial cells.

Epidemiological studies have shown that coke oven emissions (COEs) affect the deterioration of asthma, but has not been proven by experimental results. In this study, we found for the first time that COEs exacerbate allergen house dust mite (HDM)-induced allergic asthma in the mouse model. The findings reveal that airway inflammation, airway remodeling and allergic reaction were aggravated in the COE + HDM combined exposure group compared with the individual exposure group. Mechanism studies indicated higher levels of iron and MDA in the COE + HDM combined exposure group, along with increased expression of Ptgs2 and reduced GPX4 expression. Iron chelator deferoxamine (DFO) effectively inhibited ferroptosis induced by COE synergistically with HDM in vitro. Further studies highlighted the role of ferritinophagy in the COE + HDM-induced ferroptosis. 3-methyladenine (3-MA) could inhibit ferroptosis in the COE + HDM exposure group. Interestingly, we injected DFO intraperitoneally into mice in the combined exposure group and found DFO could significantly inhibit the COE-exacerbated ferroptosis and allergic asthma. Our findings link ferroptosis with COE-exacerbated allergic asthma, implying that ferroptosis may have important therapeutic potential for asthma in patients with occupational exposure of COE.

[Prevalence of Allergen-Specific Immunoglobulin E in 57558 Patients in 2012-2022]. / 2012­2022å¹´57558ä¾‹æ‚£è€ è¿‡æ•åŽŸç‰¹å¼‚æ€§IgE阳性特征分析.

Objective: The study aims to preliminarily investigate the prevalence characteristics of allergen-specific immunoglobulin E (IgE) in 57558 patients over the past decade by examining its distribution in the province and exploring its associations with age, sex, temperature, and relative humidity, providing insights for the prevention and diagnosis of allergic diseases in the Sichuan region. Methods: A retrospective analysis was conducted on a cohort of 57558 patients who underwent allergen testing (by means of EUROIMMUN immunoblotting method) at West China Hospital, Sichuan University between August 2012 and February 2022. The clinical data of these patients were collected to establish a comprehensive database, while the temperature and humidity records of the corresponding timeframe were gathered for further analysis. The positive results from the allergen tests were categorized into four levels, including weakly positive (±), positive (+), moderately positive (++), and strongly positive (+++). Statistical analyses were performed using SPSS 25.0, with Chi-square tests conducted to compare count data and Pearson's correlation tests done conducted to assess the relationships between different types of allergens and temperature/relative humidity. P<0.05 was applied to determine statistically significant differences. GraphPad Prism 9.0.0 was utilized to generate visual representations of the data. Results: The overall positivity rate of allergen-specific IgE among the 57558 samples was 30.69%. The top five allergens that elicited positive results were dust mite mix 1 (14.46%), crab (6.67%), soybean (4.72%), fish mix 1 (4.64%), and cockroach (4.34%). Notably, weakly positive (±) results were predominant for allergens such as eggs, peanuts, soybeans, cow's milk, beef, mutton, crab, shrimp, fish mix 1, cockroach, humulus japonicus, ambrosia artemisifolia, artemisia vulgaris, tree mix 2, house dust, and mold mix 1, collectively constituting over 40% of the positive outcomes. In contrast, cat hair and dog dander exhibited an equal distribution of approximately 25% for each positive levels, while mite mix 1 demonstrated the highest proportion of strongly positive results (+++), accounting for 37.66% of all positive results. Sex disparities in positivity rates were evident for various allergens, with significant differences observed for peanut, soybean, crab, shrimp, fish mix 1, cockroach, ambrosia artemisifolia, tree mix 2, cat hair, dog dander, and mite mix 1. Furthermore, the study identified age-related trends in allergen positivity rates, with a general decline observed across most allergens with increasing age. The positive rate of at least one food allergen was highest in the 0-10 age group (36.18%), and the positive rate of at least one inhalation allergen was highest in the 11-20 age group (45.35%). Noteworthy correlations were observed between allergen-specific IgE positivity and environmental factors, including a strong negative correlation between cow's milk allergy and relative humidity ( r=-0.640, P<0.05), a strong negative correlation of artemisia vulgaris sensitivity with temperature ( r Mean high temperature=-0.695, r Mean low temperature=-0.692, P<0.05), and a very strong positive correlation of mold mix 1 sensitivity with relative humidity ( r=0.704, P<0.05). Conclusion: Allergen-specific IgE positivity is associated with genetic factors, demonstrates significant sex- and age-related characteristics in the population, and is influenced by changes in local temperature and relative humidity.

Heterogeneous IL-9 Production by Circulating Skin-Tropic and Extracutaneous Memory T Cells in Atopic Dermatitis Patients.

Interleukin (IL)-9 is present in atopic dermatitis (AD) lesions and is considered to be mainly produced by skin-homing T cells expressing the cutaneous lymphocyte-associated antigen (CLA). However, its induction by AD-associated triggers remains unexplored. Circulating skin-tropic CLA+ and extracutaneous/systemic CLA- memory T cells cocultured with autologous lesional epidermal cells from AD patients were activated with house dust mite (HDM) and staphylococcal enterotoxin B (SEB). Levels of AD-related mediators in response to both stimuli were measured in supernatants, and the cytokine response was associated with different clinical characteristics. Both HDM and SEB triggered heterogeneous IL-9 production by CLA+ and CLA- T cells in a clinically homogenous group of AD patients, which enabled patient stratification into IL-9 producers and non-producers, with the former group exhibiting heightened HDM-specific and total IgE levels. Upon allergen exposure, IL-9 production depended on the contribution of epidermal cells and class II-mediated presentation; it was the greatest cytokine produced and correlated with HDM-specific IgE levels, whereas SEB mildly induced its release. This study demonstrates that both skin-tropic and extracutaneous memory T cells produce IL-9 and suggests that the degree of allergen sensitization reflects the varied IL-9 responses in vitro, which may allow for patient stratification in a clinically homogenous population.

CD11c+ dendritic cells PlexinD1 deficiency exacerbates airway hyperresponsiveness, IgE and mucus production in a mouse model of allergic asthma.

Dendritic cells (DCs) are pivotal in regulating allergic asthma. Our research has shown that the absence of Sema3E worsens asthma symptoms in acute and chronic asthma models. However, the specific role of PlexinD1 in these processes, particularly in DCs, remains unclear. This study investigates the role of PlexinD1 in CD11c+ DCs using a house dust mite (HDM) model of asthma. We generated CD11c+ DC-specific PlexinD1 knockout (CD11cPLXND1 KO) mice and subjected them, alongside wild-type controls (PLXND1fl/fl), to an HDM allergen protocol. Airway hyperresponsiveness (AHR) was measured using FlexiVent, and immune cell populations were analyzed via flow cytometry. Cytokine levels and immunoglobulin concentrations were assessed using mesoscale and ELISA, while collagen deposition and mucus production were examined through Sirius-red and periodic acid Schiff (PAS) staining respectively. Our results indicate that CD11cPLXND1 KO mice exhibit significantly exacerbated AHR, characterized by increased airway resistance and tissue elastance. Enhanced mucus production and collagen gene expression were observed in these mice compared to wild-type counterparts. Flow cytometry revealed higher CD11c+ MHCIIhigh CD11b+ cell recruitment into the lungs, and elevated total and HDM-specific serum IgE levels in CD11cPLXND1 KO mice. Mechanistically, co-cultures of B cells with DCs from CD11cPLXND1 KO mice showed significantly increased IgE production compared to wild-type mice.These findings highlight the critical regulatory role of the plexinD1 signaling pathway in CD11c+ DCs in modulating asthma features.