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International Immunopharmacology Apr 2024Heat Shock protein 90 α (HSP90α), an main subtype of chaperone protein HSP90, involves important biological functions such as DNA damage repair, protein modification,...
Heat Shock protein 90 α (HSP90α), an main subtype of chaperone protein HSP90, involves important biological functions such as DNA damage repair, protein modification, innate immunity. However, the potential role of HSP90α in asthma occurrence and development is still unclear. This study aimed to elucidate the underlying mechanism of HSP90α in asthma by focusing on the cGAS-STING-Endoplasmic Reticulum stress pathway in inflammatory airway epithelial cell death (i.e., pyroptosis; inflammatory cell death). To accomplish that, we modeled allergen exposure in C57/6BL mice and bronchial epithelial cells with house dust mite. Protein technologies and immunofluorescence utilized to study the expression of HSP90α, activation of cGAS-STING pathway and pyroptosis. The effect of inhibitors on HDM-exposed mice detected by histological techniques and examination of bronchoalveolar lavage fluid. Results showed that HSP90α promotes asthma inflammation via pyroptosis and activation of the cGAS-STING-ER stress pathway. Treatment with the HSP90 inhibitor tanespimycin (17-AAG) significantly relieved airway inflammation and abrogated the effect of HSP90α on pyroptosis and cGAS-STING-ER stress in vitro and in vivo models of HDM. Further data indicated that up-regulation of HSP90α stabilized STING through interaction, which increased localization of STING on the ER. Activation of STING triggered ER stress and leaded to pyroptosis-related airway inflammation. The finding showed the potential role of pyroptosis caused by dysregulation of HSP90α on airway epithelial cells in allergic inflammation, suggested that targeting HSP90α in airway epithelial cells might prove to be a potential additional treatment strategy for asthma.
Topics: Mice; Animals; Pyroptosis; Up-Regulation; Asthma; Pyroglyphidae; Epithelial Cells; Nucleotidyltransferases; Inflammation
PubMed: 38527402
DOI: 10.1016/j.intimp.2024.111917 -
Tierarztliche Praxis. Ausgabe K,... Dec 2023While feline asthma (FA) is considered to be of allergic origin, the etiology of feline chronic bronchitis (CB) to date is unknown. Aim of the study was to compare the...
OBJECTIVES
While feline asthma (FA) is considered to be of allergic origin, the etiology of feline chronic bronchitis (CB) to date is unknown. Aim of the study was to compare the results of intradermal testing (IDT) and serum testing for allergen-specific immunoglobulin E (SAT) in cats diagnosed with FA and CB.
MATERIAL AND METHODS
Twenty-seven client-owned cats with clinical signs, suggestive of feline inflammatory bronchial disease (FBD) were prospectively enrolled in the study. Patients were assigned to 3 groups based on results of bronchoalveolar-lavage-fluid (BALF)-cytology: FA (n=8), CB (n=10), or cats with a physiological BALF cytology (PB; n=9). A standardized IDT for 27 allergens was performed in all cats. In addition, allergen-specific IgE was measured in serum samples using an FcεRIα-ELISA. The number of positive reactions in both tests was compared between groups, and agreement between test results of both tests was evaluated.
RESULTS
Regarding the number of positive reactions, no statistically significant difference was detected between groups in IDT (p=0.65) and SAT (p=0.51). When comparing the 2 test systems, a weak correlation was found for the allergens (k=0.256), (k=0.276), and rye (k=0.273). The most commonly observed reactions were to house dust mites, storage mites, rye and nettle in IDT and to sheep sorrel, storage mites, and house dust mites in SAT.
CONCLUSION AND RELEVANCE
IDT and SAT in cats with feline inflammatory bronchial disease (FBD) cannot be used interchangeably for allergen detection. Sensitization to environmental allergens can occur in cats with and without airway inflammation. Therefore, a positive test result should always be assessed in context with clinical signs and allergen exposure.
Topics: Sheep; Cats; Animals; Allergens; Immunoglobulin E; Intradermal Tests; Bronchial Diseases; Pyroglyphidae; Cat Diseases; Sheep Diseases
PubMed: 38056477
DOI: 10.1055/a-2190-4139 -
Frontiers in Immunology 2024Allergic diseases in children are major public health concerns due to their widespread and rising prevalence. Food-specific immunoglobulin G4(FS-IgG4) has been detected...
Allergic diseases in children are major public health concerns due to their widespread and rising prevalence. Food-specific immunoglobulin G4(FS-IgG4) has been detected in patients with allergic diseases, but its clinical significance is still debated. In the present study, 407 children with allergic diseases were recruited and categorized into three groups according to the different systems involved: the respiratory system group, the skin system group, and a multiple system group, with the collection of clinical symptoms and serum antibodies, including total immunoglobulin E (IgE), house dust mite (HDM) IgE, food-specific IgE (FS-IgE), and FS-IgG4. Part of these patients were followed up with the intervention of FS-IgG4-guided diet elimination with or without add-on probiotics supplement. The analysis at baseline revealed distinct serum levels of different antibodies. The positive rate of FS-IgG4 in all groups was more than 80%, and the proportion of total IgE and FS-IgG4 both positive in the multi-system group was the highest (p=0.039). Egg and milk were the foods with the highest positive rate of FS-IgG4 in all groups. After diet elimination for more than 3 months, serum FS-IgG4 in children significantly decreased (P<0.05) along with the improvement of clinical symptoms, regardless of the add-on of probiotics. However, the intervention did not impact the serum levels of total IgE, FS-IgE, and HDM IgE. There was no further decrease of serum FS-IgG4 level in children followed up for more than 1 year, which may be related to noncompliance with diet elimination. Multivariate regression analysis revealed that the decline of serum FS-IgG4 was an independent predictable factor for the improvement of clinical symptoms (adjusted OR:1.412,95%CI 1.017-1.96, p=0.039). The add-on of probiotics showed less efficiency in reducing the FS-IgG4 level in more patients with relief of clinical symptoms. Our results confirmed the correlation between FS-IgG4 and allergic diseases, and the decreased FS-IgG4 could be a useful predictor for the improvement of allergic symptoms. FS-IgG4-guided diet elimination is an efficient treatment for allergic diseases. Our study adds solid data to the clinical significance of FS-IgG4 in allergic diseases.
Topics: Child; Animals; Humans; Immunoglobulin G; Hypersensitivity; Allergens; Immunoglobulin E; Diet; Pyroglyphidae; Dermatophagoides pteronyssinus; Milk
PubMed: 38420126
DOI: 10.3389/fimmu.2024.1281741 -
Respiratory Research Apr 2024Longitudinal studies have identified childhood asthma as a risk factor for obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) where persistent airflow...
BACKGROUND
Longitudinal studies have identified childhood asthma as a risk factor for obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) where persistent airflow limitation can develop more aggressively. However, a causal link between childhood asthma and COPD/ACO remains to be established. Our study aimed to model the natural history of childhood asthma and COPD and to investigate the cellular/molecular mechanisms that drive disease progression.
METHODS
Allergic airways disease was established in three-week-old young C57BL/6 mice using house dust mite (HDM) extract. Mice were subsequently exposed to cigarette smoke (CS) and HDM for 8 weeks. Airspace enlargement (emphysema) was measured by the mean linear intercept method. Flow cytometry was utilised to phenotype lung immune cells. Bulk RNA-sequencing was performed on lung tissue. Volatile organic compounds (VOCs) in bronchoalveolar lavage-fluid were analysed to screen for disease-specific biomarkers.
RESULTS
Chronic CS exposure induced emphysema that was significantly augmented by HDM challenge. Increased emphysematous changes were associated with more abundant immune cell lung infiltration consisting of neutrophils, interstitial macrophages, eosinophils and lymphocytes. Transcriptomic analyses identified a gene signature where disease-specific changes induced by HDM or CS alone were conserved in the HDM-CS group, and further revealed an enrichment of Mmp12, Il33 and Il13, and gene expression consistent with greater expansion of alternatively activated macrophages. VOC analysis also identified four compounds increased by CS exposure that were paradoxically reduced in the HDM-CS group.
CONCLUSIONS
Early-life allergic airways disease worsened emphysematous lung pathology in CS-exposed mice and markedly alters the lung transcriptome.
Topics: Humans; Animals; Mice; Mice, Inbred C57BL; Pyroglyphidae; Cigarette Smoking; Pulmonary Emphysema; Emphysema; Hypersensitivity; Inflammation; Asthma
PubMed: 38614991
DOI: 10.1186/s12931-024-02774-6 -
Frontiers in Immunology 2023Group 2 innate lymphoid cells (ILC2s) play a crucial role in house dust mite (HDM)-induced allergic inflammation, and allergen immunotherapy (AIT) holds promise for...
INTRODUCTION
Group 2 innate lymphoid cells (ILC2s) play a crucial role in house dust mite (HDM)-induced allergic inflammation, and allergen immunotherapy (AIT) holds promise for treating the disease by reducing the frequency of ILC2s. Despite significant progress in AIT for allergic diseases, there remains a need to improve the control of allergic symptoms.
METHODS
We investigated the synergistic effect of the Notch signaling pathway and subcutaneous immunotherapy (SCIT) in treating allergic airway inflammation in mice and their impact on the ratio of ILC2s in lung tissues. This was achieved by establishing the HDM-induced airway allergic disorders (HAAD) model and SCIT model. Additionally, we conducted investigations into the effect of the Notch signaling pathway on the secretory function of activated ILC2s using fluorescence-activated cell sorting. Furthermore, we explored the coactivation of the Notch signaling pathway with SCIT by sorting ILC2s from the lung tissues of mice after SCIT modeling.
RESULTS
Previously, our group demonstrated that Notch signaling pathway inhibitors can reduce allergic airway inflammation in mice. Notch signaling induces lineage plasticity of mature ILC2s. In this study, we showed that AIT alleviates allergic airway inflammation and suppresses the frequency of ILC2s induced by HDM. Interestingly, AIT combined with a γ-secretase inhibitor (GSI), an inhibitor of the Notch signaling pathway, significantly inhibited the frequency of ILC2s, reduced airway inflammation, and suppressed Th2-type responses in a mouse model. Furthermore, lung ILC2s from HDM-challenged mice with or without AIT were treated with GSI , and we found that GSI dramatically reduced the secretion of type 2 inflammatory factors in ILC2s.
DISCUSSION
These findings suggest that Notch signaling pathway inhibitors can be used as adjuvant therapy for AIT and may hold potential treatment value in the cooperative control of allergic airway inflammation during early AIT.
Topics: Mice; Animals; Pyroglyphidae; Immunity, Innate; Lymphocytes; Lung; Hypersensitivity; Desensitization, Immunologic; Inflammation
PubMed: 38371944
DOI: 10.3389/fimmu.2023.1264071 -
Journal of Ethnopharmacology Jan 2024Andrographis paniculata Burm. Nees (AP) is an herb used traditionally in Indian and Chinese traditional medicine for the treatment of various inflammatory and...
An Andrographis paniculata Burm. Nees extract standardized for three main Andrographolides prevents house dust mite-induced airway inflammation, remodeling, and hyperreactivity by regulating Th1/Th2 gene expression in mice.
ETHNOPHARMACOLOGICAL RELEVANCE
Andrographis paniculata Burm. Nees (AP) is an herb used traditionally in Indian and Chinese traditional medicine for the treatment of various inflammatory and respiratory tract diseases. However, the anti-inflammatory potential of standardized Andrographis paniculata 50% ethanol extract (APEE) in the murine model of asthma has not been investigated.
AIM OF THE STUDY
This study aimed to evaluate the protective anti-inflammatory potential and better understand the underlying mechanism of action of APEE in a clinically-relevant mouse asthma model. Thereafter, develop the ethanolic extract of AP as a supplement for asthma prophylaxis.
MATERIALS AND METHOD
APEE was prepared and standardized for AGP, NAG, and DDAG using a high-performance liquid chromatography system. Asthma was induced according to a 14-day house dust mite (HDM) induction protocol. The prophylactic potential of APEE (50 mg/kg - 200 mg/kg) was determined by assessing cardinal asthma features, which included BALF leukocyte and differential cell count, BALF cytokine assay, histology, gene expression, and airway hyperreactivity study.
RESULTS
APEE significantly inhibited HDM-induced airway eosinophilia and neutrophilia. In addition to decreased levels of IL-4, IL-5, IL-13, and eotaxin in bronchoalveolar fluid, APEE abrogated HDM-induced airway mucus over-secretion and airway hyper-responsiveness. Administration of APEE downregulated HDM-induced upregulation of the oxidative stress enzyme Duox1 (dual oxidase 1) and marginally induced Nfe2l2 (nuclear factor erythroid 2-related factor 2) gene expressions. Similarly, Th2-related (Serpinb2, Clca3a1, Il4 and Il13) and Muc5ac gene expression were significantly downregulated.
CONCLUSION
Prophylactic administration of APEE prevented the progression of HDM-induced asthmatic responses by down-regulating Th2 cytokine gene expression and oxidative stress level.
Topics: Mice; Animals; Pyroglyphidae; Andrographis paniculata; Th2 Cells; Asthma; Cytokines; Inflammation; Dermatophagoides pteronyssinus; Interleukin-13; Anti-Inflammatory Agents; Gene Expression; Disease Models, Animal; Airway Remodeling
PubMed: 37652197
DOI: 10.1016/j.jep.2023.117082 -
Tissue Barriers Jan 2024House dust mite (HDM) is a common aeroallergen that can disrupt the airway epithelial barrier leading to dysregulated immune response, resulting in allergic lung...
House dust mite (HDM) is a common aeroallergen that can disrupt the airway epithelial barrier leading to dysregulated immune response, resulting in allergic lung diseases such as asthma. Cryptochrome (CRY), a circadian clock gene, plays an important role in the regulation of metabolism, and immune response. It remains unclear whether stabilizing CRY using KL001 can attenuate HDM/Th2 cytokine-induced epithelial barrier dysfunction in 16-HBE cells. We evaluate the effect of KL001 (20 µM) pre-treatment (4 hrs) in HDM/Th2 cytokine (IL-4 or IL-13)-mediated change in epithelial barrier function. HDM and Th2 cytokine-induced changes in transepithelial electrical resistance (TEER) were determined by an xCELLigence real-time cell analyzer and delocalization of adherens junction complex (AJC: E-cadherin and β-catenin) and tight junction proteins (TJP: Occludin and Zonula occludens-1) by immunostaining and confocal microscopy. Finally, quantitative real-time PCR (qRT-PCR) and Western blotting were used to measure altered gene expression and protein abundance of the epithelial barrier function and core clock genes, respectively. HDM and Th2 cytokine treatment significantly decreased TEER associated with altered gene expression and protein abundance of the selected epithelial barrier function and circadian clock genes. However, pre-treatment with KL001 attenuated HDM and Th2 cytokine-induced epithelial barrier dysfunction as early as 12-24 hrs. KL001 pre-treatment showed attenuation of HDM and Th2 cytokine-induced alteration in the localization and gene expression of AJP and TJP ( and ) and core clock genes ( and ). We demonstrate, for the first time, the protective role of KL001 in HDM and Th2 cytokine-mediated epithelial barrier dysfunction.
Topics: Animals; Pyroglyphidae; Cytokines; Cell Line; Hypersensitivity; Carbazoles; Sulfonamides
PubMed: 37079442
DOI: 10.1080/21688370.2023.2203841 -
International Forum of Allergy &... Jan 2024Allergic rhinitis (AR) impairs quality of life and affects nearly 40% of the Japanese population. Sublingual immunotherapy (SLIT) is the disease-modifying treatment for...
BACKGROUND
Allergic rhinitis (AR) impairs quality of life and affects nearly 40% of the Japanese population. Sublingual immunotherapy (SLIT) is the disease-modifying treatment for AR, but requires the selection of a biomarker associate with clinical efficacy in patients with AR who are treated with SLIT. The present study sought to examine objective biomarkers used for assessing the clinical efficacy of SLIT.
METHODS
The authors examined the effects of 1 year of SLIT treatment with house dust mites (HDMs) using peripheral blood mononuclear cells (PBMCs) and serum from patients with AR. The prevalences of follicular regulatory T (Tfr), type 2 follicular helper T (Tfh2), type 2 helper T (Th2), conventional regulatory T (Treg), and type 1 regulatory T (Tr1) cells were examined by flow cytometry. Serum concentrations of HDM-specific IgA, IgE, and IgG4 antibodies, and HDM-induced production of interleukin (IL) 5 and IL-10 from cultured PBMCs were evaluated by enzyme-linked immunosorbent assay.
RESULTS
Following 1 year of SLIT, the prevalences of Tfr, conventional Treg, and Tr1 cells were significantly increased, whereas that of Th2 cells and Tfh2 cells were significantly decreased; the serum concentration of HDM-specific IgG4 was significantly increased; and HDM-induced production of IL-5 from PBMCs was significantly decreased, while that of IL-10 was significantly increased. The increase in the prevalence of Tfr cells after SLIT correlated positively with the improvement of clinical symptom scores.
CONCLUSION
An increase in Tfr cells may play an important role in SLIT, and may be a useful indicator for the clinical efficacy of SLIT.
Topics: Animals; Humans; Sublingual Immunotherapy; T-Lymphocytes, Regulatory; Interleukin-10; Prevalence; Pyroglyphidae; Leukocytes, Mononuclear; Quality of Life; Allergens; Rhinitis, Allergic; Treatment Outcome; Biomarkers; Immunoglobulin G; Antigens, Dermatophagoides
PubMed: 37345377
DOI: 10.1002/alr.23221 -
Allergy Apr 2024The German Therapy Allergen Ordinance (TAO) triggered an ongoing upheaval in the market for house dust mite (HDM) allergen immunotherapy (AIT) products. Three HDM... (Observational Study)
Observational Study
BACKGROUND
The German Therapy Allergen Ordinance (TAO) triggered an ongoing upheaval in the market for house dust mite (HDM) allergen immunotherapy (AIT) products. Three HDM subcutaneous AIT (SCIT) products hold approval in Germany and therefore will be available after the scheduled completion of the TAO procedure in 2026. In general, data from clinical trials on the long-term effectiveness of HDM AIT are rare. We evaluated real-world data (RWD) in a retrospective, observational cohort study based on a longitudinal claims database including 60% of all German statutory healthcare prescriptions to show the long-term effectiveness of one of these products in daily life. Aim of this analysis was to provide a per product analysis on effectiveness of mite AIT as it is demanded by international guidelines on AIT.
METHODS
Subjects between 5 and 70 years receiving their first (index) prescription of SCIT with a native HDM product (SCIT group) between 2009 and 2013 were included. The exactly 3:1 matched control group received prescriptions for only symptomatic AR medication (non-AIT group); the evaluation period for up to 6 years of follow-up ended in February 2017. Study endpoints were the progression of allergic rhinitis (AR) and asthma, asthma occurrence and time to the onset of asthma after at least 2 treatment years.
RESULTS
In total, 892 subjects (608 adults and 284 children/adolescents) were included in the SCIT group and 2676 subjects (1824 adults and 852 children/adolescents) in the non-AIT group. During the follow-up period after at least 2 years of SCIT, the number of prescriptions in the SCIT group was reduced by 62.8% (p < .0001) for AR medication and by 42.4% for asthma medication (p = .0003). New-onset asthma risk was significantly reduced in the SCIT vs non-AIT group by 27.0% (p = .0212). The asthma-preventive effect of SCIT occurred 15 months after start of the treatment. In the SCIT group, the time to onset of asthma was prolonged compared to the non-AIT group (p = .0010).
CONCLUSION
In this first product based RWD analysis on SCIT with a native HDM product, patients aged 5 to 70 years benefited from AIT in the long term in terms of reduced progression of AR and asthma after at least 2 years of treatment. The effects seemed to last for up to 6 years after treatment termination. A significantly reduced risk of asthma onset was observed, starting after 15 months of treatment.
Topics: Child; Adult; Animals; Adolescent; Humans; Pyroglyphidae; Desensitization, Immunologic; Retrospective Studies; Asthma; Dermatophagoides pteronyssinus; Rhinitis, Allergic; Allergens; Antigens, Dermatophagoides
PubMed: 38429981
DOI: 10.1111/all.16052 -
Research in Veterinary Science Nov 2023Canine atopic dermatitis (CAD) is a chronic, inflammatory, and pruritic disease of the skin resulting from the loss of the epidermal barrier, sensitization, and...
Canine atopic dermatitis (CAD) is a chronic, inflammatory, and pruritic disease of the skin resulting from the loss of the epidermal barrier, sensitization, and exacerbated production of IgE antibodies mainly directed against environmental allergens, especially to house dust mites. To select specific allergen immunotherapies with high efficacy, there are necessary studies with house dust mite allergens to improve both serological and intradermal tests. Therefore, the objective of this study was to evaluate the seroprevalence of IgE against Der f 2, Zen 1, and crude Dermatophagoides farinae allergens in dogs with AD in the State of São Paulo, Brazil. The sera of 85 dogs with clinically confirmed atopic dermatitis from the State of São Paulo (Brazil) was collected. In addition, an indirect ELISA test was conducted to detect allergen-specific serum IgE. IgE seropositivity was observed in 97.5% of the dogs for Der f 2, 95.0% for Zen 1, and 92.5% for the crude mite allergens. Due to this high prevalence of IgE specific to these allergens, we suggest that Der f 2 and Zen 1 can be considered major allergens for dogs in the State of São Paulo.
Topics: Dogs; Animals; Dermatitis, Atopic; Dermatophagoides farinae; Brazil; Seroepidemiologic Studies; Dog Diseases; Allergens; Inflammation; Immunoglobulin E
PubMed: 37713746
DOI: 10.1016/j.rvsc.2023.105002