RESUMEN
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.
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Asma , Pulmón , Pyroglyphidae , Animales , Ratones , Pyroglyphidae/inmunología , Pulmón/inmunología , Pulmón/patología , Asma/inmunología , Asma/patología , Femenino , Neumonía/inmunología , Neumonía/patología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Acaridae/inmunología , Alérgenos/inmunología , Eosinófilos/inmunología , Eosinófilos/patologíaRESUMEN
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.
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Inmunoglobulina E , Células Plasmáticas , Animales , Células Plasmáticas/inmunología , Inmunoglobulina E/inmunología , Ratones , Pyroglyphidae/inmunología , Ratones Endogámicos C57BL , Isotipos de Inmunoglobulinas/inmunología , Isotipos de Inmunoglobulinas/genética , FemeninoRESUMEN
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.
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Degranulación de la Célula , Dermatitis Atópica , Modelos Animales de Enfermedad , Mastocitos , Probióticos , Animales , Dermatitis Atópica/terapia , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Mastocitos/efectos de los fármacos , Probióticos/farmacología , Ratones , Degranulación de la Célula/efectos de los fármacos , Inmunoglobulina E/sangre , Ratones Endogámicos BALB C , Lactobacillus plantarum , Pyroglyphidae/inmunología , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Linfocitos T Reguladores/inmunología , QuimasasRESUMEN
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.
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Linfocitos T CD4-Positivos , Pyroglyphidae , Rinitis Alérgica , Linfocitos T Reguladores , Humanos , Niño , Animales , Rinitis Alérgica/terapia , Rinitis Alérgica/inmunología , Rinitis Alérgica/sangre , Masculino , Estudios Transversales , Femenino , Pyroglyphidae/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígeno CTLA-4/análisis , Desensibilización Inmunológica/métodos , AdolescenteRESUMEN
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.
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Biomarcadores , Inmunoterapia Sublingual , Humanos , Niño , Biomarcadores/sangre , Masculino , Femenino , Estudios Longitudinales , Rinitis Alérgica Perenne/terapia , Rinitis Alérgica Perenne/inmunología , Rinitis Alérgica Perenne/diagnóstico , Pyroglyphidae/inmunología , Animales , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Adolescente , PreescolarRESUMEN
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.
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Asma , Factor Nuclear 1-alfa del Hepatocito , Proteínas de Homeodominio , Inmunidad Innata , Memoria Inmunológica , Linfocitos , Animales , Femenino , Humanos , Masculino , Ratones , Traslado Adoptivo , Asma/inmunología , Modelos Animales de Enfermedad , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Interleucina-13/metabolismo , Interleucina-13/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Intestinos/inmunología , Intestinos/patología , Linfocitos/inmunología , Ratones Endogámicos C57BL , Pyroglyphidae/inmunología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismoRESUMEN
The topic of ragweed pollen (RW) versus house dust mites (HDMs) has often been deliberated, but the increasing incidence of co-sensitization between them has been scarcely addressed. Utilizing Sprague Dawley rats, we explored the effects of co-sensitization with the combination of HDMs and RW pollen extracts in correlation with high-fructose diet (HFrD) by in vitro tracheal reactivity analysis in isolated organ bath and biological explorations. Our findings unveiled interrelated connections between allergic asthma, dyslipidemia, and HFrD-induced obesity, shedding light on their compounding role through inflammation. The increased CRP values and airway hyperresponsiveness to the methacholine challenge suggest a synergistic effect of obesity on amplifying the existing inflammation induced by asthma. One of the major outcomes is that the co-sensitization to HDMs and RW pollen led to the development of a severe allergic asthma phenotype in rats, especially in those with HFrD. Therefore, the co-sensitization to these allergens as well as the HFrD may play a crucial role in the modulation of systemic inflammation, obesity, and airway reactivity.
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Biomarcadores , Fructosa , Pyroglyphidae , Ratas Sprague-Dawley , Animales , Ratas , Biomarcadores/sangre , Pyroglyphidae/inmunología , Asma/inmunología , Asma/sangre , Asma/etiología , Masculino , Alérgenos/inmunología , Obesidad/inmunología , Obesidad/sangre , Antígenos de Plantas/inmunología , Polen/inmunología , Extractos VegetalesRESUMEN
BACKGROUND: COVID-19 is a new infectious disease. To investigate whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the adverse reactions of subcutaneous specific immunotherapy (SCIT) in children. METHODS: This study was conducted by collecting relevant data from children who underwent house dust mite SCIT from April 3, 2021, to March 18, 2023, including information on the time of COVID-19 infection, symptoms, and adverse reactions after each allergen injection. A mixed effects model was used to analyze the changes in adverse reactions before and after the COVID-19 infection. RESULTS: Among the records of adverse reactions from 2658 injections in 123 children who underwent SCIT, the overall adverse reaction rate before COVID-19 infection was 39.8% and 30.0% after COVID-19 infection. Compared with pre-infection with COVID-19, the risks of overall adverse reactions, local adverse reactions, and systemic adverse reactions of immunotherapy after COVID-19 infection were reduced (odds ratio [OR] = 0.24, 0.31, and 0.28, all P < 0.05). Among the local adverse reactions, the incidence of the unvaccinated group was the highest (15.3% vs. 7.1%). The incidence of overall and local adverse reactions to SCIT decreased in 2-vaccinated COVID-19 recipients (OR = 0.29-0.31, P < 0.05). CONCLUSIONS: In children, SARS-CoV-2 infection does not increase the incidence of adverse reactions to SCIT. This finding can provide a basis for the implementation of allergen-specific immunotherapy (AIT) during the COVID-19 pandemic.
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COVID-19 , Desensibilización Inmunológica , SARS-CoV-2 , Humanos , COVID-19/terapia , COVID-19/inmunología , Niño , Estudios Retrospectivos , Masculino , Femenino , Preescolar , SARS-CoV-2/inmunología , Inyecciones Subcutáneas , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Adolescente , Animales , Pyroglyphidae/inmunología , Alérgenos/inmunología , Alérgenos/efectos adversos , Alérgenos/administración & dosificación , LactanteRESUMEN
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.
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Asma , Antígeno CD11c , Células Dendríticas , Modelos Animales de Enfermedad , Inmunoglobulina E , Ratones Noqueados , Moco , Animales , Asma/inmunología , Asma/metabolismo , Asma/patología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Ratones , Antígeno CD11c/metabolismo , Moco/metabolismo , Pyroglyphidae/inmunología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Alérgenos/inmunología , Ratones Endogámicos C57BL , Glicoproteínas de Membrana , Péptidos y Proteínas de Señalización IntracelularRESUMEN
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.
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Asma , Células Epiteliales , Ferroptosis , Ratones Endogámicos BALB C , Animales , Ferroptosis/efectos de los fármacos , Asma/inducido químicamente , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Pyroglyphidae/inmunología , Ratones , Deferoxamina/farmacología , Femenino , Contaminantes Atmosféricos/toxicidad , Hierro/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
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.
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Dermatitis Atópica , Enterotoxinas , Interleucina-9 , Células T de Memoria , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Humanos , Interleucina-9/metabolismo , Femenino , Masculino , Adulto , Enterotoxinas/inmunología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Piel/inmunología , Piel/metabolismo , Pyroglyphidae/inmunología , Animales , Inmunoglobulina E/inmunología , Inmunoglobulina E/sangre , Persona de Mediana Edad , Antígenos de Diferenciación de Linfocitos T/metabolismo , Adulto Joven , Alérgenos/inmunología , Adolescente , Glicoproteínas de MembranaRESUMEN
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.
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Alérgenos , Inmunoglobulina E , Humanos , Alérgenos/inmunología , Inmunoglobulina E/inmunología , Inmunoglobulina E/sangre , Estudios Retrospectivos , Masculino , Femenino , China/epidemiología , Animales , Prevalencia , Adulto , Persona de Mediana Edad , Hipersensibilidad/epidemiología , Hipersensibilidad/inmunología , Adulto Joven , Niño , Adolescente , Humedad , Preescolar , Hipersensibilidad a los Alimentos/inmunología , Temperatura , Anciano , Pyroglyphidae/inmunologíaRESUMEN
Allergic rhinitis (AR) is a series of allergic reactions to allergens in the nasal mucosa and is one of the most common allergic diseases that affect both children and adults. Shi-Bi-Lin (SBL) is the modified formula of Cang Er Zi San (CEZS), a traditional Chinese herbal formula used for treating AR. Our study aims to elucidate the anti-inflammatory effects and mechanisms of SBL in house dust mite-induced AR by regulating gut microflora metabolism. In vivo studies showed that nasal allergies and the infiltration of inflammatory cells in the nasal epithelium were significantly suppressed by SBL. Moreover, SBL restored the impaired nasal epithelial barrier function with an increased tight junction protein expression and reduced the endothelial nitric oxide synthase (eNOS). Interestingly, SBL significantly reconstituted the abundance and composition of gut microbiota in AR mice; it increased the relative abundance of potentially beneficial genera and decreased the relative abundance of harmful genera. SBL also restored immune-related metabolisms, which were significantly increased and correlated with suppressing inflammatory cytokines. Furthermore, a network analysis and molecular docking indicated IL-6 was a possible target drug candidate for the SBL treatment. SBL dramatically reduced the IL-6 level in the nasal lavage fluid (NALF), suppressing the IL-6 downstream Erk1/2 and AKT/PI3K signaling pathways. In conclusion, our study integrates 16S rRNA sequencing, microflora metabolism, and network pharmacology to explain the immune mechanism of SBL in alleviating HDM-induced allergic rhinitis.
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Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Farmacología en Red , ARN Ribosómico 16S , Rinitis Alérgica , Rinitis Alérgica/tratamiento farmacológico , Rinitis Alérgica/microbiología , Rinitis Alérgica/metabolismo , Animales , ARN Ribosómico 16S/genética , Ratones , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/microbiología , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/inmunología , Pyroglyphidae/inmunología , Simulación del Acoplamiento Molecular , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , FemeninoRESUMEN
BACKGROUND: Subcutaneous immunotherapy (SCIT) can induce systemic reactions (SRs) in certain patients, but the underlying mechanisms remain to be fully elucidated. METHODS: AR patients who were undergoing standardized HDM SCIT (Alutard, ALK) between 2018 and 2022 were screened. Those who experienced two consecutive SRs were included in the study group. A control group was established, matched 1:1 by gender, age, and disease duration with the study group, who did not experience SRs during SCIT. Clinical and immunological parameters were recorded and analyzed both before SCIT and after 1 year of treatment. RESULTS: A total of 161 patients were included, with 79 (49.07%) in the study group. The study group had a higher proportion of AR combined asthma (26.8% vs. 51.8%, p < 0.001) and higher levels of sIgE to HDM and HDM components (all p < .001). Serum IL-4 and IL-13 levels in the study group were higher than those in the control group (p < .05). The study group received a lower maintenance dosage of HDM extracts injections than control group due to SRs (50000SQ vs. 100000SQ, p < .05). After 1 year of SCIT, the VAS score, the lung function parameters of asthmatic patients over 14 years old significantly improved in both groups (all p < .05). After a 7-day exposure to 20 µg/mL HDM extracts, the percentages of Th1, Th17, Tfh10, and Th17.1 in PBMCs decreased, while the Tfh13 cells significantly increased in the study group (p < .05). CONCLUSION: The type 2 inflammatory response is augmented in HDM-induced AR patients who experienced SRs during SCIT. Despite this, SCIT remains effective in these patients when administered with low-dosage allergen extracts.
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Desensibilización Inmunológica , Pyroglyphidae , Rinitis Alérgica , Humanos , Masculino , Femenino , Desensibilización Inmunológica/métodos , Niño , Rinitis Alérgica/inmunología , Rinitis Alérgica/terapia , Pyroglyphidae/inmunología , Inyecciones Subcutáneas , Animales , Adolescente , Antígenos Dermatofagoides/inmunología , Antígenos Dermatofagoides/administración & dosificación , Asma/inmunología , Asma/terapia , Inmunoglobulina E/sangre , Alérgenos/inmunología , Alérgenos/administración & dosificación , Células Th2/inmunologíaRESUMEN
BACKGROUND: Asthma is a heterogeneous, inflammatory disease with several phenotypes and endotypes. Severe asthmatics often exhibit mixed granulocytosis with reduced corticosteroid sensitivity. Bronchom is a newly developed Ayurvedic prescription medicine, indicated for the treatment of obstructive airway disorders. The purpose of the present study was to evaluate the in-vivo efficacy of Bronchom in mouse model of mixed granulocytic asthma with steroidal recalcitrance. METHODS: High-performance thin layer chromatography (HPTLC) and Ultra-high performance liquid chromatography (UHPLC) were employed to identify and quantitate the phytometabolites present in Bronchom. The preclinical effectiveness of Bronchom was assessed in house dust mite (HDM) and Complete Freund's adjuvant (CFA)-induced mixed granulocytic asthma model in mice. High dose of dexamethasone was tested parallelly. Specific-pathogen-free C57BL/6 mice were immunized with HDM and CFA and nineteen days later, they were intranasally challenged with HDM for four consecutive days. Then the mice were challenged with nebulized methacholine to evaluate airway hyperresponsiveness (AHR). Inflammatory cell influx was enumerated in the bronchoalveolar lavage fluid (BALF) followed by lung histology. Additionally, the concentrations of Th2 and pro-inflammatory cytokines was assessed in the BALF by multiplexed immune assay. The mRNA expression of pro-inflammatory cytokines and Mucin 5AC (MUC5AC) was also evaluated in the lung. RESULTS: HPTLC fingerprinting and UHPLC quantification of Bronchom revealed the presence of bioactive phytometabolites, namely, rosmarinic acid, gallic acid, methyl gallate, piperine, eugenol and glycyrrhizin. Bronchom effectively reduced AHR driven by HDM-CFA and the influx of total leukocytes, eosinophils and neutrophils in the BALF. In addition, Bronchom inhibited the infiltration of inflammatory cells in the lung as well as goblet cell metaplasia. Further, it also suppressed the elevated levels of Th2 cytokines and pro-inflammatory cytokines in the BALF. Similarly, Bronchom also regulated the mRNA expression of pro-inflammatory cytokines as well as MUC5AC in mice lungs. Reduced effectiveness of a high dose of the steroid, dexamethasone was observed in the model. CONCLUSIONS: We have demonstrated for the first time the robust pharmacological effects of an herbo-mineral medicine in an animal model of mixed granulocytic asthma induced by HDM and CFA. The outcomes suggest the potential utility of Bronchom in severe asthmatics with a mixed granulocytic phenotype.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma , Modelos Animales de Enfermedad , Animales , Asma/tratamiento farmacológico , Asma/inmunología , Asma/metabolismo , Ratones , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Corticoesteroides/uso terapéutico , Corticoesteroides/farmacología , Citocinas/metabolismo , Medicina Ayurvédica , Líquido del Lavado Bronquioalveolar , Femenino , Ratones Endogámicos C57BL , Dexametasona/farmacología , Dexametasona/uso terapéutico , Extractos Vegetales/farmacología , Pulmón/efectos de los fármacos , Pulmón/patología , Inflamación/tratamiento farmacológico , Hipersensibilidad Respiratoria/tratamiento farmacológico , Pyroglyphidae/inmunologíaRESUMEN
Surfactant Protein A (SP-A) is an innate immune modulator produced by the lung with known protective effects against bacteria and viruses. Its role in asthma, an inflammatory lung disease that affects 10% of the world's population, is not entirely known. In this review, we demonstrate that SP-A confers protection against exposure to interleukin-13, a type 2 cytokine integral to eosinophilic asthma, in a mouse model of SP-A deficiency, a house dust mite model of asthma, and in human bronchial epithelial cells from participants with asthma. We also show that small peptides derived from SP-A, such as the major allele of single nucleotide polymorphism (SNP) rs1965708, which includes the carbohydrate recognition domain of SP-A2 at position 223, reduce airway hyperresponsiveness, airway eosinophils, and mucus in a mouse model of asthma. These data suggest that SP-A has beneficial effects relevant to asthma and that an SP-A peptide may have a new therapeutic use in asthma.
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Asma , Modelos Animales de Enfermedad , Inmunidad Innata , Proteína A Asociada a Surfactante Pulmonar , Asma/inmunología , Asma/tratamiento farmacológico , Animales , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína A Asociada a Surfactante Pulmonar/inmunología , Humanos , Ratones , Polimorfismo de Nucleótido Simple , Interleucina-13/metabolismo , Interleucina-13/inmunología , Interleucina-13/genética , Pulmón/inmunología , Pulmón/metabolismo , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Pyroglyphidae/inmunologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Hyssopus cuspidatus Boriss., a classic Uyghur medicine, is used to treat inflammatory lung diseases such as asthma. But the therapeutic effect and mechanism of the volatile oil of Hyssopus cuspidatus Boriss.(HVO) in asthma therapy remain unclear. AIM OF THE STUDY: We aim to characterize the constituents of HVO, investigate the therapeutic effect in OVA-induced allergic asthmatic mice and further explore the molecular mechanism. MATERIALS AND METHODS: In this study, we applied two-dimensional gas chromatography quadrupole time-of-flight mass spectrometry (GC × GC-QTOF MS) to identify the ingredients of HVO. We established OVA-induced asthmatic model to investigate the therapeutic effect of HVO. To further explore the potential molecular pathways, we used network pharmacology approach to perform GO and KEGG pathways enrichment, and then built an ingredient-target-pathway network to identify key molecular pathways. Finally, LPS-induced RAW 264.7 macrophages and OVA-induced asthmatic model were used to validate the potential signaling pathways. RESULTS: GC × GC-QTOF MS analysis revealed the presence of 123 compounds of HVO. The sesquiterpenes and monoterpenes are the main constituents. The in vivo study indicated that HVO suppressed OVA-induced eosinophilic infiltration in lung tissues, inhibited the elevation of IgE, IL-4, IL-5, and IL-13 levels, downregulated the expressions of phosphorylated PI3K, Akt, JNK and P38, and maintained epithelial barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin. The in vitro study also revealed an inhibition of NO release and downregulation of phosphorylated PI3K, Akt, JNK and P38 levels. CONCLUSION: HVO alleviates airway inflammation in OVA-induced asthmatic mice by inhibiting PI3K/Akt/JNK/P38 signaling pathway and maintaining airway barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin.
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Asma , Aceites Volátiles , Ovalbúmina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Femenino , Ratones , Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Asma/inducido químicamente , Modelos Animales de Enfermedad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Aceites Volátiles/farmacología , Aceites Volátiles/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pyroglyphidae/inmunología , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosRESUMEN
Introduction: Environmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen. Methods: We utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization. Results: Our findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure. Discussion: These results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.
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Macrófagos Alveolares , Transcriptoma , Animales , Ratones , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Pyroglyphidae/inmunología , Hipersensibilidad Respiratoria/inmunología , Pulmón/inmunología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Alérgenos/inmunología , Lipopolisacáridos , Femenino , Hipersensibilidad/inmunologíaRESUMEN
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of amyloid-ß (Aß) plaques, neuroinflammation, and neuronal death. Besides aging, various comorbidities increase the risk of AD, including obesity, diabetes, and allergic asthma. Epidemiological studies have reported a 2.17-fold higher risk of dementia in asthmatic patients. However, the molecular mechanism(s) underlying this asthma-associated AD exacerbation is unknown. This study was designed to explore house dust mite (HDM)-induced asthma effects on AD-related brain changes using the AppNL-G-F transgenic mouse model of disease. Male and female 8-9 months old C57BL/6J wild type and AppNL-G-F mice were exposed to no treatment, saline sham, or HDM extract every alternate day for 16 weeks for comparison across genotypes and treatment. Mice were euthanized at the end of the experiment, and broncho-alveolar lavage fluid (BALF), blood, lungs, and brains were collected. BALF was used to quantify immune cell phenotype, cytokine levels, total protein content, lactate dehydrogenase (LDH) activity, and total IgE. Lungs were sectioned and stained with hematoxylin and eosin, Alcian blue, and Masson's trichrome. Serum levels of cytokines and soluble Aß1-40/42 were quantified. Brains were sectioned and immunostained for Aß, GFAP, CD68, and collagen IV. Finally, frozen hippocampi and temporal cortices were used to perform Aß ELISAs and cytokine arrays, respectively. HDM exposure led to increased levels of inflammatory cells, cytokines, total protein content, LDH activity, and total IgE in the BALF, as well as increased pulmonary mucus and collagen staining in both sexes and genotypes. Levels of serum cytokines increased in all HDM-exposed groups. Serum from the AppNL-G-F HDM-induced asthma group also had significantly increased soluble Aß1-42 levels in both sexes. In agreement with this peripheral change, hippocampi from asthma-induced male and female AppNL-G-F mice demonstrated elevated Aß plaque load and increased soluble Aß 1-40/42 and insoluble Aß 1-40 levels. HDM exposure also increased astrogliosis and microgliosis in both sexes of AppNL-G-F mice, as indicated by GFAP and CD68 immunoreactivity, respectively. Additionally, HDM exposure elevated cortical levels of several cytokines in both sexes and genotypes. Finally, HDM-exposed groups also showed a disturbed blood-brain-barrier (BBB) integrity in the hippocampus of AppNL-G-F mice, as indicated by decreased collagen IV immunoreactivity. HDM exposure was responsible for an asthma-like condition in the lungs that exacerbated Aß pathology, astrogliosis, microgliosis, and cytokine changes in the brains of male and female AppNL-G-F mice that correlated with reduced BBB integrity. Defining mechanisms of asthma effects on the brain may identify novel therapeutic targets for asthma and AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Asma , Encéfalo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Transgénicos , Pyroglyphidae , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Asma/metabolismo , Asma/inmunología , Femenino , Ratones , Péptidos beta-Amiloides/metabolismo , Masculino , Encéfalo/metabolismo , Encéfalo/patología , Pyroglyphidae/inmunología , Placa Amiloide/patología , Placa Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismoRESUMEN
Allergic asthma is a complex inflammatory disorder predominantly orchestrated by T helper 2 (Th2) lymphocytes. The anti-inflammatory protein Clara Cell 10-kDa (CC10), also known as secretoglobin family 1A member 1 (SCGB1A1), shows promise in modulating respiratory diseases. However, its precise role in asthma remains unclear. This study examines the potential of CC10 to suppress allergic asthma inflammation, specifically assessing its regulatory effects on Th2 cell responses and dendritic cells (DCs). Lower CC10 levels in asthma were observed and correlated with increased IgE and lymphocytes. Cc10-/- mice exhibited exacerbated allergic airway inflammation marked by increased inflammatory cell infiltration, Th2 cytokines, serum antigen-specific IgE levels, and airway hyperresponsiveness (AHR) in house dust mite (HDM)-induced models. Conversely, recombinant CC10 significantly attenuated these inflammatory responses. Intriguingly, CC10 did not directly inhibit Th cell activation but significantly downregulated the population of CD11b+CD103- DCs subsets in lungs of asthmatic mice and modulated the immune activation functions of DCs through NF-κB signaling pathway. The mixed lymphocyte response assay revealed that DCs mediated the suppressive effect of CC10 on Th2 cell responses. Collectively, CC10 profoundly mitigates Th2-type allergic inflammation in asthma by modulating lung DC phenotype and functions, highlighting its therapeutic potential for inflammatory airway conditions and other related immunological disorders.