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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 -
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 -
Biochimica Et Biophysica Acta.... Apr 2024Type 2 inflammation in asthma develops with exposure to stimuli to include inhaled allergens from house dust mites (HDM). Features include mucus hypersecretion and the...
Type 2 inflammation in asthma develops with exposure to stimuli to include inhaled allergens from house dust mites (HDM). Features include mucus hypersecretion and the formation of pro-secretory ion transport characterised by elevated basal Cl current. Studies using human sinonasal epithelial cells treated with HDM extract report a higher protease activated receptor-2 (PAR-2) agonist-induced calcium mobilisation that may be related to airway sensitisation by allergen-associated proteases. Herein, this study aimed to investigate the effect of HDM on Ca signalling and inflammatory responses in asthmatic airway epithelial cells. Primary bronchial epithelial cells (hPBECs) from asthma donors cultured at air-liquid interface were used to assess electrophysiological, Ca signalling and inflammatory responses. Differences were observed regarding Ca signalling in response to PAR-2 agonist 2-Furoyl-LIGRLO-amide (2-FLI), and equivalent short-circuit current (I) in response to trypsin and 2-FLI, in ALI-asthma and healthy hPBECs. HDM treatment led to increased levels of intracellular cations (Ca, Na) and significantly reduced the 2-FLI-induced change of I in asthma cells. Apical HDM-induced Ca mobilisation was found to mainly involve the activation of PAR-2 and PAR-4-associated store-operated Ca influx and TRPV1. In contrast, PAR-2, PAR-4 antagonists and TRPV1 antagonist only showed slight impact on basolateral HDM-induced Ca mobilisation. HDM trypsin-like serine proteases were the main components leading to non-amiloride sensitive I and also increased interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) from asthma hPBECs. These studies add further insight into the complex mechanisms associated with HDM-induced alterations in cell signalling and their relevance to pathological changes within asthma.
Topics: Humans; Animals; Alarmins; Trypsin; Asthma; Epithelial Cells; Allergens; Pyroglyphidae
PubMed: 38367901
DOI: 10.1016/j.bbadis.2024.167079 -
The Journal of Allergy and Clinical... May 2024House dust mite (HDM) is the most common allergen trigger globally for allergic rhinitis and atopic asthma.
Accurate determination of house dust mite sensitization in asthma and allergic rhinitis through cytometric detection of Der p 1 and Der p 2 binding on basophils (CytoBas).
BACKGROUND
House dust mite (HDM) is the most common allergen trigger globally for allergic rhinitis and atopic asthma.
OBJECTIVES
To expedite accurate confirmation of allergen sensitization, we designed fluorescent allergen tetramers to directly stain specific IgE on basophils to detect specific allergen sensitization using the flow cytometric CytoBas assay.
METHODS
Recombinant proteins of major HDM allergens (component), Der f 1, Der p 1, and Der p 2 were biotinylated and conjugated with fluorochrome streptavidins as tetramers. Blood samples from 64 patients who are HDM-allergic and 26 controls that are non-HDM-sensitized were incubated with allergen tetramers for evaluation of basophil binding (CytoBas) and activation (BAT) with flow cytometry.
RESULTS
The tetramers effectively bound and activated basophils from patients who are allergic but not from controls who are nonsensitized. CytoBas with Der p 1 as a single allergen had comparable sensitivity and specificity (92% and 100%) to BAT (91% and 100%) in detecting allergen sensitization, as did CytoBas with Der p 2 (95% and 96%) to BAT (95% and 87%). A positive staining for Der p 1 and/or Der p 2 in CytoBas was 100% sensitive and 96% specific for HDM allergy.
CONCLUSIONS
CytoBas has diagnostic accuracy for group 1 and group 2 HDM allergens that is comparable to BAT, but with additional advantages of multiple allergen components in a single tube and no requirement for in vitro basophil activation. These findings endorse a single, multiplex CytoBas assay for accurate and component-resolved diagnosis of aeroallergen sensitization in patients with allergic asthma and/or rhinitis.
Topics: Humans; Antigens, Dermatophagoides; Arthropod Proteins; Basophils; Cysteine Endopeptidases; Animals; Rhinitis, Allergic; Asthma; Female; Adult; Flow Cytometry; Male; Pyroglyphidae; Middle Aged; Adolescent; Young Adult; Immunoglobulin E; Allergens; Sensitivity and Specificity; Child
PubMed: 38360181
DOI: 10.1016/j.jaci.2024.02.002 -
Allergology International : Official... Jul 2024Although it has been reported that cellular senescence is important in the pathogenesis of asthma, the differential effects of diesel exhaust particle (DEP)-induced...
BACKGROUND
Although it has been reported that cellular senescence is important in the pathogenesis of asthma, the differential effects of diesel exhaust particle (DEP)-induced cellular senescence on the development of asthma according to age have not been thoroughly studied.
METHODS
We first confirmed that DEP induced cellular senescence in mouse lungs, and then that DEP-induced cellular senescence followed by intranasal instillation of a low-dose house dust mite (HDM) allergen resulted in murine asthma. Second, we examined age-dependent differential effects using 6-week-old (young) and 18-month-old mice (old), and tested whether the mammalian target of the rapamycin (mTOR) pathway plays an important role in this process. Finally, we performed in vitro experiments using human bronchial epithelial cells (HBEC) originating from young and elderly adults to identify the underlying mechanisms.
RESULTS
DEP induced cellular senescence in the airway epithelial cells of young and old mice characterized by increased senescence-associated beta-galactosidase, S100A8/9, and high mobility group box 1 (HMGB1) expressions. DEP-induced cellular senescence with subsequent exposure to a low-dose HDM allergen resulted in asthma in young and old mice. Rapamycin (mTOR pathway inhibitor) administration before DEP instillation significantly attenuated these asthmatic features. In addition, after treatment with a low-dose HDM allergen, S100A9 and HMGB1 over-expressed HBEC originating from young and elderly adults greatly activated co-cultured monocyte-derived dendritic cells (DCs).
CONCLUSIONS
This study showed that DEP-induced senescence made both young and old mice susceptible to allergic sensitization and resultant asthma development by enhancing DC activation. Public health efforts to reduce DEP exposure are warranted.
Topics: Animals; Asthma; Cellular Senescence; Vehicle Emissions; Mice; TOR Serine-Threonine Kinases; Humans; Disease Models, Animal; Epithelial Cells; Female; Allergens; Age Factors; Pyroglyphidae; Signal Transduction
PubMed: 38350817
DOI: 10.1016/j.alit.2024.01.010 -
Allergology International : Official... Jul 2024This study aimed to clarify the diagnostic and predictive factors for perennial allergic rhinitis (PAR) onset in children by analyzing the results of the Chiba High-risk...
BACKGROUND
This study aimed to clarify the diagnostic and predictive factors for perennial allergic rhinitis (PAR) onset in children by analyzing the results of the Chiba High-risk Birth Cohort for Allergy study, which examined newborns with a family history of allergies.
METHODS
Overall, 306 pregnant women were recruited. Their newborns were examined by otolaryngologists and pediatric allergists at 1, 2, and 5 years of age. Participants with clinical and laboratory data available at all consultation points were considered eligible.
RESULTS
Among 187 eligible participants, the prevalence rates of PAR were 2.1%, 4.3%, and 24.1% at 1, 2, and 5 years of age, respectively. AR-specific nasal local findings and eosinophils in nasal smear were observed in a substantial number of patients with PAR at 1 and 2 years of age. Factors present up to 2 years of age that were associated with PAR onset at 5 years of age, in descending order, were as follows: sensitization to house dust mites (HDM), nasal eosinophilia, and sensitization to cat dander. In 44 cases with HDM sensitization, nasal eosinophilia up to 2 years of age achieved a sensitivity of 76.0% and a specificity of 73.7% for predicting PAR onset at 5 years.
CONCLUSIONS
Rhinitis findings and nasal eosinophilia are useful auxiliary diagnostic items for pediatric PAR. Sensitization to HDM and nasal eosinophilia were the most influential factors associated with future PAR onset. A combination of these factors may facilitate the prediction of PAR onset.
Topics: Humans; Female; Child, Preschool; Male; Infant; Rhinitis, Allergic, Perennial; Allergens; Prevalence; Infant, Newborn; Risk Factors; Japan; Animals; Pyroglyphidae; Eosinophilia; Pregnancy
PubMed: 38350815
DOI: 10.1016/j.alit.2024.01.012 -
Respiratory Research Feb 2024Asthma is a heterogeneous disease characterized by airway inflammation and remodeling, whose pathogenetic complexity was associated with abnormal responses of various...
BACKGROUND
Asthma is a heterogeneous disease characterized by airway inflammation and remodeling, whose pathogenetic complexity was associated with abnormal responses of various cell types in the lung. The specific interactions between immune and stromal cells, crucial for asthma pathogenesis, remain unclear. This study aims to determine the key cell types and their pathological mechanisms in asthma through single-cell RNA sequencing (scRNA-seq).
METHODS
A 16-week mouse model of house dust mite (HDM) induced asthma (n = 3) and controls (n = 3) were profiled with scRNA-seq. The cellular composition and gene expression profiles were assessed by bioinformatic analyses, including cell enrichment analysis, trajectory analysis, and Gene Set Enrichment Analysis. Cell-cell communication analysis was employed to investigate the ligand-receptor interactions.
RESULTS
The asthma model results in airway inflammation coupled with airway remodeling and hyperresponsiveness. Single-cell analysis revealed notable changes in cell compositions and heterogeneities associated with airway inflammation and remodeling. GdT17 cells were identified to be a primary cellular source of IL-17, related to inflammatory exacerbation, while a subpopulation of alveolar macrophages exhibited numerous significantly up-regulated genes involved in multiple pathways related to neutrophil activities in asthma. A distinct fibroblast subpopulation, marked by elevated expression levels of numerous contractile genes and their regulators, was observed in increased airway smooth muscle layer by immunofluorescence analysis. Asthmatic stromal-immune cell communication significantly strengthened, particularly involving GdT17 cells, and macrophages interacting with fibroblasts. CXCL12/CXCR4 signaling was remarkedly up-regulated in asthma, predominantly bridging the interaction between fibroblasts and immune cell populations. Fibroblasts and macrophages could jointly interact with various immune cell subpopulations via the CCL8/CCR2 signaling. In particular, fibroblast-macrophage cell circuits played a crucial role in the development of airway inflammation and remodeling through IL1B paracrine signaling.
CONCLUSIONS
Our study established a mouse model of asthma that recapitulated key pathological features of asthma. ScRNA-seq analysis revealed the cellular landscape, highlighting key pathological cell populations associated with asthma pathogenesis. Cell-cell communication analysis identified the crucial ligand-receptor interactions contributing to airway inflammation and remodeling. Our findings emphasized the significance of cell-cell communication in bridging the possible causality between airway inflammation and remodeling, providing valuable hints for therapeutic strategies for asthma.
Topics: Mice; Animals; Ligands; Asthma; Lung; Inflammation; Cell Communication; Single-Cell Analysis; Airway Remodeling; Pyroglyphidae; Disease Models, Animal
PubMed: 38317239
DOI: 10.1186/s12931-024-02706-4 -
The Journal of Allergy and Clinical... Jun 2024Allergic rhinitis with or without conjunctivitis can negatively impact many aspects of quality of life (QoL). The efficacy and safety of standardized quality (SQ)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Allergic rhinitis with or without conjunctivitis can negatively impact many aspects of quality of life (QoL). The efficacy and safety of standardized quality (SQ) sublingual immunotherapy (SLIT) tablets have been confirmed across large clinical trials in adults with grass, tree, ragweed, and house dust mite (HDM) allergic rhinitis with or without conjunctivitis.
OBJECTIVE
This pooled analysis investigates whether the reduction in symptom burden found across the clinical trials is supported by improvements in QoL.
METHODS
A total of 11 phase II/III randomized placebo-controlled trials across the SQ grass, tree, ragweed, and HDM SLIT tablets (grass: N = 3179; ragweed: N = 767; tree: N = 634; HDM: N = 2221) were included. QoL was assessed using the standardized Rhinitis Quality of Life Questionnaire (RQLQ), with the exception of 3 grass trials, which used the nonstandardized version. The overall RQLQ scores were expressed as a mean of 7 domains. In the pooled analysis, treatment was used as fixed effect; and the trial, and the interaction between region/country and trial as random effects.
RESULTS
The pooled analysis showed consistent and statistically significant improvements in overall RQLQ scores across all 4 SQ SLIT tablets versus placebo (pooled estimate [95% CI], P value-grass: -0.20 [-0.28 to -0.12], P < .001; tree: -0.42 [-0.58 to -0.26], P < .001; ragweed: -0.36 [-0.55 to -0.17], P < .001; HDM: -0.28 [-0.39 to -0.17], P < .001). Furthermore, significant improvements versus placebo for all 4 SQ SLIT tablets were seen across the 7 individual domains.
CONCLUSIONS
The proven efficacy of SQ SLIT tablets to reduce symptoms across 4 of the most common respiratory allergens is supported by concurrent significant improvements in RQLQ scores overall and for all 7 domains.
Topics: Humans; Quality of Life; Sublingual Immunotherapy; Adult; Conjunctivitis, Allergic; Allergens; Pyroglyphidae; Rhinitis, Allergic; Animals; Ambrosia; Tablets; Male; Female; Randomized Controlled Trials as Topic; Clinical Trials, Phase III as Topic; Poaceae; Trees; Clinical Trials, Phase II as Topic; Treatment Outcome
PubMed: 38307205
DOI: 10.1016/j.jaip.2024.01.038 -
Frontiers in Immunology 2023DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role...
DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. PINK1-Parkin mitophagy, NLRP3 inflammasome, and apoptosis were examined after gene silencing or treatment with specific inhibitors (MitoTEMPO, MCC950, and Ac-DEVD-CHO) in house dust mite (HDM) or recombinant DEK (rmDEK)-induced WT and DEK-/- asthmatic mice and BEAS-2B cells. The regulatory role of DEK on ATAD3A was detected using ChIP-sequence and co-immunoprecipitation. rmDEK promoted eosinophil recruitment, and co-localization of TOM20 and LC3B, MFN1 and mitochondria, LC3B and VDAC, and ROS generation, reduced protein level of MnSOD in HDM induced-asthmatic mice. Moreover, rmDEK also increased DRP1 expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. These effects were partially reversed in DEK mice. In BEAS-2B cells, siDEK diminished the Parkin, LC3B, and DRP1 translocation to mitochondria, mtROS, TOM20, and mtDNA. ChIP-sequence analysis showed that DEK was enriched on the ATAD3A promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models and interacted with DRP1, and siATAD3A could down-regulate DRP1 and mtDNA-mediated mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
Topics: Animals; Mice; Asthma; Dermatophagoides pteronyssinus; DNA, Mitochondrial; Inflammasomes; Inflammation; Mitophagy; NLR Family, Pyrin Domain-Containing 3 Protein; Protein Kinases; Pyroglyphidae; Ubiquitin-Protein Ligases
PubMed: 38274803
DOI: 10.3389/fimmu.2023.1289774 -
Frontiers in Immunology 2023We investigated the effect of global Plexin B1 deficiency on allergic airway responses to house dust mite (HDM) or ovalbumin (OVA). In the HDM model, there were higher...
We investigated the effect of global Plexin B1 deficiency on allergic airway responses to house dust mite (HDM) or ovalbumin (OVA). In the HDM model, there were higher Th2 cytokine levels in the BALF of Plexin B1 knock-out (KO) mice compared to wild type (WT), and tissue inflammation and mucus production were modestly enhanced. In the OVA model, Plexin B1 deficiency led to increases in lung inflammation, mucus production, and lung Th2 cytokines accompanied by dysregulated mucin gene expression without affecting anti-OVA IgE/IgG1 levels. Spleen cells from Plexin B1 KO mice proliferated more robustly than WT cells to a variety of stimuli. Plexin B1 KO CD4+ T cells from spleens expressed higher levels of Ki-67 and CD69 compared to WT cells. Spleen cells from naïve Plexin B1 KO mice secreted increased amounts of IL-4 and IL-6 when pulsed with OVA whereas OVA-primed spleen cells produced IL-4/IL-5 when subjected to OVA restimulation. The upregulated allergic inflammatory response in Plexin B1 KO mice was associated with a lower number of Tregs in the lung tissues. Moreover, these mice displayed lower numbers of Treg cells in the lymphoid tissues at the baseline. These results demonstrate a previously unrecognized link between Plexin B1, Treg cells, and mucus in allergic lung inflammation.
Topics: Animals; Mice; Cytokines; Dermatophagoides pteronyssinus; Hypersensitivity; Inflammation; Interleukin-4; Mucins; Nerve Tissue Proteins; Ovalbumin; Pneumonia; T-Lymphocytes, Regulatory; Receptors, Cell Surface
PubMed: 38259471
DOI: 10.3389/fimmu.2023.1297354