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Respiratory Research Nov 2023Allergic asthma is a common respiratory disease that significantly impacts human health. Through in silico analysis of human lung RNASeq, we found that asthmatic lungs...
BACKGROUND
Allergic asthma is a common respiratory disease that significantly impacts human health. Through in silico analysis of human lung RNASeq, we found that asthmatic lungs display lower levels of Isthmin-1 (ISM1) expression than healthy lungs. ISM1 is an endogenous anti-inflammatory protein that is highly expressed in mouse lungs and bronchial epithelial cells, playing a crucial role in maintaining lung homeostasis. However, how ISM1 influences asthma remains unclear. This study aims to investigate the potential involvement of ISM1 in allergic airway inflammation and uncover the underlying mechanisms.
METHODS
We investigated the pivotal role of ISM1 in airway inflammation using an ISM1 knockout mouse line (ISM1) and challenged them with house dust mite (HDM) extract to induce allergic-like airway/lung inflammation. To examine the impact of ISM1 deficiency, we analyzed the infiltration of immune cells into the lungs and cytokine levels in bronchoalveolar lavage fluid (BALF) using flow cytometry and multiplex ELISA, respectively. Furthermore, we examined the therapeutic potential of ISM1 by administering recombinant ISM1 (rISM1) via the intratracheal route to rescue the effects of ISM1 reduction in HDM-challenged mice. RNA-Seq, western blot, and fluorescence microscopy techniques were subsequently used to elucidate the underlying mechanisms.
RESULTS
ISM1 mice showed a pronounced worsening of allergic airway inflammation and hyperresponsiveness upon HDM challenge. The heightened inflammation in ISM1 mice correlated with enhanced lung cell necroptosis, as indicated by higher pMLKL expression. Intratracheal delivery of rISM1 significantly reduced the number of eosinophils in BALF and goblet cell hyperplasia. Mechanistically, ISM1 stimulates adiponectin secretion by type 2 alveolar epithelial cells partially through the GRP78 receptor and enhances adiponectin-facilitated apoptotic cell clearance via alveolar macrophage efferocytosis. Reduced adiponectin expression under ISM1 deficiency also contributed to intensified necroptosis, prolonged inflammation, and heightened severity of airway hyperresponsiveness.
CONCLUSIONS
This study revealed for the first time that ISM1 functions to restrain airway hyperresponsiveness to HDM-triggered allergic-like airway/lung inflammation in mice, consistent with its persistent downregulation in human asthma. Direct administration of rISM1 into the airway alleviates airway inflammation and promotes immune cell clearance, likely by stimulating airway adiponectin production. These findings suggest that ISM1 has therapeutic potential for allergic asthma.
Topics: Animals; Humans; Mice; Adiponectin; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Hypersensitivity; Inflammation; Lung; Macrophages, Alveolar; Pyroglyphidae; Intercellular Signaling Peptides and Proteins
PubMed: 37932719
DOI: 10.1186/s12931-023-02569-1 -
The Journal of Allergy and Clinical... Mar 2024Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents...
BACKGROUND
Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common β (βc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation.
OBJECTIVE
To determine the pathogenesis of βc receptor-mediated inflammation and remodeling in severe asthma and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease.
METHODS
βc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling.
RESULTS
βc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung.
CONCLUSIONS
βc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.
Topics: Mice; Animals; Humans; Receptors, Cytokine; Airway Remodeling; Asthma; Lung; Cytokines; Mice, Transgenic; Inflammation; Allergens; Steroids; Fibrosis; Pyroglyphidae
PubMed: 37931708
DOI: 10.1016/j.jaci.2023.10.021 -
Annals of Allergy, Asthma & Immunology... Mar 2024A lower adherence rate existed in patients receiving allergen-specific immunotherapy due to its lengthy period and adverse effects even though it is the only curative... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A lower adherence rate existed in patients receiving allergen-specific immunotherapy due to its lengthy period and adverse effects even though it is the only curative treatment for IgE-mediated allergies. Therefore, exploring innovative allergen-specific immunotherapy routes is necessary.
OBJECTIVE
To explore the efficacy and safety of the intratonsillar injection of house dust mite (HDM) extract in patients with HDM-induced allergic rhinitis (AR).
METHODS
A randomized, double-blind, placebo-controlled clinical trial was conducted. A total of 80 patients with HDM-induced AR were randomized to receive 6 intratonsillar injections with HDM extract or placebo in 3 months. The total nasal symptom score (TNSS), visual analogue scale of nasal symptoms, combined symptom and medication score, mini rhinoconjunctivitis quality of life questionnaire, and serum allergen-specific IgG4 to Dermatophagoides pteronyssinus were all monitored at baseline and 3 months, 6 months, and 12 months after the treatment was finished. The intent-to-treat and per-protocol set (PPS) are both analyzed.
RESULTS
The primary end points TNSS and ΔTNSS were improved significantly at 3 months after the patients with AR finished a 3-month 6-injection intratonsillar immunotherapy compared with those in the placebo treatment in both intent-to-treat and PPS. Results of visual analogue scale, combined symptom and medication score, and mini rhinoconjunctivitis quality of life questionnaire were also improved significantly at 3 months after the treatment in PPS. However, the improvement effect of intratonsillar immunotherapy at 6 and 12 months was limited and uncertain based on the data. The increase of serum Der p IgG4 in the active group was significantly higher than that in the placebo group at 3, 6, and 12 months after the treatment was finished. Adverse events were monitored, and no systemic adverse reactions were observed.
CONCLUSION
The clinical trial revealed that intratonsillar injection with HDM extract was safe and effective in patients with AR. Optimizing the protocol and allergen formulations is expected to increase and maintain the efficacy of this novel approach.
TRIAL REGISTRATION
https://www.chictr.org.cn/index.html, identifier: ChiCTR-TRC-13003600.
Topics: Animals; Humans; Quality of Life; Pyroglyphidae; Sublingual Immunotherapy; Treatment Outcome; Antigens, Dermatophagoides; Rhinitis, Allergic; Allergens; Rhinitis, Allergic, Perennial; Double-Blind Method; Conjunctivitis; Immunoglobulin G
PubMed: 37913839
DOI: 10.1016/j.anai.2023.10.029 -
Immunity, Inflammation and Disease Oct 2023Maintenance doses for allergen immunotherapy (AIT) have been recommended for at least 3 years but little data on long-term efficacy is available depending on AIT...
BACKGROUND
Maintenance doses for allergen immunotherapy (AIT) have been recommended for at least 3 years but little data on long-term efficacy is available depending on AIT duration. To show sustained efficacy 10 years after completion of treatment with depigmented-polymerized house dust mite (dpg-pol HDM) allergen extract in adults with asthma and/or rhinoconjunctivitis.
METHODS
Patients included in a double-blind placebo-controlled AIT study with dpg-pol HDM allergen extract were reviewed at completion of the perennial treatment and 10-year follow-up (10y-FU). Change in symptom and rescue medication score was the primary objective. Visual analog scale (VAS), asthma control test (ACT), and degree of disease control were the secondary objectives. A comparative analysis between patients who underwent AIT treatment for <3 years and ≥3 years was performed.
RESULTS
Data from 31 patients (mean age 38 years) were available at 10y-FU. All had asthma and 29 had rhinoconjunctivitis at baseline. Twenty-three patients were treated ≥3 years and 8 for <3 years. Seventeen (55%) patients were asymptomatic at completion of AIT, with significant differences for nasal, conjunctival, and bronchial symptoms (p < .0001) compared with baseline only in those patients treated ≥3 years. Nine (52.9%) patients remained completely asymptomatic at 10y-FU, all were treated for ≥3 years. Moreover, significant reduction in the number of patients with rhinitis (p = .0117), conjunctivitis (p < .0001), and bronchial (p = .0005) symptoms was observed at 10y-FU compared with baseline only in the ≥3 years treated. Ten (32.3%) patients did not require any rescue medication at 10y-FU, all had been treated for ≥3 years. ACT at 10y-FU showed a good control of asthma (median 23.5; 95% IC[22.0, 25.0]). No significant differences were observed between VAS at end of treatment compared with VAS at 10y-FU.
CONCLUSIONS
Sustained clinical efficacy is achieved 10 years after completion of depigmented-polymerized HDM, however, these findings were observed only if patients are treated for at least 3 years.
Topics: Adult; Animals; Humans; Allergens; Asthma; Dermatophagoides pteronyssinus; Desensitization, Immunologic; Follow-Up Studies; Pyroglyphidae; Rhinitis, Allergic; Double-Blind Method
PubMed: 37904678
DOI: 10.1002/iid3.1004 -
International Archives of Allergy and... 2024Allergen-specific immunotherapy (AIT), an established treatment for allergic diseases, prevents the development of other allergic manifestations. Although the mechanisms...
BACKGROUND
Allergen-specific immunotherapy (AIT), an established treatment for allergic diseases, prevents the development of other allergic manifestations. Although the mechanisms remain unclear, AIT has been shown to reduce basophil activation (BA) against nontarget allergens.
OBJECTIVES
The aim of this study was to assess immunological changes in Dermatophagoides farinae (Der f) after Japanese cedar pollen (JCP)-based subcutaneous immunotherapy (SCIT) monotherapy.
METHOD
The data of 16 patients (age: 6-37 years) with JCP-induced allergic rhinitis who were sensitive to Der f (serum Der f-specific immunoglobulin E [IgE] level >0.34 kUA/L) and received JCP-based SCIT for 5 years were reviewed retrospectively. BA by Der f and JCP extracts and serum-specific IgE and immunoglobulin G4 (IgG4) levels against these allergens were evaluated before and after completing 5 years of JCP-based SCIT monotherapy.
RESULTS
The areas under the dose-response curves of BA by Der f and JCP extracts were significantly reduced (p = 0.02 and p = 0.002, respectively). JCP-specific IgE levels decreased and JCP-specific IgG4 levels increased significantly (p < 0.001 for both), whereas Der f-specific IgE and IgG4 levels did not change significantly.
CONCLUSIONS
JCP-based SCIT monotherapy reduced Der f-specific BA. These findings suggest that JCP-based SCIT has the potential to modulate immune response toward nontarget allergens.
Topics: Animals; Humans; Child; Adolescent; Young Adult; Adult; Rhinitis, Allergic, Seasonal; Pyroglyphidae; Retrospective Studies; Pollen; Cryptomeria; Basophils; Allergens; Dermatophagoides pteronyssinus; Immunoglobulin E; Desensitization, Immunologic; Immunoglobulin G
PubMed: 37852197
DOI: 10.1159/000533724 -
Science Immunology Oct 2023Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and the interplay between inflammatory and...
Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the consequences of disrupting and its receptor in a mouse model of house dust mite (HDM)-induced allergic dermatitis. -deficient mice displayed a deficit in HDM dermatitis-associated scratching, consistent with its well-established role as a pruritogen. In contrast, deficiency increased the number and proportion of cutaneous type 2 cytokine-producing CD4 T cells and serum IgE in response to HDM. Furthermore, monocytes and macrophages capable of fueling a feedforward type 2 inflammatory loop were selectively enriched in -deficient HDM dermatitis skin. Thus, IL-31 is not strictly a proinflammatory cytokine but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin. Our data support a model wherein IL-31 activation of IL31RA pruritoceptors triggers release of calcitonin gene-related protein (CGRP), which can mediate neurogenic inflammation, inhibit CD4 T cell proliferation, and reduce T cell production of the type 2 cytokine IL-13. Together, these results illustrate a previously unrecognized neuroimmune pathway that constrains type 2 tissue inflammation in the setting of chronic cutaneous allergen exposure and may explain paradoxical dermatitis flares in atopic patients treated with anti-IL31RA therapy.
Topics: Animals; Mice; Cytokines; Dermatitis, Atopic; Immunity; Neurogenic Inflammation; Pyroglyphidae; Skin; Interleukins
PubMed: 37831760
DOI: 10.1126/sciimmunol.abi6887 -
American Journal of Physiology. Lung... Dec 2023Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. DNA methylation is one form of epigenetic modification that regulates gene...
Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. DNA methylation is one form of epigenetic modification that regulates gene expression and is both inherited and modified by environmental exposures throughout life. Prenatal development is a particularly vulnerable time period during which exposure to maternal asthma increases asthma risk in offspring. How maternal asthma affects DNA methylation in offspring and what the consequences of differential methylation are in subsequent generations are not fully known. In this study, we tested the effects of grandmaternal house dust mite (HDM) allergen sensitization during pregnancy on airway physiology and inflammation in HDM-sensitized and challenged second-generation mice. We also tested the effects of grandmaternal HDM sensitization on tissue-specific DNA methylation in allergen-naïve and -sensitized second-generation mice. Descendants of both allergen- and vehicle-exposed grandmaternal founders exhibited airway hyperreactivity after HDM sensitization. However, grandmaternal allergen sensitization significantly potentiated airway hyperreactivity and altered the epigenomic trajectory in second-generation offspring after HDM sensitization compared with HDM-sensitized offspring from vehicle-exposed founders. As a result, biological processes and signaling pathways associated with epigenetic modifications were distinct between lineages. A targeted analysis of pathway-associated gene expression found that Smad3 was significantly dysregulated as a result of grandmaternal allergen sensitization. These data show that grandmaternal allergen exposure during pregnancy establishes a unique epigenetic trajectory that reprograms allergen responses in second-generation offspring and may contribute to asthma risk. Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. This study shows that maternal allergen exposure during pregnancy promotes unique epigenetic trajectories in second-generation offspring at baseline and in response to allergen sensitization, which is associated with the potentiation of airway hyperreactivity. These effects are one mechanism by which maternal asthma may influence the inheritance of asthma risk.
Topics: Pregnancy; Humans; Female; Mice; Animals; Allergens; Epigenomics; Prenatal Exposure Delayed Effects; Asthma; Disease Susceptibility; Epigenesis, Genetic; Pyroglyphidae
PubMed: 37814791
DOI: 10.1152/ajplung.00103.2023 -
Frontiers in Immunology 2023Allergic airway inflammation (AAI) is a chronic respiratory disease that is considered a severe restriction in daily life and is accompanied by a constant risk of acute...
Allergic airway inflammation (AAI) is a chronic respiratory disease that is considered a severe restriction in daily life and is accompanied by a constant risk of acute aggravation. It is characterized by IgE-dependent activation of mast cells, infiltration of eosinophils, and activated T-helper cell type 2 (Th2) lymphocytes into airway mucosa. Purinergic receptor signaling is known to play a crucial role in inducing and maintaining allergic airway inflammation. Previous studies in an ovalbumin (OVA)-alum mouse model demonstrated a contribution of the P2Y2 purinergic receptor subtype (P2RY2) in allergic airway inflammation. However, conflicting data concerning the mechanism by which P2RY2 triggers AAI has been reported. Thus, we aimed at elucidating the cell-type-specific role of P2RY2 signaling in house dust mite (HDM)-driven model of allergic airway inflammation. Thereupon, HDM-driven AAI was induced in conditional knockout mice, deficient or intact for in either alveolar epithelial cells, hematopoietic cells, myeloid cells, helper T cells, or dendritic cells. To analyze the functional role of P2RY2 in these mice models, flow cytometry of bronchoalveolar lavage fluid (BALF), cytokine measurement of BALF, invasive lung function measurement, HDM re-stimulation of mediastinal lymph node (MLN) cells, and lung histology were performed. Mice that were subjected to an HDM-based model of allergic airway inflammation resulted in reduced signs of acute airway inflammation including eosinophilia in BALF, peribronchial inflammation, Th2 cytokine production, and bronchial hyperresponsiveness in mice deficient for in alveolar epithelial cells, hematopoietic cells, myeloid cells, or dendritic cells. Furthermore, the migration of bone-marrow-derived dendritic cells and bone-marrow-derived monocytes, both deficient in , towards ATP was impaired. Additionally, we found reduced levels of MCP-1/CCL2 and IL-8 homologues in the BALF of mice deficient in in myeloid cells and lower concentrations of IL-33 in the lung tissue of mice deficient in in alveolar epithelial cells. In summary, our results show that P2RY2 contributes to HDM-induced airway inflammation by mediating proinflammatory cytokine production in airway epithelial cells, monocytes, and dendritic cells and drives the recruitment of lung dendritic cells and monocytes.
Topics: Mice; Animals; Receptors, Purinergic P2Y2; Cytokines; Lung; Pyroglyphidae; Inflammation
PubMed: 37790940
DOI: 10.3389/fimmu.2023.1209097 -
Scientific Reports Oct 2023A subgroup of patients suffering from atopic dermatitis (AD) does not respond to biologics therapy targeting the key players of type-2 inflammation, and it is an ongoing...
A subgroup of patients suffering from atopic dermatitis (AD) does not respond to biologics therapy targeting the key players of type-2 inflammation, and it is an ongoing discussion whether skin-infiltrating Th17 cells may underlie this phenomenon. This study aimed to investigate the potential of allergen-induced, immune-cell derived IL-17 on the induction of inflammatory processes in keratinocytes. Peripheral blood mononuclear cells derived from respectively sensitized AD patients were stimulated with house dust mite (HDM) extract and cell culture supernatants were applied subsequently in absence or presence of secukinumab to primary human keratinocytes. Hereby we confirm that the immune response of sensitized AD patients to HDM contains aside from type-2 cytokines significant amounts of IL-17. Blocking IL-17 efficiently reduced the stimulation-induced changes in keratinocyte gene expression. IL-17-dependent transcriptional changes included increased expression of the cytokines IL-20 and IL-24 as well as Suppressor of Cytokine Siganling 3 (SOCS3), a negative feedback-regulator of the STAT3/IL-17/IL-24 immune response. We conclude that the immune response to HDM can induce pro-inflammatory cytokines from keratinocytes in AD, which in part is mediated via IL-17. Targeting IL-17 may turn out to be a reasonable alternative therapy in a subgroup of patients with moderate to severe AD and HDM sensitization.
Topics: Animals; Humans; Allergens; Cytokines; Dermatitis, Atopic; Dermatophagoides pteronyssinus; Interleukin-17; Keratinocytes; Leukocytes, Mononuclear; Pyroglyphidae
PubMed: 37789035
DOI: 10.1038/s41598-023-42595-z -
Hong Kong Medical Journal = Xianggang... Oct 2023
Topics: Humans; Animals; Hypersensitivity; Allergens; Pyroglyphidae; Immunotherapy
PubMed: 37749053
DOI: 10.12809/hkmj2310696