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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 -
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 -
Frontiers in Immunology 2024Myeloid-derived suppressor cells (MDSCs) are a phenotypically heterogenous group of cells that potently suppress the immune response. A growing body of evidence supports...
Myeloid-derived suppressor cells (MDSCs) are a phenotypically heterogenous group of cells that potently suppress the immune response. A growing body of evidence supports the important role of MDSCs in a variety of lung diseases, such as asthma. However, the role of MDSCs in asthma exacerbation has so far not been investigated. Here, we studied the role of MDSCs in a murine model of influenza virus-induced asthma exacerbation. BALB/c mice were exposed to house dust mite (HDM) three times a week for a total of five weeks to induce a chronic asthmatic phenotype, which was exacerbated by additional exposure to the A/Hamburg/5/2009 hemagglutinin 1 neuraminidase 1 (H1N1) influenza virus. Induction of lung inflammatory features, production of T helper (Th) 1- and Th2- associated inflammatory cytokines in the lavage fluid and an increased airway hyper-responsiveness were observed, establishing the asthma exacerbation model. The number and activity of pulmonary M-MDSCs increased in exacerbated asthmatic mice compared to non-exacerbated asthmatic mice. Furthermore, depletion of MDSCs aggravated airway hyper-responsiveness in exacerbated asthmatic mice. These findings further denote the role of MDSCs in asthma and provide some of the first evidence supporting a potential important role of MDSCs in asthma exacerbation.
Topics: Animals; Asthma; Myeloid-Derived Suppressor Cells; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Disease Models, Animal; Cytokines; Influenza A Virus, H1N1 Subtype; Female; Pyroglyphidae; Disease Progression; Lung; Th2 Cells
PubMed: 38694499
DOI: 10.3389/fimmu.2024.1342497 -
Acta Biochimica Et Biophysica Sinica Oct 2023The downregulation of adhesion molecule catenin alpha-like 1 (CTNNAL1) in airway epithelial cells of asthma patients and house dust mite (HDM)-induced asthma animal...
The downregulation of adhesion molecule catenin alpha-like 1 (CTNNAL1) in airway epithelial cells of asthma patients and house dust mite (HDM)-induced asthma animal models was illustrated in our previous study. It is assumed to contribute to airway inflammation and mucus hypersecretion. In this work, we further explore the underlying mechanism of CTNNAL1 in asthma. -silenced female mice exhibit a decreased level of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated and ATP-gated Cl channel that correlates with mucus hypersecretion. Our previous study demonstrated that ROCK1 expression decreases but ROCK2 expression increases in the lungs of a -silenced mouse model. Inhibition of ROCK1 leads to a reduction in CFTR expression in CTNNAL1-overexpressing and -silenced human bronchial epithelial (HBE) cells. It has been reported that ROCK1 is a downstream target of RhoA and that activation of RhoA increases CFTR expression after CTNNAL1 deficiency and . The above results indicate that CTNNAL1 regulates CFTR expression through the ROCK1 pathway. In addition, the expression of CFTR-associated ligand (CAL) is increased after silencing, and immunoprecipitation results confirm the interaction between ROCK1 and CAL. Inhibition of CAL does not influence ROCK1 expression but increases CFTR expression in -silenced HBE cells. These data suggest that CTNNAL1 deficiency decreases CFTR expression in the HDM-induced asthma mouse model through the ROCK1-CAL signaling pathway.
Topics: Animals; Female; Humans; Mice; alpha Catenin; Asthma; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Epithelial Cells; Pyroglyphidae; rho-Associated Kinases; Signal Transduction
PubMed: 37715489
DOI: 10.3724/abbs.2023152 -
European Annals of Allergy and Clinical... Mar 2024The sensitization profile of patients allergic to house dust mites (HDM) and its molecular diagnosis may determine treatment and evolution of the disease. The present...
The sensitization profile of patients allergic to house dust mites (HDM) and its molecular diagnosis may determine treatment and evolution of the disease. The present study investigates the prevalence of Der p 23 sensitization and its relation to asthma in a population of HDM-allergic patients. We conducted a cross-sectional study of 891 patients with HDM allergy with symptoms of rhinitis and 52.1% of them with asthma. Total and specific IgE (sIgE) was measured against and its molecular components and the storage mite using ImmunoCAP. Prevalence of sensitization and levels of sIgE were analyzed according to asthma diagnosis and asthma severity. Der p 23 was the predominant allergen in this population (83.7%), but IgE levels were lower than those of sIgE to Der p 1 and Der p 2. A good correlation was found between sIgE to Der p 23 and the other allergens. A total of 8.2% patients were monosensitized to Der p 23. Asthma was more frequent in patients with positive sIgE against Der p 23 than in patients without this sensitization (p = 0.027). A tendency to increase both total IgE and sIgE was observed in relation to the severity of asthma from intermittent mild asthma to persistent moderate asthma, but a substantial decrease in total IgE and sIgE was detected in more severe asthmatics. Der p 23 might be a prevalent allergen in regions with high rates of HDM exposure and its presence could increase the risk of asthma.
Topics: Animals; Humans; Cross-Sectional Studies; Antigens, Dermatophagoides; Immunoglobulin E; Pyroglyphidae; Asthma; Hypersensitivity; Allergens
PubMed: 35899400
DOI: 10.23822/EurAnnACI.1764-1489.264 -
Immunity, Inflammation and Disease Dec 2023To analyze the effects of different types of inhalant allergens on the lung functions of adult patients with bronchial asthma.
OBJECTIVE
To analyze the effects of different types of inhalant allergens on the lung functions of adult patients with bronchial asthma.
METHODS
This cross-sectional study included a total of 47 adults diagnosed with bronchial asthma at the Respiratory Outpatient Department of Tianjin First Central Hospital. Patients were divided into non-sensitized and sensitized groups based on the number of positive allergens detected and classified into four groups (the dust mite mixed group, animal dander mixed group, pollen-mixed group, and mold mixed group) based on the type of positive allergen detected. They were tested for the serum concentration of allergen-specific immunoglobulin E (sIgE) using a fluorescence immunoassay analyzer, and lung function was assessed using a pulmonary function testing machine. One-way analysis of variance was used to compare normally distributed data, while the rank sum test was utilized for non-normally distributed data.
RESULTS
There was no statistically significant difference in lung function indicators between these two groups (p > .05). There were statistically significant differences in forced expiratory volume in one second as a percentage of the predicted value (FEV %pred) (p = .028), FEV /forced vital capacity as a percentage of the predicted value; (FVC%pred) (p = .016), peak expiratory flow as a percentage of the predicted value (PEF%pred) (p = .001), forced expiratory flow at 50% of the predicted value of forced vital capacity (FEF50%pred) (p = .003), forced expiratory flow at 75% of the predicted value of forced vital capacity (FEF75%pred) (p = .023), and maximal midexpiratory flow (MM)EF75/25%pred (p = .002) among the four groups. The pollen-mixed group had higher PEF%pred (pollen vs. animal dander, p = .067; pollen vs. dust-mites, p = .008; pollen vs. molds, p = .001) and MMEF75/25%pred (pollen vs. animal dander, p = .048; pollen vs. dust-mites, p = .003; pollen vs. molds, p = .001) than the other three groups. The pollen-mixed group had higher FEF50%pred than the dust-mites mixed group (p = .008) and molds-mixed group (p = .001). The pollen-mixed group had higher FEF75%pred (p = .005), FEV %pred (p = .001), and FEV /FVC%pred (p = .001) than the molds-mixed group.
CONCLUSION
Different inhalant allergens had different effects on lung functions in adults with asthma.
Topics: Adult; Animals; Humans; Allergens; Cross-Sectional Studies; Lung; Asthma; Pyroglyphidae; Dust
PubMed: 38156394
DOI: 10.1002/iid3.1118 -
Immunity, Inflammation and Disease Apr 2024Asthma is widely recognized as an inflammatory disorder. In the context of this inflammatory microenvironment, the involvement of hypoxia and its impact on related...
BACKGROUND
Asthma is widely recognized as an inflammatory disorder. In the context of this inflammatory microenvironment, the involvement of hypoxia and its impact on related pathways have drawn considerable attention. However, the exact role of hypoxia, a prevalent environmental factor, in the development and progression of asthma remains poorly understood.
METHODS
Mice were treated with house dust mite (HDM) extracts for 23 days to induce asthma. Mice were divided into room air (RA) group and intermittent hypoxic (IH) group by exposing to different conditions and IH preconditioning (IHP) were underwent to the above groups before the hypoxic regimen. Airway inflammation in mice was evaluated by airway hyperresponsiveness, excessive mucus secretion, and recruitment of inflammatory cells. Immunohistochemistry was employed to quantify the expression levels of NF-κB. Subsequently, the dose of allergen was modified to investigate whether the impact of hypoxia on asthma is affected by different doses of allergens.
RESULT
Compared to the RA and IH groups, HDM-treated mice in the IHP group exhibited aggravated inflammatory cell infiltration and airway hyperresponsiveness (p<.05). Moreover, there was an increased release of inflammatory mediators and higher expression levels of NF-κB (p<.05). Importantly, the impact ia on asthma was found to be influenced by high dose of allergen (p<.05).
CONCLUSION
IHP treatment potentially exacerbates HDM-induced airway inflammation in asthma, with the involvement of NF-κB, particularly under high-dose allergen stimulation.
Topics: Mice; Animals; Pyroglyphidae; NF-kappa B; Asthma; Dermatophagoides pteronyssinus; Respiratory Hypersensitivity; Allergens; Inflammation; Hypoxia
PubMed: 38629734
DOI: 10.1002/iid3.1253 -
Frontiers in Immunology 2024The house dust mite (HDM) is widely recognized as the most prevalent allergen in allergic diseases. Allergen-specific immunotherapy (AIT) has been successfully...
BACKGROUND
The house dust mite (HDM) is widely recognized as the most prevalent allergen in allergic diseases. Allergen-specific immunotherapy (AIT) has been successfully implemented in clinical treatment for HDM. Hypoallergenic B-cell epitope-based vaccine designed by artificial intelligence (AI) represents a significant progression of recombinant hypoallergenic allergen derivatives.
METHOD
The three-dimensional protein structure of Der f 36 was constructed using Alphafold2. AI-based tools were employed to predict B-cell epitopes, which were subsequently verified through IgE-reaction testing. Hypoallergenic Der f 36 was then synthesized, expressed, and purified. The reduced allergenicity was assessed by enzyme-linked immunosorbent assay (ELISA), immunoblotting, and basophil activation test. T-cell response to hypoallergenic Der f 36 and Der f 36 was evaluated based on cytokine expression in the peripheral blood mononuclear cells (PBMCs) of patients. The immunogenicity was evaluated and compared through rabbit immunization with hypoallergenic Der f 36 and Der f 36, respectively. The inhibitory effect of the blocking IgG antibody on the specific IgE-binding activity and basophil activation of Der f 36 allergen was also examined.
RESULTS
The final selected non-allergic B-cell epitopes were 25-48, 57-67, 107-112, 142-151, and 176-184. Hypoallergenic Der f 36 showed significant reduction in IgE-binding activity. The competitive inhibition of IgE-binding to Der f 36 was investigated using the hypoallergenic Der f 36, and only 20% inhibition could be achieved, which is greatly reduced when compared with inhibition by Der f 36 (98%). The hypoallergenic Der f 36 exhibited a low basophil-stimulating ratio similar to that of the negative control, and it could induce an increasing level of IFN-γ but not Th2 cytokines IL-5 and IL-13 in PBMCs. The vaccine-specific rabbit blocking IgG antibodies could inhibit the patients' IgE binding and basophil stimulation activity of Derf 36.
CONCLUSION
This study represents the first application of an AI strategy to facilitate the development of a B-cell epitope-based hypoallergenic Der f 36 vaccine, which may become a promising immunotherapy for HDM-allergic patients due to its reduced allergenicity and its high immunogenicity in inducing blocking of IgG.
Topics: Animals; Humans; Rabbits; Epitopes, B-Lymphocyte; Leukocytes, Mononuclear; Artificial Intelligence; Immunoglobulin E; Arthropod Proteins; Vaccines; Hypersensitivity; Allergens; Pyroglyphidae; Dermatophagoides pteronyssinus; Cytokines; Immunoglobulin G
PubMed: 38601166
DOI: 10.3389/fimmu.2024.1325998