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Expert Review of Respiratory Medicine 2023The aim of this study was to assess the efficacy and safety of oral antihistamines (AHs), intranasal antihistamines (INAH) intranasal glucocorticosteroids (INCS),... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The aim of this study was to assess the efficacy and safety of oral antihistamines (AHs), intranasal antihistamines (INAH) intranasal glucocorticosteroids (INCS), subcutaneous immunotherapy (SCIT), and sublingual immunotherapy (SLIT) in the management of allergic rhinitis (AR). The authors focused on the division into selected AR's triggers: house dust mites (HDMs), grass pollen, and birch pollen.
METHODS
For each drug and allergen class, a meta-analysis of the efficacy and adverse events (AEs) was performed. The obtained results were presented as a therapeutic index (TIX-Score).
RESULTS
Twenty-seven randomized clinical trials (RCTs) were included. The best total efficacy was observed for: HDMs for INCS and grass pollen for combination of INCS with INAH in a single device and for INAH. Considering the data that was obtained for birch pollen, SLIT showed statistically significant total efficacy. Summation scores for efficacy and AEs showed highest TIX-Score for combination of INCS and INAH in a single device in grass pollen.
CONCLUSIONS
Treatment methods selected for this review may serve as an effective and safe treatment in reducing perennial and seasonal AR's symptoms. However, due to high heterogeneity probably associated with potential confounders existence in control in some cases, results should be interpreted with caution.
Topics: Animals; Humans; Allergens; Betula; Pyroglyphidae; Poaceae; Randomized Controlled Trials as Topic; Rhinitis, Allergic; Pollen; Sublingual Immunotherapy; Histamine Antagonists; Treatment Outcome
PubMed: 37489655
DOI: 10.1080/17476348.2023.2241364 -
Frontiers in Immunology 2023Extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation....
BACKGROUND
Extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation. However, the role of local GC synthesis in the lung is less well studied. Based on previous studies and the uncontentious efficacy of corticosteroid therapy in asthma patients, we here investigated the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1/)-dependent local GC reactivation in the regulation of allergic airway inflammation.
METHODS
Airway inflammation in Hsd11b1-deficient and C57BL/6 wild type mice was analyzed after injection of lipopolysaccharide (LPS) and anti-CD3 antibody, and in acute and chronic models of airway hypersensitivity induced by house dust mite (HDM) extract. The role of 11β-HSD1 in normal and inflammatory conditions was assessed by high dimensional flow cytometry, histological staining, RT-qPCR analysis, tissue cultures, GC-bioassays and protein detection by ELISA and immunoblotting.
RESULTS
Here we show that lung tissue from Hsd11b1-deficient mice synthesized significantly less GC compared with wild type animals in response to immune cell stimulation. We further observed a drastically aggravated phenotype in Hsd11b1-deficient mice treated with HDM extract compared to wild type animals. Besides eosinophilic infiltration, Hsd11b1-deficient mice exhibited aggravated neutrophilic infiltration caused by a strong Th17-type immune response.
CONCLUSION
We propose an important role of 11β-HSD1 and local GC in regulating Th17-type rather than Th2-type immune responses in HDM-induced airway hypersensitivity in mice by potentially controlling Toll-like receptor 4 (TLR4) signaling and cytokine/chemokine secretion by airway epithelial cells.
Topics: Humans; Animals; Mice; Glucocorticoids; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Mice, Inbred C57BL; Inflammation; Dust Mite Allergy; Allergens; Pyroglyphidae
PubMed: 37936704
DOI: 10.3389/fimmu.2023.1252874 -
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 -
The British Journal of Dermatology Aug 2023Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte...
BACKGROUND
Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea.
OBJECTIVES
To verify if HDM can contribute to melanocyte detachment in vitiligo and if so, by which mechanism(s).
METHODS
Using primary human keratinocytes, human skin biopsies from healthy donors and patients with vitiligo, and 3D reconstructed human epidermis, we studied the effect of HDM on cutaneous immunity, tight and adherent junction expression and melanocyte detachment.
RESULTS
HDM increased keratinocyte production of vitiligo-associated cytokines and chemokines and increased expression of toll-like receptor (TLR)-4. This was associated with increased in situ matrix-metalloproteinase (MMP)-9 activity, reduced cutaneous expression of adherent protein E-cadherin, increased soluble E-cadherin in culture supernatant and significantly increased number of suprabasal melanocytes in the skin. This effect was dose-dependent and driven by cysteine protease Der p1 and MMP-9. Selective MMP-9 inhibitor, Ab142180, restored E-cadherin expression and inhibited HDM-induced melanocyte detachment. Keratinocytes from patients with vitiligo were more sensitive to HDM-induced changes than healthy keratinocytes. All results were confirmed in a 3D model of healthy skin and in human skin biopsies.
CONCLUSIONS
Our results highlight that environmental mite may act as an external source of pathogen-associated molecular pattern molecules in vitiligo and topical MMP-9 inhibitors may be useful therapeutic targets. Whether HDM contributes to the onset of flares in vitiligo remains to be tested in carefully controlled trials.
Topics: Animals; Humans; Vitiligo; Matrix Metalloproteinase 9; Pyroglyphidae; Melanocytes; Keratinocytes; Cadherins
PubMed: 37140010
DOI: 10.1093/bjd/ljad148 -
Inflammation Dec 2023House dust mite (HDM) acts as an environmental antigen that might cause chronic allergic diseases. Neferine (NEF) shows anti-inflammation therapeutic effects. This study...
House dust mite (HDM) acts as an environmental antigen that might cause chronic allergic diseases. Neferine (NEF) shows anti-inflammation therapeutic effects. This study is to explore the protection role of NEF against HDM-induced allergic inflammation. HDM-induced allergic asthmatic C57BL/6J mice models were established. Differential histological staining was used to analyze lung tissue pathological scores. Flow cytometry was used to analyze subtypes and biomarker expression of immune cells. RT-PCR and ELISA were used to test cytokines-related gene and/or protein expression levels. Western blot was performed to investigate the signaling pathway that mediates allergic inflammation from mice lung tissue and bone marrow-derived dendritic cells (BMDCs). H&E and PAS staining results indicate NEF significantly attenuated inflammatory index and the percentage of goblet cells in the lung tissue induced by HDM. The HDM-elevated TH2 and TH17 cells were significantly decreased by NEF; inflammatory cytokines Il-4, Il-13 and Il-17 were dramatically downregulated in the NEF plus HDM group compared with HDM alone. CD40 and CD86 DCs, eosinophils and mast cells, and ILC2 cells were decreased by NEF which was elevated under HDM stimulation. In vivo and ex vivo investigations indicated NEF can attenuate the activated NF-κB signaling induced by HDM is involved in allergic inflammatory immune response and regulates cytokines-related gene expression. HDM-activated DCs promoted differentiation of TH2 and TH17 cells but were attenuated by NEF. This study suggests NEF interrupts the overexpression of some cytokines released by DCs, TH2, and TH17 cells; NEF attenuates HDM-induced allergic inflammation via inhibiting NF-κB signaling of DCs.
Topics: Mice; Animals; Pyroglyphidae; Immunity, Innate; NF-kappa B; Lymphocytes; Mice, Inbred C57BL; Lung; Hypersensitivity; Cytokines; Inflammation; Dendritic Cells; Th2 Cells; Disease Models, Animal
PubMed: 37702907
DOI: 10.1007/s10753-023-01891-6 -
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 -
The Journal of Allergy and Clinical... Aug 2023Severe anaphylactic reactions to home doses may occur during food allergy oral immunotherapy (OIT).
BACKGROUND
Severe anaphylactic reactions to home doses may occur during food allergy oral immunotherapy (OIT).
OBJECTIVE
To study the rate and risk factors for such reactions.
METHODS
We studied all patients aged greater than 3.5 years who completed OIT in a single center between April 2010 and January 2020. All home epinephrine-treated reactions (HETRs) were identified. High-grade HETRs (HG-HETRs) were defined as HETRs involving respiratory (SpO of 94% or less), cardiovascular (low blood pressure), or central nervous system impairment (loss of consciousness). We investigated the rate and risk factors for HG-HETRs.
RESULTS
A total of 1,637 OIT treatments were studied: milk (880), peanut (346), tree nuts (221), sesame (115), and egg (75). Of 390 identified HETRs, 30 HG-HETRs occurred during 27 treatments (1.65% of all treatments). Nearly all (26 of 30) were during milk OIT in patients with house dust mite (HDM) sensitization and asthma (26 of 30 each). Of the 30 patients with HG-HETRs, 21 recovered with one or two epinephrine treatments, but nine (0.55% of all treatments) did not respond to a second dose of epinephrine and were deemed to have refractory anaphylaxis. Three patients required intensive care unit admission and three received epinephrine drip, but none required ventilatory support. Risk factors for HG-HETRs included milk OIT (P = .031), asthma (P = .02) and HDM sensitization (P = .02). No specific triggers for HG-HETR were identified. Of patients with HG-HETRs, 25.9% were fully desensitized, including the four non-milk treated patients; 22.2% were partially desensitized; and 51.9% failed.
CONCLUSIONS
High-grade HETRs are uncommon, particularly refractory anaphylactic reactions to home OIT doses. Although milk OIT, asthma, and HDM sensitization are the main risk factors for such reactions, identification of patients who are at risk is challenging.
Topics: Animals; Humans; Aged; Anaphylaxis; Desensitization, Immunologic; Food Hypersensitivity; Epinephrine; Risk Factors; Allergens; Administration, Oral; Dermatophagoides pteronyssinus
PubMed: 36925102
DOI: 10.1016/j.jaip.2023.03.005 -
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 -
Microbiology Spectrum Aug 2023House dust mites (HDMs) are a major source of indoor allergens that cause airway allergic disease. , a predominant species of HDMs in China, has demonstrated pathogenic...
House dust mites (HDMs) are a major source of indoor allergens that cause airway allergic disease. , a predominant species of HDMs in China, has demonstrated pathogenic role in allergic disorders. Exosomes derived from human bronchoalveolar lavage fluid have been strongly associated with allergic respiratory diseases progression. However, the pathogenic role of -derived exosomes in allergic airway inflammation has remained unclear until now. Here, was stirred overnight in phosphate-buffered saline, and the supernatant was used to extract exosomes by ultracentrifugation. Then, shotgun liquid chromatography-tandem mass spectrometry and small RNA sequencing were performed to identify proteins and microRNAs contained in exosomes. Immunoblotting, Western blotting, and enzyme-linked immunosorbent assay demonstrated the specific immunoreactivity of -specific serum IgE antibody against exosomes, and exosomes were found to induce allergic airway inflammation in a mouse model. In addition, exosomes invaded 16-HBE bronchial epithelial cells and NR8383 alveolar macrophages to release the inflammation-related cytokines interleukin-33 (IL-33), thymic stromal lymphopoietin, tumor necrosis factor alpha, and IL-6, and comparative transcriptomic analysis of 16-HBE and NR8383 cells revealed that immune pathways and immune cytokines/chemokines were involved in the sensitization of exosomes. Taken together, our data demonstrate that exosomes are immunogenic and may induce allergic airway inflammation via bronchial epithelial cells and alveolar macrophages. , a predominant species of house dust mites in China, has displayed pathogenic role in allergic disorders, and exosomes derived from human bronchoalveolar lavage fluid have been strongly associated with allergic respiratory diseases progression. However, the pathogenic role of -derived exosomes in allergic airway inflammation has remained unclear until now. This study, for the first time, extracted exosomes from , and sequenced their protein cargo and microRNAs using shotgun liquid chromatography-tandem mass spectrometry and small RNA sequencing. -derived exosomes trigger allergen-specific immune responses and present satisfactory immunogenicity, as revealed by immunoblotting, Western blotting, and enzyme-linked immunosorbent assay and may induce allergic airway inflammation via bronchial epithelial cells and alveolar macrophages. Our data provide insights into the mechanisms of allergic airway inflammation caused with -derived exosomes and the treatment of house dust mite-induced allergic airway inflammation.
Topics: Animals; Mice; Humans; Dermatophagoides farinae; Exosomes; Inflammation; Allergens; Cytokines; MicroRNAs; Respiratory Tract Diseases
PubMed: 37314339
DOI: 10.1128/spectrum.05054-22 -
Experimental Dermatology Jul 2023Atopy may be a facilitating factor in some alopecia areata (AA) patients with early disease onset and more severe/extensive AA. The underlying immune mechanisms are...
Atopy may be a facilitating factor in some alopecia areata (AA) patients with early disease onset and more severe/extensive AA. The underlying immune mechanisms are unknown, but allergen responses may support a pro-inflammatory environment that indirectly promotes AA. To investigate the long-term effect of allergen immunotherapy (AIT) against house dust mite (HDM) allergy on disease severity and prognosis for AA patients. An observational comparative effectiveness study was conducted on 69 AA patients with HDM allergy. 34 patients received conventional/traditional AA treatment (TrAA) plus AIT (AIT-TrAA), and 35 patients received TrAA alone. Serum total immunoglobulin E (tIgE), HDM specific IgE (sIgE), HDM specific IgG4 (sIgG4) and cytokines (IL-4, IL-5, IL-10, IL-12, IL-13, IL-33, IFNγ) were quantified in these patients, together with 58 non-allergic AA patients and 40 healthy controls. At the end of the 3-year desensitization course, the AIT-TrAA group presented with lower SALT scores than the TrAA group, especially in non-alopecia totalis/universalis (AT/U) patients and pre-adolescent AT/U patients (age ≤ 14). In patients with elevated tIgE levels before AIT, a decrease in tIgE was correlated to reduced extent of AA on completion of the AIT course. After desensitization, elevation of IL-5 and decrease of IL-33 were observed in HDM allergic-AA patients. Desensitization to HDM in allergic AA patients reduces the severity of relapse-related hair loss over the 3-year AIT treatment course, possibly via opposing Th2 dominance. This adjunctive treatment may help reduce disease severity and curtail the disease process in allergic patients with AA.
Topics: Animals; Adolescent; Humans; Allergens; Interleukin-33; Alopecia Areata; Interleukin-5; Antigens, Dermatophagoides; Hypersensitivity; Desensitization, Immunologic; Immunoglobulin E; Pyroglyphidae; Dust Mite Allergy; Dust
PubMed: 37114716
DOI: 10.1111/exd.14819