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Allergy May 2024Identifying predictive biomarkers for allergen immunotherapy response is crucial for enhancing clinical efficacy. This study aims to identify such biomarkers in patients...
BACKGROUND
Identifying predictive biomarkers for allergen immunotherapy response is crucial for enhancing clinical efficacy. This study aims to identify such biomarkers in patients with allergic rhinitis (AR) undergoing subcutaneous immunotherapy (SCIT) for house dust mite allergy.
METHODS
The Tongji (discovery) cohort comprised 72 AR patients who completed 1-year SCIT follow-up. Circulating T and B cell subsets were characterized using multiplexed flow cytometry before SCIT. Serum immunoglobulin levels and combined symptom and medication score (CSMS) were assessed before and after 12-month SCIT. Responders, exhibiting ≥30% CSMS improvement, were identified. The random forest algorithm and logistic regression analysis were used to select biomarkers and establish predictive models for SCIT efficacy in the Tongji cohort, which was validated in another Wisco cohort with 43 AR patients.
RESULTS
Positive SCIT response correlated with higher baseline CSMS, allergen-specific IgE (sIgE)/total IgE (tIgE) ratio, and frequencies of Type 2 helper T cells, Type 2 follicular helper T (T2) cells, and CD23 nonswitched memory B (B) and switched memory B (B) cells, as well as lower follicular regulatory T (T) cell frequency and T/T2 cell ratio. The random forest algorithm identified sIgE/tIgE ratio, T/T2 cell ratio, and B frequency as the key biomarkers discriminating responders from nonresponders in the Tongji cohort. Logistic regression analysis confirmed the predictive value of a combination model, including sIgE/tIgE ratio, T/T2 cell ratio, and CD23 B frequency (AUC = 0.899 in Tongji; validated AUC = 0.893 in Wisco).
CONCLUSIONS
A T- and B-cell signature combination efficiently identified SCIT responders before treatment, enabling personalized approaches for AR patients.
Topics: Humans; Rhinitis, Allergic; Male; Desensitization, Immunologic; Animals; Female; Adult; Pyroglyphidae; Biomarkers; Treatment Outcome; Immunoglobulin E; Middle Aged; Young Adult; Allergens; Antigens, Dermatophagoides; Injections, Subcutaneous; Adolescent; Prognosis
PubMed: 38403941
DOI: 10.1111/all.16068 -
The Journal of Clinical Investigation Mar 2024Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the...
Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLSs), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.
Topics: Humans; Child; Animals; Mice; Mast Cells; Pericytes; Endothelial Cells; Asthma; Lung; Allergens; Pyroglyphidae; Disease Models, Animal
PubMed: 38487999
DOI: 10.1172/JCI173676 -
Clinical and Experimental Immunology Dec 2023Airway remodeling is a major feature of asthma. Interleukin (IL)-36γ is significantly upregulated and promotes airway hyper-responsiveness (AHR) in asthma, but its role...
Airway remodeling is a major feature of asthma. Interleukin (IL)-36γ is significantly upregulated and promotes airway hyper-responsiveness (AHR) in asthma, but its role in airway remodeling is unknown. Here, we aimed to investigate the role of IL-36γ in airway remodeling, and whether IL-38 can alleviate airway remodeling in chronic asthma by blocking the effects of IL-36γ. IL-36γ was quantified in mice inhaled with house dust mite (HDM). Extracellular matrix (ECM) deposition in lung tissues and AHR were assessed following IL-36γ administration to mice. Airway inflammation, AHR, and remodeling were evaluated after IL-38 or blocking IL-36 receptor (IL-36R) treatment in asthmatic mice. The effects of lung fibroblasts stimulated with IL-36γ and IL-38 were quantified in vitro. Increased expression of IL-36γ was detected in lung tissues of HDM-induced asthmatic mice. The intratracheal instillation of IL-36γ to mice significantly enhanced the ECM deposition, AHR, and the number of activated lung fibroblasts around the airways. IL-38 or blocking IL-36R treated asthmatic mice showed a significant alleviation in the airway inflammation, AHR, airway remodeling, and number of activated fibroblasts around airways as compared with the HDM group. In vitro, IL-36γ promoted the activation and migration of human lung fibroblasts (HFL-1). The administration of IL-38 can counteract these biological processes induced by IL-36γ in HFL-1cells. The results indicated that IL-38 can mitigate airway remodeling by blocking the profibrotic effects of IL-36γ in chronic asthma. IL-36γ may be a new therapeutic target, and IL-38 is a potential candidate agent for inhibiting airway remodeling in asthma.
Topics: Animals; Humans; Mice; Airway Remodeling; Asthma; Interleukins; Lung; Inflammation; Disease Models, Animal; Pyroglyphidae; Mice, Inbred BALB C
PubMed: 37586814
DOI: 10.1093/cei/uxad099 -
Respiratory Research Mar 2024The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven...
BACKGROUND
The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored.
METHODS
House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed.
RESULTS
Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum.
CONCLUSION
Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation.
Topics: Animals; Humans; Mice; Asthma; Caspases; Chemokines; Gasdermins; Inflammation; Lectins, C-Type; Lung; Macrophages; Neutrophils; Pyroglyphidae; Pyroptosis
PubMed: 38459541
DOI: 10.1186/s12931-024-02743-z -
International Immunopharmacology Dec 2023The aim of this study was to examine the frequency of sensitization to house dust mite (HDM) components among allergic rhinitis patients receiving subcutaneous...
BACKGROUND
The aim of this study was to examine the frequency of sensitization to house dust mite (HDM) components among allergic rhinitis patients receiving subcutaneous immunotherapy (SCIT), and to assess the correlation between SCIT efficacy and specific IgE (sIgE) levels for allergenic HDM components.
METHODS
Serum samples and clinical data were collected from 38 allergic rhinitis patients receiving HDM-SCIT at baseline and after 1 year of treatment. Effective treatment was defined as a therapeutic index (TI) of at least 50% after 1 year. Cytokine levels were analyzed using commercial ELISA kits, while serum total and specific IgE levels were determined by the fluoroenzymeimmunoassay technique. The ALLEOS 2000 magnetic particle chemiluminescence system was used to measure sIgE levels for Der f, Der p 1, Der p 2, Der p 10, and Der p 23.
RESULTS
Allergic rhinitis patients undergoing HDM-SCIT had a high rate of allergic sensitization to the HDM major allergens Der p (100%), Der f (100%), Der p 1 (94.74%), Der p 2 (94.74%), and Der p 23 (36.84%). Patients who responded to SCIT had higher levels of IgE for HDM components at baseline, while those with ineffective treatment showed an opposite performance, particularly for Der p 1 (P<0.05). After 1 year of treatment, effective and ineffective patients showed opposite trends in sIgE for dust mite components (decreased in effective patients, increased in ineffective patients). HDM-SCIT led to a significant reduction in IL-2, IL-4, IL-6, and EOS% (P<0.05). IgE for Der p, Der f, Der p 1, Der p 2, and HDM sIgE were significantly positively correlated (P < 0.001). The correlation heatmap analysis based on changes in values reveals a negative correlation between CSMS score changes and sIgE for Der f and Der p 1, and a positive correlation with IL-2, IL-10, and TNF (P < 0.05).
CONCLUSIONS
The molecular sensitization profiles during HDM-SCIT are variable and relate to treatment efficacy. Molecular diagnosis can assist allergists in identifying patients eligible for HDM-SCIT, thereby enhancing the treatment's clinical efficacy. Serum cytokine levels of IL-2, IL-4, IL-6,and EOS% may serve as useful biomarkers for monitoring HDM-SCIT efficacy.
Topics: Animals; Humans; Allergens; Interleukin-2; Interleukin-4; Interleukin-6; Pyridinolcarbamate; Pyroglyphidae; Dermatophagoides pteronyssinus; Rhinitis, Allergic; Immunotherapy; Cytokines; Immunoglobulin E; Antigens, Dermatophagoides; Dust
PubMed: 37925948
DOI: 10.1016/j.intimp.2023.111111 -
Scientific Reports Sep 2023Collagen, a major structural protein in mammalian tissues, is effective against skin wounds and osteoarthritis. Although bovine and porcine collagens have mainly been...
Collagen, a major structural protein in mammalian tissues, is effective against skin wounds and osteoarthritis. Although bovine and porcine collagens have mainly been used, several potential risks of mammalian collagen have led to the use of fish collagen (FC) as an alternative. FC and its peptides are used as common cosmeceutical products because of their antihypertensive, anti-bacterial, and antioxidant activities. Despite the effects of FC on wrinkle reduction, UV-protection, and wound healing, the relationship between FC and atopic dermatitis (AD) has not yet been reported. Therefore, we investigated the anti-AD effects of FC against house dust mite (Dermatophagoides farinae, HDM)-induced AD in NC/Nga mice and TNF-α/IFN-γ-stimulated HaCaT keratinocytes. FC alleviated AD apparent symptoms, such as dermatitis score, transepidermal water loss, epidermal thickness, and mast cell infiltration upon declining pro-inflammatory cytokines and mediators, IL-6, IL-5, IL-13, TSLP, and TNF-α. The skin barrier protein, filaggrin, was also recovered by FC administration in vivo and in vitro. Immune response and skin barrier dysfunction are both mitigated by three routes of FC administration: oral, topical, and both routes via the regulation of IκB, MAPKs, and STATs pathways. In summary, FC could be a potential therapeutic agent for AD by regulating immune balance and skin barrier function.
Topics: Swine; Animals; Cattle; Mice; Pyroglyphidae; Tumor Necrosis Factor-alpha; Dermatophagoides pteronyssinus; Keratinocytes; Collagen; Dermatitis, Atopic; Fishes; Mammals
PubMed: 37689763
DOI: 10.1038/s41598-023-41831-w -
Environmental Pollution (Barking, Essex... Jul 2023Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust...
Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust particles (DEP) is implicated in both exacerbation and development of asthma. Since exposure to DEP is associated with a neutrophilic component, we aimed to investigate how exposure to the combination of allergens and DEP modulates neutrophilic responses. Human bronchial epithelial cells (HBEC) were exposed to house dust mite (HDM), DEP or HDM + DEP in vitro to determine the expression of neutrophil-recruiting chemokines. Female (C57BL/6 J) mice were intranasally instilled with saline, DEP, HDM or combined HDM + DEP for 3 weeks (subacute) or 6 weeks (chronic). The neutrophilic responses were determined in lung tissue and bronchoalveolar lavage fluid (BALF). Simultaneous exposure to HDM + DEP resulted in increased CXCL1 and CXCL8 mRNA expression by HBEC in vitro. In mice, subacute exposure to HDM + DEP induced a strong mixed eosinophilic/neutrophilic inflammation in BALF and lung and was associated with higher expression of neutrophil-attracting chemokines and NET formation compared to the sole exposures. After chronic HDM + DEP exposure, a similar neutrophilic response was observed, however the NET formation was less pronounced. Interestingly, the increase of BALF eosinophils was also significantly attenuated after chronic HDM + DEP exposure compared to the subacute exposure. Subacute and chronic HDM + DEP exposure induced goblet cell hyperplasia and airway hyperresponsiveness. Our data suggest a role for neutrophils and NETs in pollutant-aggravated eosinophilic allergic asthma. Moreover, subacute exposure to HDM + DEP induces a mixed eosinophilic/neutrophilic response whereas upon chronic HDM + DEP exposure there is a shift in inflammatory response with a more prominent neutrophilic component.
Topics: Female; Humans; Mice; Animals; Environmental Pollutants; Mice, Inbred C57BL; Asthma; Lung; Hypersensitivity; Disease Models, Animal; Allergens; Pyroglyphidae
PubMed: 37105460
DOI: 10.1016/j.envpol.2023.121722 -
Allergy Aug 2023Exacerbations of asthma are thought to be strongly dependent on reactivation of allergen-induced lung tissue-resident and circulatory memory CD4 T cells. Strategies that...
BACKGROUND
Exacerbations of asthma are thought to be strongly dependent on reactivation of allergen-induced lung tissue-resident and circulatory memory CD4 T cells. Strategies that broadly inhibit multiple T cell populations might then be useful to limit asthma. Accordingly, we tested whether targeting CD3 during exposure to inhaled allergen could prevent the accumulation of lung-localized effector memory CD4 T cells and block exacerbations of asthmatic inflammation.
METHODS
House dust mite-sensitized and repetitively challenged BL/6 mice were transiently treated therapeutically with F(ab')2 anti-CD3ε and memory T cell responses and lung inflammation were assessed. PBMCs from HDM-allergic donors were examined for the effect of anti-CD3 on expansion of allergen-reactive T cells.
RESULTS
Allergen-sensitized mice undergoing exacerbations of asthma were protected from lung inflammation by transient therapeutic treatment with F(ab')2 anti-CD3. Regardless of whether sensitized mice underwent a secondary or tertiary recall response to inhaled allergen, anti-CD3 inhibited all phenotypes of effector memory CD4 T cells in the lung tissue and lung vasculature by 80%-90%, including those derived from tissue-resident and circulatory memory T cells. This did not depend on Treg cells suggesting it was primarily a blocking effect on memory T cell signaling. Correspondingly, anti-CD3 also strongly inhibited proliferation of human allergen-reactive memory CD4 T cells from allergic individuals. In contrast, the number of surviving tissue-resident memory CD4 T cells that were maintained in the lungs at later times was not robustly reduced by anti-CD3.
CONCLUSION
Anti-CD3 F(ab')2 administration at the time of allergen exposure represents a viable strategy for limiting the immediate activity of allergen-responding memory T cells and asthma exacerbations.
Topics: Animals; Mice; Humans; Memory T Cells; CD4-Positive T-Lymphocytes; Th2 Cells; Asthma; Hypersensitivity; Allergens; Pneumonia; Pyroglyphidae; Disease Models, Animal
PubMed: 36951658
DOI: 10.1111/all.15722 -
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 -
Frontiers in Immunology 2023Pediatric allergic rhinoconjunctivitis has become a public concern with an increasing incidence year by year. Conventional subcutaneous immunotherapy (SCIT) has long... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pediatric allergic rhinoconjunctivitis has become a public concern with an increasing incidence year by year. Conventional subcutaneous immunotherapy (SCIT) has long treatment time, high cost and poor compliance. The novel immunotherapy significantly shortens the course of treatment by directly injecting allergens into cervical lymph nodes, which can perform faster clinical benefits to children.
OBJECTIVE
By comparing with SCIT, this study aimed to evaluate the long-term efficacy and safety of intra-cervical lymphatic immunotherapy (ICLIT).
METHODS
This is a prospective randomized controlled study. A total of 50 allergic rhinoconjunctivitis children with dust mite allergy was randomly divided into ICLIT group and SCIT group, receiving three cervical intralymphatic injections of dust mite allergen or three years of subcutaneous injection, separately. Primary outcomes included total nasal symptom scores (TNSS), total ocular symptom scores (TOSS), total symptom scores (TSS), total medication scores (TMS), and total quality of life score. Secondary outcomes included pain perception and adverse reactions during treatment. Other secondary outcome was change in (Derp) and (Derf) -specific IgE level.
RESULTS
Both groups had significantly decreased TNSS, TOSS, TSS, TMS, and total quality of life score after 36 months of treatment (p<0.0001). Compared with SCIT, ICLIT could rapidly improve allergic symptoms (p<0.0001). The short-term efficacy was consistent between the two groups (p=0.07), while the long-term efficacy was better in SCIT group (p<0.0001). The pain perception in ICLIT group was lower than that in SCIT group (p<0.0001). ICLIT group was safer. Specifically, the children had only 3 mild local adverse reactions without systemic adverse reactions. The SCIT group had 14 systemic adverse reactions. At last, the serum Derp and Derf-specific IgE levels in ICLIT and SCIT groups decreased 3 years later (p<0.0001).
CONCLUSION
ICLIT could ameliorate significantly the allergic symptoms in pediatric patients with an advantage in effectiveness and safety, besides an improved life quality including shortened period of treatment, frequency of drug use and pain perception.
CLINICAL TRIAL REGISTRATION
https://www.chictr.org.cn/, identifier ChiCTR1800017130.
Topics: Humans; Child; Animals; Prospective Studies; Quality of Life; Immunotherapy; Conjunctivitis; Pyroglyphidae; Immunoglobulin E
PubMed: 37593733
DOI: 10.3389/fimmu.2023.1144813