Dust Mite Research Articles

Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism

BackgroundTrained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism. AimThis study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo. MethodsCompared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production. ConclusionsThis novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT7 mice in a model of allergic airway inflammation.

House dust mite allergen Der f 2 drives IL-6 and GM–CSF expression in airway epithelial cells via p38 MAPK/NF-κB signaling

Objective Der f 2, a major allergen derived from Dermatophagoides farinae, is a leading cause of allergic asthma. IL-6 and GM–CSF play essential roles in the exacerbation of asthma. However, the mechanical act by which Der f 2 mediates the expression of IL-6, IL-8, and GM–CSF in airway epithelial cells remains incompletely elucidated. Herein, we aimed to explore the effect of Der f 2 on IL-6 and GM–CSF expression in the human airway epithelial cell BEAS-2B and A549. Methods Recombinant Der f 2 (rDf2) was acquired using Pichia pastoris. BEAS-2B and A549 cells were used as cell model. The expression of genes and proteins and the involvement of the signaling cascade were assessed using RT–PCR, quantitative real-time PCR (qPCR), Western blotting, and ELISA, respectively. Results Our findings showed that rDf2 significantly induced mRNA expression and protein production of IL-6 and GM-CSF in BEAS-2B and A549 cells. In contrast, rDf2 did not influence IL-8 expression or production in both cells. Mechanistic studies revealed that rDf2 triggered activation of the p38 MAPK and JNK. Inhibition of p38, but not JNK, significantly attenuated rDf2-induced IL-6 and GM–CSF expression and production. Conclusion This study demonstrates that Der f 2 promotes the expression and production of the pro-inflammatory cytokines IL-6 and GM–CSF in airway epithelial cells via activation of the p38 signaling pathway. These findings provide insights into the molecular mechanisms that Der f 2 may exacerbate airway inflammation.

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines.

Asthma is a common obstructive airway disease with an inflammatory etiology. The main unmet need in the management of asthma is inadequate adherence to pharmacotherapy, leading to a poorly-controlled disease state, necessitating the development of novel therapies. Bronchom is a calcio-herbal formulation, which is purported to treat chronic asthma. The objective of the current study was to examine the in-vivo efficacy of Bronchom in mouse model of allergic asthma. Ultra high performance liquid chromatography was utilized to analyze the phytocompounds in Bronchom. Further, the in-vivo efficacy of Bronchom was evaluated in House dust mite (HDM)-induced allergic asthma in mice. Mice were challenged with aerosolized methacholine to assess airway hyperresponsiveness. Subsequently, inflammatory cell influx was evaluated in bronchoalveolar lavage fluid (BALF) followed by lung histology, wherein airway remodeling features were studied. Simultaneously, the levels of Th2 cytokines and chemokines in the BALF was also evaluated. Additionally, the mRNA expression of pro-inflammatory and Th2 cytokines was also assessed in the lung along with the oxidative stress markers. Phytocompounds present in Bronchom included, gallic acid, protocatechuic acid, methyl gallate, rosmarinic acid, glycyrrhizin, eugenol, 6-gingerol and piperine. Bronchom effectively suppressed HDM-induced airway hyperresponsiveness along with the influx of leukocytes in the BALF. Additionally, Bronchom reduced the infiltration of inflammatory cells in the lung and it also ameliorated goblet cell metaplasia, sub-epithelial fibrosis and increase in α-smooth muscle actin. Bronchom decreased Th2 cytokines (IL-4 and IL-5) and chemokines (Eotaxin and IP-10) in the BALF. Likewise, it could also suppress the mRNA expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6 and IL-33), and IL-13. Moreover, Bronchom restored the HDM-induced diminution of endogenous anti-oxidants (GSH and SOD) and the increase in pro-oxidants (GSSG and MDA). Furthermore, Bronchom could also decrease the nitrosative stress by lowering the observed increase in nitrite levels. Taken together, the results of the present study data convincingly demonstrate that Bronchom exhibits pharmacological effects in an animal model of allergic asthma. Bronchom mitigated airway hyperresponsiveness, inflammation and airway remodeling evoked by a clinically relevant allergen and accordingly it possesses therapeutic potential for the treatment of asthma.

Managing Dust Mite Oligonychus afrasiaticus (McGregor) (Acari: Tetranchidae) Infesting Date Palm Orchards By Using Lemongrass Extract and Nanosulfur

The dust mite Oligonychus afrasiaticus (McGregor 1939) (Acari: Tetranychidae) poses a significant threat to date palm Phoenix dactylifera L. productivity in Iraq. To address this issue, a field study was conducted in a private date palm orchard in Al-Zubair district, Basrah province, Iraq, to assess the efficacy of some treatments in controlling the dust mite population on date palm fruits. The treatments included lemongrass extract, nanosulfur, a combination of lemongrass extract and nanosulfur, liquid sulfur, and a distilled water as control treatment. Treatments were applied by spraying on leaves and fruits at three dates: five weeks, eight weeks, and eleven weeks after pollination. Dust mite mortality rates were measured at intervals of 1, 3, 5, and 7 days after treatment application. Results revealed that the second date, eight weeks after pollination, exhibited the highest mortality rate of 76.77%, significantly outperforming other dates. Among the treatments, liquid sulfur showed the highest efficiency, with an 87.83% mortality rate, followed closely by the combination of lemongrass extract and nanosulfur (84.14%). Nanosulfur alone recorded a mortality rate of 79.26%, while lemongrass extract alone showed a mortality rate of 49.15%. The mortality rate increased over time, reaching 80.79% after 7 days and 65.76% after 1 day. In conclusion, liquid sulfur emerged as the most effective treatment for controlling the dust mite population on date palm fruits. The second date, eight weeks after pollination, was the optimal time for treatment application. These findings offer valuable insights into sustainable and environmentally friendly pest control strategies for date palm cultivation in Iraq.

Particulate matter-induced gene expression patterns in human-derived cells based on 11 public gene expression datasets.

Exposure to particulate matter (PM) and house dust mite (HDM) can change the expression patterns of inflammation-, oxidative stress-, and cell death-related genes. We investigated the changes in gene expression patterns owing to PM exposure. This study examined the changes in gene expression patterns following PM exposure. We searched for differentially expressed genes (DEGs) following PM exposure using five cell line-based RNA-seq or microarray datasets and six human-derived datasets. The enrichment terms of the DEGs were assessed. DEG analysis yielded two gene sets. Thus, enrichment analysis was performed for each gene set, and the enrichment terms related to respiratory diseases were presented. The intersection of six human-derived datasets and two gene sets was obtained, and the expression patterns following PM exposure were observed. Two gene sets were obtained for cells treated with PM and their expression patterns were presented following verification in human-derived cells. Our findings suggest that exposure to PM2.5 and HDM may reveal changes in genes that are associated with diseases, such as allergies, highlighting the importance of mitigating PM2.5 and HDM exposure for disease prevention.

Heat-killed Akkermansia muciniphila ameliorates allergic airway inflammation in mice.

Allergic asthma (AA) is a common inflammatory airway disease characterized by increased airway hyper-responsiveness (AHR), inflammation, and remodeling. Akkermansia muciniphila is a strictly anaerobic bacterium residing in the gut and is a promising next-generation probiotic to improve metabolic inflammatory syndrome. A recent study suggested the beneficial effect of live A. muciniphila on allergic airway inflammation (AAI) in mice. However, whether the heat-killed form can improve AAI requires further investigation. Mice sensitized and challenged with house dust mites (HDM) develop AA hallmarks including inflammatory cell infiltration, goblet cell hyperplasia, and subepithelial collagen deposition in the lungs. These phenomena were reversed by oral administration of the heat-killed A. muciniphila strain EB-AMDK19 (AMDK19-HK) isolated from the feces of healthy Koreans. Furthermore, AMDK19-HK diminished the HDM-induced AHR to inhaled methacholine, lung mast cell accumulation, and serum HDM-specific IgE levels. It also led to the overall suppression of IL-4, IL-13, and eotaxin production in bronchoalveolar lavage fluids, and Il4, Il5, Il13, and Ccl17 gene expression in lung tissues. Moreover, AMDK19-HK suppressed Th2-associated cytokine production in the splenocytes of HDM-sensitized mice in vitro. Additionally, a combination of 16S rRNA gene sequencing and short-chain fatty acid (SCFA) analysis in cecal samples revealed that AMDK19-HK modulated the relative abundance of circulating SCFA-associated gut genera, including a positive correlation with Lachnospiraceae_ NK4A136_group and a negative correlation with Lachnoclostridium and significantly increased cecal SCFA concentrations. Finally, AMDK19-HK improved intestinal mucosal barrier function. These results suggest that the oral administration of AMDK19-HK ameliorates HDM-induced AAI in mice by suppressing Th2-mediated immune responses and could have a protective effect against AA development.

ALLERGIC CONTACT DERMATITIS AND ATOPIC DERMATITIS: HIGHLIGHTS OF THE OVERLAP SYNDROME

Introduction. The combination of atopic dermatitis (AD) with allergic contact dermatitis (ACD) or the occurrence of ACD on the background of atopic dermatitis is called the overlap syndrome. Studies have demonstrated several reasons why patients with AD have a similar or even increased risk of developing ACD compared to those without AD. Allergens and haptens are trigger factors in a group of patients with AD and ACD overlap syndrome. The aim of the study. To confirm the diagnosis of ACD in a group of patients with AD – diagnose the overlap syndrome and analyze which allergens and haptens were the trigger factors in this group. Materials and methods. To confirm IgE-dependent sensitization in atopic dermatitis, skin prick tests or determination of specific IgE in blood serum were performed. Skin patch tests (European series S-1000) were performed to determine the mechanisms of delayed-type hypersensitivity. Results. It was found that the highest specific weight of positive allergic reactions has been recorded in response to the following allergens: ticks, ticks/ambrosia, birch and mold. The absolute majority of patients demonstrated positive specific IgE-dependent sensitization to Dermatophagoides pteronyssinus and Dermatophagoides farinae – 24 (50%), in turn, on Ambrósia – 14 (29.2%), and on Alternaria alternata – 8 (16.7%). Also, the reaction was most often recorded to haptens: cobalt, nickel, formaldehyde, PPD, textile dyes. Deterioration of the clinical course and shortening of AD remission periods were observed due to the formation of ACD against the background of impaired skin barrier function and the presence of chronic immune inflammation. Conclusions. Patients with AD are more often diagnosed with ACD, which predictably worsens the course of AD. Patients with confirmed overlap syndrome "AD + ACD" most often show reactions to haptens: Cobalt, Nikel, Formaldehyde, PPD, Textile dye mix – and in the vast majority to 2 haptens or more in one patient.

NF-κB/RelA signaling in secretoglobin progenitors mediates plasticity and MMP-induced barrier disruption in house dust mite-induced allergic asthma.

The mechanisms how aeroallergens induce sensitization are incompletely understood. The house dust mite (HDM) Dermatophagoides pteronyssius (Der p) is a ubiquitous aeroallergen that represents a major cause of allergic rhinitis and asthma. Herein, we tested whether HDM-induced aeroallergen exposure sensitivity is caused by the innate-immune response in small airway epithelial cells. HDM exposure is a rapid activator of NF-κB/RelA in the Secretoglobin (Scgb1a1+) lineage associated with upregulation of NF-κB/RelA-dependent markers of epithelial plasticity. To determine the effect of epithelial NF-κB signaling, NF-κB was depleted in a tamoxifen (TMX)-inducible Scgb1a1-CreERTM mouse within a CL57B/L6 background. Corn oil or TMX-treated/RelA-depleted [RelA knockdown (KD)] mice were repetitively exposed to airway HDM challenges to induce airway hyperresponsiveness (AHR). Strikingly, we observed that HDM induces hallmarks of epithelial plasticity through upregulation of the mesenchymal core factors SNAI1 and ZEB1 and production of metalloproteinase (MMP)9 that are RelA-dependent. Downstream, HDM-induced mucous metaplasia, Th2 polarization, allergen sensitivity, and airway hyperreactivity were all reduced in the RelA-depleted mice. Mechanistically, HDM-induced functional and structural barrier disruption was dependent on RelA signaling and associated with active MMP secretion into the bronchoalveolar lavage fluid. To establish the role of MMP2/9 in barrier disruption, we observe that a small-molecule MMP inhibitor (SB-3CT) blocked HDM-induced barrier disruption and activation of plasticity in naïve wild-type (WT) mice. Loss of functional barrier was associated with MMP disruption of zona occludens (ZO)-1 containing adherens junctions. Overall, this data indicates that host innate signaling in the Scgb1a1+ progenitors is directly linked to epithelial plasticity, MMP9 secretion, and enhanced barrier permeability that allows allergen penetration, sensitization producing allergic asthma (AA) in vivo. We propose that maintenance of epithelial integrity may reduce allergic sensitization and AA.NEW & NOTEWORTHY Allergic asthma from house dust mite (HDM) allergy causes substantial morbidity. This study examines the dynamic changes in small airway epithelial cells in a mouse model of HDM exposure. Our findings indicate that NF-κB/RelA signaling mediates matrix metalloproteinase production, disrupting the epithelial barrier resulting in allergic sensitization. Our findings bring new insight into mechanisms for epithelial cell-state change in the allergen response, creating a potential therapeutic pathway for maintaining barrier function in asthma.

Oral immunotherapy with enteric-coated capsules for allergic rhinitis caused by house dust mites.

Oral immunotherapy (OIT) is a promising allergen-specific approach in the management of food allergy; however, studies on OIT for allergic rhinitis (AR) have rarely been reported. The purpose of this study is to evaluate the efficacy and safety of OIT using enteric-coated capsules for AR induced by house dust mites. A total of 49 patients with AR were enrolled, including 25 who received subcutaneous immunotherapy (SCIT) and 24 who received OIT. The clinical efficacy and safety in both groups were evaluated. After 1 year of treatment, both SCIT and OIT demonstrated significant therapeutic effects. OIT was found to be more effective than SCIT in reducing the total AR symptom score and improving the results of nasal provocation tests. Local and systemic adverse reactions were observed in the SCIT group, while none were reported in the OIT group. OIT is an effective and safe treatment for mite-induced AR.

Clinical efficacy of Dermatophagoides farina drops on allergic rhinitis in children sensitized by dust mites combined with different allergens

ObjectiveThis study aimed to investigate the clinical efficacy and safety of sublingual immunotherapy (SLIT) using standardized dermatophagoides farina drops for the treatment of allergic rhinitis (AR) in children sensitized to dust mites combined with different allergens. The findings contribute to establishing a preliminary foundation for future in-depth studies on AR treatment. MethodsA total of 152 AR children undergoing SLIT were categorized into two groups based on serological test results: the inhalation group (dust mite combined with inhalation allergy) and the ingestion group (dust mite combined with ingestion allergy). The clinical efficacy and safety were evaluated by assessing the total nasal symptoms score (TNSS), total medication scores (TMS), visual analog scale scores (VAS scores), and the incidence of adverse reactions before treatment and after two years of treatment. ResultsAfter two years of treatment, TNSS, TMS, and VAS scores significantly improved compared to pre-treatment values in both the inhalation and ingestion groups (p < 0.05). However, there were no significant differences in efficacy between the two groups after two years of treatment (p > 0.05). During the treatment period, only 15 cases (10.9 %, 9 cases in the inhalation group and 6 cases in the ingestion group) experienced mild adverse reactions. There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). ConclusionSLIT using standardized dermatophagoides farina drops demonstrates long-term efficacy in children with AR, regardless of whether they belong to the inhalation or ingestion group, without significant differences in treatment outcomes.

How to Prevent Atopic Dermatitis (Eczema) in 2024: Theory and Evidence

Atopic dermatitis (AD) or eczema is a chronic inflammatory skin disease characterized by dry, itchy, and inflamed skin. We review emerging concepts and clinical evidence addressing the pathogenesis and prevention of atopic dermatitis. We review several interventions ranging from skin barrier enhancement strategies; probiotics, prebiotics, and synbiotics, and conversely, antimicrobial exposure; vitamin D and omega fatty acid supplementation; breastfeeding and hydrolyzed formula; house dust mite avoidance and immunotherapy. We appraise the available evidence base within the context of the GRADE approach. We also contextualize our findings in relation to concepts relating atopic dermatitis and individual-patient allergic life trajectories versus a linear concept of the atopic march and provide insights into future knowledge gaps and clinical trial design considerations that must be addressed in future research. Finally, we provide implementation considerations to detect population-level differences in AD risk. Major international efforts are required to provide definitive evidence regarding what works, and what does not, for preventing AD.

Utility of silver birch and house dust mite extracts derived from licensed sublingual tablets for nasal allergen challenge.

Nasal allergen challenge (NAC) is used to investigate the effects of allergen exposure and assess treatment efficacy in allergic rhinitis (AR). This study aims to establish dose-responses to NAC using licensed silver birch (SB) pollen and house dust mite (HDM) sublingual tablets as sources of the allergen extracts in participants with AR. Sixteen volunteers with HDM-induced perennial AR and 15 volunteers with SB pollen-induced seasonal rhinitis underwent a graded up-dosing NAC with extracts derived from HDM allergen (Acarizax®) and SB (Itulazax®) tablets, respectively. Total nasal symptom score (TNSS, range 0-12) and peak nasal inspiratory flow (PNIF) were recorded before, at 10min and at the end of the NAC. The dose of each allergen that provoked a TNSS of at least 7 ("provoking dose 7") in most allergic participants was identified. NACs using the "provoking dose 7" were performed on 5 non-allergic individuals to test for irritant effects. The "provoking dose 7" of HDM extract was used in a subgroup of two SB allergic, non-HDM allergic, volunteers, and vice versa for SB extract, to test for allergen specificity of the responses. Most patients experienced a TNSS of at least 7/12 at a median concentration of 1500AU/mL for both SB pollen and HDM. The average decline in PNIF at this dose was 63.15% for SB and 63.99% for HDM. NACs using the 1500AU/mL concentrations were performed on 5 non-allergic individuals with no symptomatic or PNIF response. 1500AU/mL of HDM extract produced no symptoms in SB allergics nor 1500AU/mL SB extract in HDM allergics. For both SB and HDM extracts, the optimal allergen dose for NAC to cause a moderate-severity response ("provoking dose 7/12") was 1500AU/mL. Licensed sublingual allergen tablets provide a readily available and inexpensive source of SB and HDM extracts for use in future interventional studies in AR.

CHARACTERIZATION OF THE ROLE OF ESTROGEN RECEPTORS IN EXACERBATING AIRWAY HYPERRESPONSIVENESS

Clinical, animal, and epidemiological studies have suggested a higher prevalence of asthma in women than in men, implicating the sex steroids, most importantly, the estrogen in the lungs, as a key player. Estrogen is known to act through its alpha and beta receptors located on the lungs and several researchers have reported that they play a differential role in asthma. In this study, we evaluated the receptor-specific effect of estrogen in mediating Airway Hyperresponsiveness (AHR) using the estrogen receptors knock-out mice (Esr α KO and Esr β KO). Adult (8-10 weeks old) male and female C57BL/6J (WT), Esr α KO, and Esr β KO mice (n=2/8 per group) were challenged with 50 μl of House Dust Mite (HDM) solution (25 μg of HDM extract derived from two species, Dermatophagoides pteronyssinus and Dermatophagoides farinae) or vehicle (phosphate-buffered saline, PBS) intranasally for 5 weeks. At 72 hours after the last exposure, AHR was assessed through the Methacholine challenge (MCh) of varying doses (0, 3.13, 12.5, 25, 50, 100 mg/mL) using the flexiVent rodent ventilator system (SCIREQ) and immediately followed by the collection of bronchoalveolar lavage fluid (BALF) for the preparation of cytospin slides to analyze immune cells. Data analysis was done using GraphPad Prism 10.0.3, and the P-value &lt; 0.05 was considered significant. Resistance (Rrs), Elastance (Ers), Conducting airway resistance (Rn), Tissue resistance (G), and Tissue elastance (H) were significantly increased ( P &lt; 0.05) in male and female Esr β KO induced with HDM compared to PBS. Interestingly, Esr α KO HDM-induced mice showed a significant reduction in AHR only in the males and not the females, whereas it was not significantly different in the WT (males and females) exposed to HDM or PBS-induced. However, we observed that there was no statistically significant difference at P- value &lt; 0.05 in the macrophage and lymphocyte count in the HDM-induced mice compared to the PBS in the estrogen receptor knockout mice and the WT. Eosinophil and neutrophil recruitments were observed in all the estrogen receptor knock-out groups exposed to HDM compared to the PBS but not in the WT, however, they were prominent in the Esr β KO but were not significant at P- value &lt; 0.05. In conclusion, Esr β KO mice (males and females) showed declined lung function after exposure to allergens, indicating that Esr β plays an important role in AHR and understanding the mechanisms involved would help to develop novel therapeutics for the treatment of allergic airway inflammation in females. This study was supported by the National Heart Lung and Blood Institute: R01HL159764 (PS) and R03HL141618 (PS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lanthionine synthetase C-like receptors reduce eosinophilia, type 2 immune responses and lung inflammatory pathology in mouse models of asthma

Abstract Airway hyperresponsiveness and asthma are associated with altered glucose metabolism with inhibition of anaerobic glycolysis reducing inflammation and lung eosinophilia. LANCL receptors are key focal points for metabolism in immune cells, controlling mitochondrial mass and oxidative pathways all while promoting immunoregulatory differentiation. Knockout of LANCL receptors leads to diminished Treg differentiation, altered epithelial cell metabolism and impaired phagocytic clearance, all of which can contribute to the chronicity of asthma. We developed an oral agonist for LANCL receptors and tested it within ovalbumin and house dust mite induced models of asthma in mice. Treatment in vitro with the agonist resulted in reduced differentiation of inflammatory and allergic CD4+ T cells and reduced production of inflammatory cytokines in macrophages. In the OVA model, oral treatment with an LANCL therapeutic, beginning on the second day of aerosol challenge significantly reduced neutrophilia and eosinophilia in the lung by flow cytometry and histology. LANCL treatment significantly reduced anti-OVA IgE titers and type 2 cytokines, IL-5 and IL-13. Reduction of eosinophilia and type 2 immune responses were validated in the house dust mite model. In both models, lung gene expression trends were consistent with improved pulmonary function and mitochondrial metabolism. Thus, activation of LANCL receptors is a feasible strategy for the treatment of asthma and pulmonary inflammation.

DerP1, a house dust mite protease, directly activates airway vagal afferents and induces airway hyperreactivity after chronic exposure

Airway hyperreactivity (AHR) is one of the main symptoms of allergic asthma. Current therapeutics used in the treatment of allergic asthma do not target the AHR. Airway sensory afferents have been shown to be critical in AHR, but the mechanisms remain elusive. We have previously shown that house dust mite (HDM) extract, which contains multiple different proteases, can directly activate these airway sensory afferents in the lung via PAR1 receptors. In this study we identified the most potent protease DerP1 is capable of directly and robustly activating airway sensory vagal afferents. DerP1 caused a significant release of CGRP, a neuropeptide released after nerve terminal activation, from the airways. We observed that DerP1 caused a calcium influx in 65% of TRPV1 positive lung specific neurons. We also observed that in our two-photon ex vivo imaging of the vagal ganglia of PirtCre;R26 ‐ GCaMP6s mice, DerP1 caused a robust activation of approximately 60% of naïve airway-specific C-fibers. Calcium imaging of the lung specific vagal neurons from wild type, TRPA1 KO and TRPV1 KO revealed that the DerP1 mediated activation was absent in TRPV1 KO mice neurons. We then found that mice exposed to DerP1 chronically over a period of 12 days (without an adjuvant) had significant AHR and Th2 mediated airway inflammation. Our data suggests that direct activation of airway vagal C-fiber afferents by DerP1 via TRPV1 chronically leads to airway hyperreactivity and Th2 mediated airway inflammation. Warren Alpert Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

IL-33 downregulates human IL-33 expression in the pulmonary vasculature during allergic airway inflammation

Abstract IL-33 is abundantly expressed in the human lung, where it is involved in pathogen defense, barrier homeostasis, and development of type 2 allergic responses. We recently identified a 5 kb region within a GWAS-defined segment that acts as an enhancer barrier element in vivo and in vitro. We showed that the asthma-associated SNP rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein in human plasma. To study this human regulatory region in vivo, we engineered a novel IL33 reporter mouse containing the human 5kb regulatory element to reflect human IL33 expression. As expected, human and mouse IL33 reporters were primarily expressed in non-overlapping cell types: human IL33 reporter was mostly expressed in vascular and lymphatic endothelium, while mouse IL33 reporter was expressed in ATII epithelium. Interestingly, we demonstrate negative regulation of human IL33 in lung endothelium during house dust mite (HDM)-induced allergic airway inflammation, which was dependent on the human 5kb regulatory region. Similar downregulation of endothelium IL-33 was induced with only IL-33 treatment in vivo and in vitro. We found that this IL-33-induced negative feedback loop worked through the induction of cytoplasmic IL33 mRNA instability. Together, these data reveal the importance of the asthma-associated human 5kb enhancer element in regulating human IL33 expression in a cell type- and context-dependent manner.

Clinical efficacy and safety evaluation of Dermatophagoides farinae drops in the treatment of allergic rhinitis with epistaxis.

Background. Epistaxis is frequently observed in allergic rhinitis (AR) patients. However, few studies focus on the outcome of epistaxis with treatment of AR patients. This study aimed to retrospectively analyze the efficacy and safety of AR patients with epistaxis treated with sublingual immunotherapy (SLIT). Methods. A total of 74 patients aged 4-60 years with house dust mite (HDM)-induced AR accompanied by epistaxis and who completed 1 year of SLIT treatment with standard Dermatophagoides farinae (D. farinae) drops were enrolled in this study. The symptom scores, total medication scores (TMS), combined symptom and medication score (CSMS), visual analog scales (VAS), and bleeding score (BS) were assessed, as well as the nasal endoscopic examinations were performed to observe nasal signs. Results. The levels of symptom scores, TMS, CSMS, VAS, and BS at 0.5 year and 1 year of SLIT treatment were significantly lower than those at the baseline (all p less than 0.01). Also, statistical differences were seen in CSMS (p less than 0.05) and VAS (p less than 0.01) between 0.5 year and 1 year. As expected, BS was positively correlated with CSMS (r = 0.617, 95% CI 0.517-0.699) and VAS (r = 0.777, 95% CI 0.719-0.822) at all three time points. Conclusions. SLIT with D. farinae drops was effective and safe for AR patients with epistaxis, resulting in improving the symptoms of rhinitis while relieving the symptoms of epistaxis.

LMAN1 promotes enhanced Alternaria alternata-induced airway hyperresponsiveness through alteration of alveolar macrophage and ILC2 populations

Abstract Current biologics often fail to effectively manage symptoms in severe allergic asthmatic patients, necessitating the exploration of novel therapeutic approaches. Our laboratory has recently identified LMAN1 as a novel regulatory cell surface receptor for house dust mite (HDM). Binding of LMAN1 to HDM allergens was found to depend on mannosylation, suggesting a potential broader role of this receptor in the recognition of other highly mannosylated allergens such as molds. Alternaria alternata is a ubiquitous mold often associated with severe asthma. Whether LMAN1 can also act to regulate responses to Alternaria, remains to be explored. We demonstrate that the immunodominant Alternaria allergen Alt a 1 can also bind to purified Fc-LMAN1, indicating potential involvement of this receptor. Thus, we subjected both WT and LMAN1 knockout mice to an Alternaria alternata-induced asthma model. The absence of LMAN1 resulted in a substantial increase in airway hyperresponsiveness (AHR) compared to WT animals. Interestingly, changes in AHR did not correlate with enhanced eosinophilia but, instead, went hand in hand with a reduction in alveolar macrophages and an increase in type-2 innate lymphoid cells. Work is currently ongoing to further investigate the cellular and molecular mechanisms underlying these findings. This discovery highlights LMAN1 as a promising target for innovative therapeutic interventions.

SREBP signaling is important for pathogenic B cell responses in allergy.

Abstract Severe IgE antibody-mediated allergic conditions impacts millions worldwide, significantly influencing both the survival and quality of life of those affected. Our previous research indicated the critical role of sterol regulatory element-binding protein (SREBP) signaling in mediating lipid homeostasis during B cell activation and the formation of germinal centers following immunization and viral infection. However, it remained unclear whether this pathway is also involved in the pathogenic B cell responses triggered by chronic allergen sensitization. Our latest findings show that ablation of SREBP signaling in B cells doesn't affect overall IgE levels in the serum. However, during chronic sensitization to house dust mites (HDM), SREBP signaling was essential for allergen-triggered germinal center responses and pathogenic antibody production. These results suggest the potential of targeting the B cell SREBP pathway as a treatment approach for allergies.

Distributional Characteristics Analysis of Allergens in Patients with Allergic Rhinitis in Southern Fujian Province, China.

Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa. However, few studies focus on the distributional characteristics of allergens in AR patients in Southern Fujian Province, China. A skin prick test (SPT) was performed and eight common allergens including Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dpt), weeds, animal dander, molds, cockroaches, and mangoes were chosen. The positive reactions rate to the allergens was 65.79% in 6689 patients in Southern Fujian Province. Positive reactions to Df and Dpt had a negative association with age, whereas positive reactions to cockroach and weed had a positive association with age. A linear trend analysis demonstrated a significant positive relationship between positive reactions to various allergens from 2016 to 2019. Positive reactions to Df and Dpt were both correlated with the season. Positive reactions to Df, Dpt, cockroach and weed were related to disease duration and positive reactions to cockroach were correlated with city residence. Multivariate analysis revealed that male positive reactions gradually decreased with age (≤ 60), in contrast to female (≤ 60) positive reactions. Statistical difference was observed between the genders with regard to AR incidence from 2016 to 2019. The positive rate of skin tests was highest in summer in men, whereas in women it was lowest in summer. The gender composition ratios of positive cases in Xiamen, Zhangzhou, and Quanzhou cities differed significantly. The proportion of patients with positive reactions to the allergens in the three cities decreased with age. The highest proportions of patients with positive reactions all occurred during summer in the three cities. Furthermore, there were statistically significant differences in the age composition ratios across the seasons. This study analyzed the distributional characteristics of AR allergens in Southern Fujian Province, China. These findings will inform specific immunotherapy for AR patients.