Aspergillus fumigatus binding IgA and IgG1 are increased in bronchoalveolar lavage fluid of horses with neutrophilic asthma.

Introduction: Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute exacerbation of clinical signs and sustained local neutrophilic inflammation in susceptible horses. Aspergillus fumigatus is an EA stimulus, but it is unclear if it merely acts as an IgE-provoking allergen. We aimed to comprehensively analyze immunoglobulin (Ig) isotypes in EA, elucidating their binding to different A. fumigatus antigens, and their quantities systemically in serum and locally in bronchoalveolar lavage fluid (BALF). Methods: Serum and BALF from healthy horses (HE, n = 18) and horses with mild-moderate asthma (MEA, n = 20) or severe asthma (SEA, n = 24) were compared. Ig isotype (IgG1, IgG3/5, IgG4/7, IgG6, IgA, and IgE) binding to nine antigens (A. fumigatus lysate, and recombinant Asp f 1, Asp f 7, Asp f 8, dipeptidyl-peptidase 5, class II aldolase/adducin domain protein, glucoamylase, beta-hexosaminidase, and peptide hydrolase) was compared by enzyme-linked immunosorbent assays. Total Ig isotype contents were determined by bead-based assays. Results: MEA and SEA differed from HE but hardly from each other. Compared to HE, asthmatic horses showed increased anti-A. fumigatus binding of IgG (BALF and serum) and IgA (BALF). Serum and BALF IgE binding and total IgE contents were similar between HE and EA. Single antigens, as well as A. fumigatus lysate, yielded similar Ig binding patterns. Serum and BALF IgG1 binding to all antigens was increased in SEA and to several antigens in MEA. Serum IgG4/7 binding to two antigens was increased in SEA. BALF IgA binding to all antigens was increased in SEA and MEA. Total BALF IgG1 and IgG4/7 contents were increased in SEA, and serum IgG4/7 content was increased in MEA compared to HE. Yet, total isotype contents differentiated EA and HE less clearly than antigen-binding Ig. Discussion: A. fumigatus immunogenicity was confirmed without identification of single dominant antigens here. A. fumigatus provoked elevated BALF IgG1 and IgA binding, and these isotypes appear relevant for neutrophilic EA, which does not support allergy. BALF Ig isotype differentiation beyond IgE is crucial for a comprehensive analysis of immune responses to fungi in EA pathogenesis.

NRF2 is a spatiotemporal metabolic hub essential for the polyfunctionality of Th2 cells.

Upon encountering allergens, CD4+ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.

Respiratory infection- and asthma-prone, low vaccine responder children demonstrate distinct mononuclear cell DNA methylation pathways.

BACKGROUND: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunizations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation. Peripheral blood mononuclear cells from respiratory infection allergy/asthma-prone (IAP) infants and non-infection allergy/asthma prone (NIAP) were retrospectively selected for genome-wide DNA methylation and single nucleotide polymorphism analysis. The IAP infants were enriched for the low vaccine responsiveness (LVR) phenotype (Fisher's exact p-value = 0.02). RESULTS: An endotype signature of 813 differentially methylated regions (DMRs) comprising 238 lead CpG associations (FDR < 0.05) emerged, implicating pathways related to asthma, mucin production, antigen presentation and inflammasome activation. Allelic variation explained only a minor portion of this signature. Stimulation of mononuclear cells with monophosphoryl lipid A (MPL), a TLR agonist, partially reversed this signature at a subset of CpGs, suggesting the potential for epigenetic remodeling. CONCLUSIONS: This proof-of-concept study establishes a foundation for precision endotyping of IAP children and highlights the potential for immune modulation strategies using adjuvants for future investigation.

Multiarray screening identifies plasma proteins associated with Th17 cell differentiation and viral defense in coincident asthma and obesity.

BACKGROUND: The immunological mechanisms behind the clinical association between asthma and obesity in adolescence are not fully understood. This study aimed to find new plasma protein biomarkers associated specifically with coincident asthma and obesity in adolescents. METHODS: This was a cross-sectional study in children and adolescents 10-19 years old (N = 390). Relative plasma concentrations of 113 protein biomarkers related to inflammation and immune response were determined by proximity extension assay (Target 96; Olink, Uppsala, Sweden). Differences in protein concentrations between healthy controls (n = 84), subjects with asthma (n = 138), subjects with obesity (n = 107), and subjects with both asthma and obesity (AO; n = 58) were analyzed by ANCOVA, adjusting for age and sex, and in a separate model adjusting also for the sum of specific IgE antibody concentrations to a mix of food allergens (fx5) and aeroallergens (Phadiatop). Proteins elevated in the AO group but not in the obesity or asthma groups were considered specifically elevated in asthma and obesity. RESULTS: Five proteins were elevated specifically in the AO group compared to controls (here sorted from largest to smallest effect of asthma and obesity combined): CCL8, IL-33, IL-17C, FGF-23, and CLEC7A. The effects of adjusting also for specific IgE were small but IL-33, IL-17C, and FGF-23 were no longer statistically significant. CONCLUSION: We identified several new potential plasma biomarkers specifically elevated in coincident asthma and obesity in adolescents. Four of the proteins, CCL8, IL-33, IL-17C, and CLEC7A, have previously been associated with viral mucosal host defense and Th17 cell differentiation.

Jolkinolide B attenuates allergic airway inflammation and airway remodeling in asthmatic mice.

Asthma is a widely prevalent chronic disease that brings great suffering to patients and may result in death if it turns severe. Jolkinolide B (JB) is one diterpenoid component separated from the dried roots of Euphorbia fischeriana Steud (Euphorbiaceae), and has anti--inflammatory, antioxidative, and antitumor properties. However, the detailed regulatory role and associated regulatory mechanism in the progression of asthma remain elusive. In this work, it was demonstrated that the extensive infiltration of bronchial inflammatory cells and the thickening of airway wall were observed in ovalbumin (OVA)-induced mice, but these impacts were reversed by JB (10 mg/kg) treatment, indicating that JB relieved the provocative symptoms in OVA-induced asthma mice. In addition, JB can control OVA-triggered lung function and pulmonary resistance. Moreover, JB attenuated OVA-evoked inflammation by lowering the levels of interleukin (IL)-4, IL-5, and IL-13. Besides, the activated nuclear factor kappa B (NF-κB) and transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGFß/smad3) pathways in OVA-induced mice are rescued by JB treatment. In conclusion, it was disclosed that JB reduced allergic airway inflammation and airway remodeling in asthmatic mice by modulating the NF-κB and TGFß/smad3 pathways. This work could offer new opinions on JB for lessening progression of asthma.

[Molecular allergen IgE tests show neosensitizaions occurring during house dust mite specific immunotherapy].

Objective:Neosensitizations may be occur during the allergen specific immunotherapy（AIT） due to the differences between allergen vaccine's content and a patient's molecular sensitization profile. This study investigates whether AIT with HDM extract changes the sensitization profile, whether de novo sensitization occurs, and the clinical importance of the neosensitization. Methods:Fifty-three patients with HDM allergic rhinitis ,with/without asthma, patients were received one year HDM subcutaneous AIT . Fourteen patients were recruited as control group and received only necessary medications. Serum samples were collected at baseline, 6thmoths and 12thof AIT, respectively. Serum samples were tested specific IgE against Der p, Der p 1/2/3 and Der f, Der f 1/2/3, as well as IgG4 against Der p, Der p 1/2 and Der f, Der f 1/2. VAS were collected at the time-points as well. Results:In AIT group, Der p, Der p 1/3, and Der f 1/3 specific IgE levels were significantly higher after one-year treatment, especially for Der p 3. There were 69.2%（18/26） patients whose Der p 3 specific IgE below 0.35 kU/L at baseline but became positive（>0.35 kU/L） after treatment, that is, neosensitization occurred. All tested allergen specific IgG4 level significantly increased after one year AIT treatment and the VAS declined dramatically. However, for patients with neosensitization and without neosensitization, there were no significantly changes concerning to IgG4 level and VAS. Conclusion:Patients undergoing AIT might have a risk of neosensitization to the allergen components in the vaccines. However, the clinical importance of the neosensitization remains unclear and warrants further studies.

Helicobacter pylori Infection Does Not Protect Against Allergic Diseases: Evidence From a Pediatric Cohort From Northern Sardinia, Italy.

BACKGROUND: The "hygiene hypothesis" states that reduced exposure to microbial antigens due to an excessively hygienic environment can increase the risk of developing autoimmune diseases, including atopic disorders and asthma. In recent decades, there has been a progressive decline in the prevalence of numerous microorganisms following improved hygienic-sanitary conditions. More specifically, several studies reported an inverse association between the reduction in Helicobacter pylori infection and the rise of asthma and allergic disorders. AIM: To evaluate the prevalence of atopic disorders in a pediatric population in relation to seropositivity against H. pylori. METHODS: Children from Northern Sardinia, Italy, referred to the local Children's Hospital for any reason, were investigated to identify risk factors, especially H. pylori infection, associated with atopic disorders. A validated questionnaire, including demographics, house size, history of breastfeeding, residence, school or daycare center attendance, exposure to animals, and a defined diagnosis of atopy-including asthma-was filled out by a trained pediatrician according to parents' answers and child records. A blood sample was collected from each participant and immunoglobulin G against H. pylori was assessed by a locally validated ELISA test. RESULTS: The seroprevalence of H. pylori infection was 11.7% among 492 children (240 females). Thirty-two children had a confirmed diagnosis of asthma and 12 of allergy. No one child showed both conditions. Statistically significant differences in H. pylori seropositivity were not detected between children with or without atopy (8.4% vs. 12.6; p = 0.233). Although atopic disorders were more frequent in children exposed to traditional atopic risk factors, none of them showed to be significant after adjusting for all covariates. CONCLUSIONS: Serologically assessed H. pylori infection was not significantly associated with a reduced risk of atopic diseases in children.

AdipoRon, an adiponectin receptor agonist, modulates AMPK signaling pathway and alleviates ovalbumin-induced airway inflammation in a murine model of asthma.

Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11th day till the 16th and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5'AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.

The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation.

Introduction: Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm. Methods and results: We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages. In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo. Discussion: Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma.

SCGB1C1 Plays a Critical Role in Suppression of Allergic Airway Inflammation through the Induction of Regulatory T Cell Expansion.

The nanosized vesicles secreted from various cell types into the surrounding extracellular space are called extracellular vesicles (EVs). Although mesenchymal stem cell-derived EVs are known to have immunomodulatory effects in asthmatic mice, the role of identified pulmonary genes in the suppression of allergic airway inflammation remains to be elucidated. Moreover, the major genes responsible for immune regulation in allergic airway diseases have not been well documented. This study aims to evaluate the immunomodulatory effects of secretoglobin family 1C member 1 (SCGB1C1) on asthmatic mouse models. C57BL/6 mice were sensitized to ovalbumin (OVA) using intraperitoneal injection and were intranasally challenged with OVA. To evaluate the effect of SCGB1C1 on allergic airway inflammation, 5 µg/50 µL of SCGB1C1 was administrated intranasally before an OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), the cytokine profiles of BALF and lung-draining lymph nodes (LLN), and the T cell populations in LLNs. The intranasal administration of SCGB1C1 significantly inhibited AHR, the presence of eosinophils in BALF, eosinophilic inflammation, goblet cell hyperplasia in the lung, and serum total and allergen-specific IgE. SCGB1C1 treatment significantly decreased the expression of interleukin (IL)-5 in the BALF and IL-4 in the LLN, but significantly increased the expression of IL-10 and transforming growth factor (TGF)-ß in the BALF. Furthermore, SCGB1C1 treatment notably increased the populations of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in asthmatic mice. The intranasal administration of SCGB1C1 provides a significant reduction in allergic airway inflammation and improvement of lung function through the induction of Treg expansion. Therefore, SCGB1C1 may be the major regulator responsible for suppressing allergic airway inflammation.

Association between protein intake, serum albumin and blood eosinophil in US asthmatic adults.

Background: Presently, numerous studies have indicated that protein consumption and levels of blood albumin serve as important biomarkers for a range of respiratory illnesses. However, there have been few investigations into the correlation between protein consumption, serum albumin, and asthma. Methods: Our analysis incorporated 2509 asthmatics from the 2011-2018 NHANES dataset. The investigation employed three linear regression models and XGBoost model to investigate the potential link between protein intake, serum albumin levels, and blood eosinophil counts (BEOC) in patients with asthma. The trend test, generalized additive model (GAM), and threshold effect model were utilized to validate this correlation. As well, we undertook stratified analyses to look at the correlation of serum albumin with BEOC among distinct populations. Results: In the univariable regression model, which did not account for any covariates, we observed a positive correlation between protein intake and BEOC. However, univariable and multivariable regression analyses all suggested a negative connection of serum albumin with BEOC in asthma populations. In Model C, which took into account all possible factors, BEOC dropped by 2.82 cells/uL for every unit increase in serum albumin (g/L). Additionally, the GAM and threshold effect model validated that serum albumin and BEOC showed an inverted U-shaped correlation. Conclusion: Our investigation discovered there was no independent link between asthmatics' protein intake and BEOC. However, we observed an inverted U-shaped relationship between serum albumin levels and BEOC, suggesting a possible relationship between the overall nutritional status of asthmatics and immune system changes. Our findings provide new directions for future research in the field of asthma management and therapy.

[Preventive effects of allergen immunotherapy to pneumallergens]. / Prévention des manifestations allergiques par une immunothérapie aux pneumallergènes.

Allergen immunotherapy is still the only curative treatment for respiratory allergies. It is based on repeated administration of allergenic extracts to sensitized patients. It can be administered either by subcutaneous or by sublingual route. The purpose of the treatment is to modulate the immune response to a specific allergen and to alter the course of the disease over a long-term period. Numerous studies and meta-analyses have demonstrated its efficacy in terms of symptoms and quality of life improvement as well as reduction of the allergic march. Indication of allergen immunotherapy includes moderate to severe allergic rhinitis and mild to moderate allergic asthma from GINA step 3. Early intervention in sensitized patients is nowadays promoted.

L'immunothérapie allergénique représente, encore aujourd'hui, le seul traitement curatif des allergies respiratoires. Elle consiste en l'administration répétée d'extraits allergéniques auxquels le patient est allergique. Elle peut se faire par voie sous-cutanée ou sublinguale. L'objectif est de moduler la réponse immunitaire afin de réduire les symptômes de l'allergie et de modifier le cours de la maladie allergique avec des effets perdurant sur le long terme. De nombreuses études et méta-analyses ont prouvé son efficacité en termes d'amélioration symptomatique, d'amélioration de la qualité de vie mais également de la réduction de l'évolution de la marche allergique. L'immunothérapie allergénique est indiquée dans le traitement de la rhinite allergique modérée à sévère et de l'asthme allergique dès le palier 3 du GINA («Global Initiative for Asthma¼). Une utilisation plus précoce est de plus en plus mise en avant pour bénéficier des effets préventifs de la modulation immunitaire.

IgE-Mediated Sensitization to Blo t 21 and Blo t 5 Is Associated With Asthma in the Tropics: A Case-Control Study.

BACKGROUND AND OBJECTIVE: Sensitization to Blomia tropicalis is associated with asthma in various tropical and subtropical countries; however, information about the specific molecular components associated with this disease is scarce. Using molecular diagnosis, we sought to identify B tropicalis allergens associated with asthma in Colombia. METHODS: Specific IgE (sIgE) to 8 B tropicalis recombinant allergens (Blo t 2, 5, 7, 8, 10, 12, 13, and 21) was determined using an in-house ELISA system in asthma patients (n=272) and controls (n=298) recruited in a national prevalence study performed in several Colombian cities (Barranquilla, Bogotá, Medellín, Cali, and San Andrés). The study sample included children and adults (mean [SD] age, 28 [17] years). Cross-reactivity between Blo t 5 and Blo t 21 was evaluated using ELISA-inhibition. RESULTS: Specific IgE (sIgE) to 8 B tropicalis recombinant allergens (Blo t 2, 5, 7, 8, 10, 12, 13, and 21) was determined using an in-house ELISA system in asthma patients (n=272) and controls (n=298) recruited in a national prevalence study performed in several Colombian cities (Barranquilla, Bogotá, Medellín, Cali, and San Andrés). The study sample included children and adults (mean [SD] age, 28 [17] years). Cross-reactivity between Blo t 5 and Blo t 21 was evaluated using ELISA-inhibition. CONCLUSION: Although Blo t 5 and Blo t 21 are considered common sensitizers, this is the first report of their association with asthma. Both components should be included in molecular panels for diagnosis of allergy in the tropics.

Effect of dupilumab on asthma and aeroallergen sensitization in pediatric atopic dermatitis patients: Results of the BioDay registry.

BACKGROUND: Atopic dermatitis (AD) is frequently associated with asthma and allergic rhinitis (AR). Dupilumab is an effective treatment for pediatric AD, although the effect on atopic comorbidities in pediatric AD patients is limited. OBJECTIVE: To investigate the prevalence of asthma and AR in pediatric AD patients starting dupilumab treatment and to evaluate the effect of dupilumab on these comorbidities. METHODS: This study included pediatric AD patients (aged 3-17 years) treated with dupilumab between 2019 and 2023. Patients were screened at baseline by a pulmonologist for the presence of asthma and AR. Screening included evaluation of medical history and current symptoms, spirometry (including Forced Expiratory Volume in 1 s (FEV1)), Fractional exhaled Nitric Oxide (FeNO), and measurement of aeroallergen-specific IgE levels. In patients diagnosed with comorbid asthma and/or AR, measurements were repeated at weeks 16 and 52. Spirometry measurements, FeNO, and aeroallergen-specific IgE levels during treatment were analyzed using a covariance pattern model. RESULTS: Eighty-four patients were included. Asthma was diagnosed in 50 patients (59.5%) and AR in 72 patients (85.7%). Baseline FeNO levels were elevated in both patients with (29.0 ppb (95% CI 22.0-54.0)) and without asthma (26.0 ppb (95% CI 22.0-30.0)). During treatment, FeNO levels decreased (p < .001) and FEV1 scores increased (p < .001) in patients with asthma. In patients with asthma and/or AR, all aeroallergen-specific IgE levels decreased between 61.3% and 89.1% at 52 weeks of treatment. CONCLUSION: One year of dupilumab treatment, primarily indicated for AD, resulted in a significant improvement in comorbid asthma and a profound decrease in aeroallergen-specific IgE levels in patients with asthma and/or AR.

Succinate coenzyme A ligase ß-like protein from Trichinella spiralis is a potential therapeutic molecule for allergic asthma.

BACKGROUND: For decades, studies have demonstrated the anti-inflammatory potential of proteins secreted by helminths in allergies and asthma. Previous studies have demonstrated the immunomodulatory capabilities of Succinate Coenzyme A ligase beta-like protein (SUCLA-ß) derived from Trichinella spiralis, a crucial excretory product of this parasite. OBJECTIVE: To explore the therapeutic potential of SUCLA-ß in alleviating and controlling ovalbumin (OVA)-induced allergic asthma, as well as its influence on host immune modulation. METHODS: In this research, we utilized the rTs-SUCLA-ß protein derived from T. spiralis to investigate its potential in mitigating airway inflammation in a murine model of asthma induced by OVA sensitization/stimulation, both pre- and post-challenge. The treatment's efficacy was assessed by quantifying the extent of inflammation in the lungs. RESULTS: Treatment with rTs-SUCLA-ß demonstrated efficacy in ameliorating OVA-induced airway inflammation, as evidenced by a reduction in eosinophil infiltration, levels of OVA-specific Immunoglobulin E, interferon-γ, interleukin (IL)-9, and IL-17A, along with an elevation in IL-10. The equilibrium between Th17 and Treg cells plays a pivotal role in modulating the abundance of inflammatory cells within the organism, thereby ameliorating inflammation and alleviating symptoms associated with allergic asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Our data revealed that T. spiralis-derived Ts-SUCLA-ß protein may inhibit the allergic airway inflammation by regulating host immune responses.

The New Paradigm: The Role of Proteins and Triggers in the Evolution of Allergic Asthma.

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action-eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen-immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients.

Innate immune responses are increased in children with acute asthma exacerbation.

BACKGROUND: Little is known about the immune responses during acute asthma exacerbation. In this study, we examined immune responses in children following an acute asthma exacerbation. METHODS: We evaluated pro-inflammatory cytokine levels and gene expression profiles in blood samples from pediatric patients admitted for acute asthma exacerbation. Viral PCR was performed to differentiate between viral or non-viral-associated exacerbations. RESULTS: Following informed consent, clinical data were obtained from 20 children with asthma (median [interquartile range, IQR]: age 11.5 [8.0, 14.2]) years and 14 healthy age-matched controls (10.5 [7.0, 13.0]). Twelve had positive nasopharyngeal Polymerase chain reaction (PCR) for viral infection (11 rhinoviruses and 1 respiratory syncytial virus (RSV)). Nine were in the pediatric intensive care unit (PICU) and among them five required continuous positive airway pressure (CPAP). Mean (±SD) days on systemic steroids before drawing blood sample were 2.5 ± 1.6. Twelve had history of environmental allergies with 917 (274, 1396) IU/mL total IgE (median (IQR)). Compared with controls, IL-1RA and IL-10 levels were significantly increased and TNF-α significantly decreased in asthma subjects (p < .05 for all). RNA-seq analysis revealed 852 differentially expressed genes in subjects with asthma. Pathway analysis found upregulated genes and pathways involved in innate immune responses in subjects with asthma. Significantly reduced genes included pathways associated with T helper cell differentiation and activation. CONCLUSIONS: In acute asthma exacerbation, innate immune pathways remained increased while adaptive immune responses related to T helper cells are blunted and are independent of trigger or asthma severity. Our novel findings highlight the need to identify new therapies to target persistent innate immune responses to improve outcomes in acute asthma.