Allergic Airway Disease Research Articles

Profile of immune response during nasal challenge with dermatophagoides pteronyssinus in subjects with allergic airway diseases

BackgroundT lymphocyte helper (Th) 2 plays the main role in pathogenesis of allergic airway diseases (AAD). Recent studies showed that interleukin (IL) 33, Th17 and Th22 also may be involved in allergic inflammation. The aim is to evaluate cytokine level before and after nasal challenge with Dermatophagoides pteronyssinus in patients with AAD.MethodsPatients with persistent allergic rhinitis (AR) with or without allergic asthma (AA) allergic to house dust mite and healthy individuals underwent nasal challenge with Dermatophagoides pteronyssinus. Measurements of IL-13, IL-17, IL-22 and IL-33 in serum and nasal lavage were performed before, 2 and 22 h after nasal challenge by ELISA.Results. Ten patients with AR only, 6 patients with AR and AA and 7 healthy individuals were involved in the study. Serum IL-22 level significantly increased in patients with AR and AA and nasal lavage IL-22 tended to increase in patients with AAD after nasal challenge. Serum IL-13 level tended to increase in patients with AR and AA. IL-13 level in nasal lavage fluid decreased at 22 h after nasal challenge in patients with AR only. IL-17 level in serum and nasal lavage decreased in patients with AAD. Serum IL-33 tended to increase after nasal challenge whereas IL-33 in nasal lavage significantly decreased.ConclusionCytokine profile differs between local and systemic compartments and between patients with allergic rhinitis only and patients with allergic rhinitis and asthma after nasal challenge.

House dust mite allergen directly activates ILC2 cells via the TLR4 signaling pathway in allergic airway diseases

BackgroundUnlike T cells and B cells, the activation process of group 2 innate lymphoid cells (ILC2s) is mainly driven by epithelial cell derived cytokines rather than specific antigen recognition. Whether antigens have a direct role in activating ILC2s remains poorly understood. MethodsFollowing stimulation, type 2 cytokine secretions and cell death were assessed in house dust mite (HDM)-stimulated ILC2s. To investigate the underlying mechanisms, RNA-sequencing (RNA-seq) was performed on HDM-stimulated ILC2s. The validation experiments were done through in vitro stimulation assays and an HDM-induced asthmatic murine model, using specific inhibitors targeting receptor and relevant proteins of signaling pathways. ResultsHDM stimulation increased the secretion of IL-5 and IL-13 cytokines from ILC2s, inhibited apoptosis of ILC2, and promoted the proliferation of ILC2s. As confirmed by RNA-seq, HDM stimulation upregulated genes in ILC2s, including those responsible for type 2 cytokines, ILC2s-specific transcriptional factors, and related receptors. Both toll-like receptor (TLR) 1 and TLR4 were constitutively expressed on ILC2s, however, only TLR4 was predominantly upregulated upon HDM stimulation. TAK242, a specific TLR4 inhibitor, significantly blocked the effect of HDM on ILC2s, in terms of type 2 cytokine secretions and cell death. Using specific inhibitors in pathways, we confirmed that HDM promoted ILC2s activation via TLR4-ERK, p38, and NF-κB signaling pathways. ConclusionsAllergen HDM directly activates ILC2s through TLR4 mediated-ERK/p38/NF-κB signaling pathway. These findings provide new insights into how antigens propagate type 2 immune response via ILC2s, contributing to chronic inflammations in allergic airway diseases.

Cell-Specific Contribution of IL4 Receptor α Signaling Shapes the Overall Manifestation of Allergic Airway Disease.

IL-4 and IL-13 play a critical role in allergic asthma pathogenesis via their common receptor, i.e., IL4Rα. However, the cell-specific role of IL4Rα in mixed allergens (MA)-induced allergic asthma has remained unclear. Therefore, we aimed to identify the cell-specific contribution of IL4Rα signaling in the manifestation of various pathological outcomes in mice with allergic airway disease. We compared MA-induced pathological outcomes between hematopoietic progenitor cells (HPCs)- or non-HPCs-specific IL4Rα-deficient chimera, myeloid cell-specific IL4Rα-deficient (LysMcre+/+/IL4Rαfl/fl), and airway epithelial cell-specific IL4Rα-deficient (CCSP-Cre+ /IL4Rαfl/fl) mice. Chimeric mice with systemic IL4Rα sufficiency displayed hallmark features of allergic asthma, including eosinophilic and lymphocytic infiltration, type 2 (Th2) cytokine/chemokine production, IgE production, and lung pathology. These features were markedly reduced in chimeric mice with systemic IL4Rα deficiency. Non-HPCs-specific IL4Rα-deficient mice displayed typical inflammatory features of allergic asthma but with markedly reduced mucous cell metaplasia (MCM). Deletion of IL4Rα signaling on airway epithelial cells, a subpopulation within the non-HPC lineage, resulted in almost complete absence of MCM. In contrast, all features of allergic asthma except for MCM and mucin production were mitigated in HPCs-specific IL4Rα-deficient chimeric mice. Deleting IL4Rα signaling in myeloid cells, a subpopulation within the HPC lineage, significantly alleviated MA-induced allergic airway inflammatory responses, but similar to the HPCs-specific IL4Rα-deficient chimeric mice, these mice showed significant MCM and mucin production. Our findings demonstrate that the differential allergen responsiveness seen in mice with HPCs-specific and non-HPCs-specific IL4Rα deficiency is predominantly driven by the absence of IL4Rα in myeloid cells and airway epithelial cells, respectively. Our findings also highlight distinct and mutually exclusive roles of IL4Rα signaling in mediating pathological outcomes within the myeloid and airway epithelial cell compartments.

Withaferin A reduces pulmonary eosinophilia and IL-25 production in a mouse model of allergic airways disease.

Several studies report that ashwagandha, a traditional Ayurvedic supplement, has anti-inflammatory properties. Type 2 (T2) asthma is characterized by eosinophilic airway inflammation. We hypothesized that allergen-induced eosinophilic airway inflammation in mice would be reduced following administration of Withaferin A (WFA), the primary active phytochemical in Ashwagandha. C57BL/6J mice were given 10 total intra-peritoneal injections of 2 mg/kg WFA or vehicle control, concurrent with 6 total intranasal administrations of 50 µg house dust mite extract (HDM) or saline control over 2 weeks. We observed that treatment with WFA reduced allergen-induced peribronchial inflammation and airway eosinophil counts compared to mice treated with controls. In addition, we observed that treatment with WFA reduced lung levels of interleukin-25 (IL-25) but increased lung gene expression levels of its co-receptor, Il17ra , in HDM-challenged mice compared to HDM-challenged mice that received the vehicle control. This study pinpoints a potential mechanism by which WFA modulates allergen-induced airway eosinophilia via the IL-25 signaling pathway. Future studies will investigate the effects of WFA administration on lung eosinophilia and IL-25 signaling in the context of chronic allergen-challenge.

Study of the role of genes involved in the metabolism of histamine in the development of allergic respiratory diseases

The interaction of genetic, epigenetic and environmental factors underlies the pathogenesis of allergic diseases. Allergic rhinitis and atopic bronchial asthma are closely related and often concurrent respiratory allergic diseases. The chronic recurrent course of these diseases establishes the importance of further and more profound studies of the mechanisms underlying the development of these pathologies. Histamine is one of the most significant inflammatory mediators secreted during allergic reactions. The aim of the research was to study the role of polymorphic variants of AOC1, HRH2, HRH3, ALDH7A1, ADCYAP1, HNMT, PSAP, SCG3, genes involved in the histamine metabolism in the development of different endophenotypes of the allergic airway diseases in individuals living in the Republic of Bashkortostan. DNA samples of 358 individuals with allergic diseases of the respiratory tract of different ethnicity (Russians – 165, Tatars – 143, Bashkirs – 50) and 200 controls with unweighted heredity in allergic diseases (Russians – 75, Tatars – 83, Bashkirs – 42). Genotyping of polymorphic variants was performed by real-time PCR and PCR-RFLP analysis. It was revealed that the rs104979793*CC genotype and the rs104979793*C allele of the AOC1 gene were associated with allergic diseases of the respiratory tract and asthma with concomitant allergic rhinitis in Russians. A significant increase of total IgE level was revealed in Russian patients with allergic diseases of the respiratory tract with the rs1049793*CC genotype of the AOC1 gene compared to carriers of the rs1049793*CG and rs1049793*GG genotypes. The association of the C allele of the rs17525472 polymorphic variant localized near the SCG3 gene with allergic rhinitis in Russians was established. The results revealed that AOC1 and SCG3 genes involved in the metabolism of histamine are related to the development of different endophenotypes of airway diseases in children.

E-cigarette Vapor Extract Alters Human Eosinophil Gene Expression in an Effect Mediated by Propylene glycol, Glycerin, and Nicotine.

E-cigarette use has become widespread, and its effects on airway inflammation and disease are not fully delineated. E-cigarette vapor extract (EVE) profoundly affects neutrophil function. We hypothesized that EVE also alters eosinophil function and thus could impact allergic airways disease. We employed RNA-sequencing to measure the ex vivo effect of EVE components on human eosinophil transcription. Blood eosinophils from 9 non-vaping subjects without asthma were isolated by negative selection. Cells were incubated for 48 hours with EVE consisting of glycerin, propylene glycol and nicotine (EVE+), EVE without nicotine ("EVE-"), air-exposed media termed Extract Buffer (EB), or untreated media. Bulk RNA-sequencing was performed. Transcriptomic analysis revealed that the EB, EVE-, and EVE+ conditions showed highly variable gene expression with respect to No Treatment and each other. Differential gene expression analysis comparing a combination of EVE+, EVE-, and EB revealed 3,030 differentially expressed genes (DEG) with adjusted p value < 0.05 and log2 fold change >0.5 or <0.5. There were 645 DEG between EB and EVE-, 1,713 between EB and EVE+, and 404 between EVE- and EVE+. Gene set enrichment analysis demonstrated that DEG between both EVE+ and EVE- and the EB control were positively enriched for heme metabolism and apoptosis and negatively enriched TNFα signaling, IFNγ signaling, and inflammatory response. Thus, EVE significantly alters eosinophil metabolic and inflammatory pathways, mediated by propylene glycol and glycerin with both enhancing and unique effects of nicotine. This study motivates further research into the pathogenic effects of vaping on airway eosinophils and allergic airways disease.

Causal Effects of Asthma on Upper Airway Diseases and Allergic Diseases: A Two-Sample Mendelian Randomization

Introduction: Asthma is associated with upper airway diseases and allergic diseases; however, the causal effects need to be investigated further. Thus, we performed this two-sample Mendelian randomization (MR) analysis to explore and measure the causal effects of asthma on allergic rhinitis (AR), vasomotor rhinitis (VMR), allergic conjunctivitis (AC), atopic dermatitis (AD), and allergic urticaria (AU). Methods: The data for asthma, AR, VMR, AC, AD, and AU were obtained from large-scale genome-wide association studies summarized recently. We defined single-nucleotide polymorphisms satisfying the MR assumptions as instrumental variables. Inverse-variance weighted (IVW) approach under random-effects was applied as the dominant method for causal estimation. The weighted median approach, MR-Egger regression analysis, MR pleiotropy residual sum and outlier test, and leave-one-out sensitivity analysis were performed as sensitivity analysis. Horizontal pleiotropy was measured using MR-Egger regression analysis. Significant causal effects were attempted for replication and meta-analysis. Results: We revealed that asthma had causal effects on AR (IVW, odds ratio [OR] = 1.93; 95% confidence interval [CI], 1.74−2.14; p < 0.001), VMR (IVW, OR = 1.40; 95% CI, 1.15−1.71; p < 0.001), AC (IVW, OR = 1.65; 95% CI, 1.49−1.82; p < 0.001), and AD (IVW, OR = 2.13; 95% CI, 1.82−2.49; p < 0.001). No causal effect of asthma on AU was observed. Sensitivity analysis further assured the robustness of these results. The evaluation of the replication stage and meta-analysis further confirmed the causal effect of asthma on AR (IVW OR = 1.81, 95% CI 1.62–2.02, p < 0.001), AC (IVW OR = 1.44, 95% CI 1.11–1.87, p < 0.001), and AD (IVW OR = 1.85, 95% CI 1.42–2.41, p < 0.001). Conclusions: We revealed and quantified the causal effects of asthma on AR, VMR, AC, and AD. These findings can provide powerful causal evidence of asthma on upper airway diseases and allergic diseases, suggesting that the treatment of asthma should be a preventive and therapeutic strategy for AR, VMR, AC, and AD.

Sex-based differences in severity of chronic rhinosinusitis as reported by SNOT-22 scores

ObjectivesChronic rhinosinusitis (CRS) is a widely prevalent condition, however its degree of severity according to sex requires further study. The literature shows that sex-based differences exist in the severity of asthma and allergic airway disease in the population. These findings point to a potential hormonal cause for this difference, but there is no study suggesting the role of sex in CRS with nasal polyps (CRSwNP). The purpose of this study was to examine the association of sex and CRSwNP severity in the United States. MethodsThis study was conducted on data gathered from 181 participants in the NAVIGATE I and NAVIGATE II randomized control trials within the OPTINOSE database. Participants were analyzed based on sex controlling for airway-related comorbidities, including history of asthma, race, and ethnicity. SNOT-22 scores were assessed as a quality-of-life outcome measure for CRS. The association between sex and SNOT-22 scores was determined using multiple linear regression. ResultsThere were 81 female and 100 male participants. SNOT-22 scores were significantly higher in females. The average reported SNOT-22 score was 53.8 ± 16.5 in females and 46.8 ± 18.8 in males. On adjusted regression, the association of sex and SNOT-22 scores approached but didn't reach significance (β: −4.97; 95 % CI: −10.68–0.73; p = 0.09). ConclusionsOn average, females had more severe manifestations of CRSwNP in comparison to males, with the adjusted association approaching statistical significance. Further studies, potentially looking at hormones as a cause of pathogenesis, are needed to better elucidate the role of sex in CRSwNP.

Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation

Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and −challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung Acod1 mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (LysM-cre+Acod1flox/flox) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower Acod1 expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.

Myeloperoxidase-ANCA IgG induces different forms of small vessel vasculitis based on type of synergistic immune stimuli

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis has diverse patterns of injury including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Necrotizing and crescentic glomerulonephritis (NCGN) occurs in all syndromes and as renal limited vasculitis (RLV). Single dose intravenous ANCA IgG-specific for mouse myeloperoxidase (MPO) causes RLV in mice. Although multiple mouse models have elucidated ANCA-IgG induced necrotizing and crescentic glomerulonephritis (NCGN), pathogenesis of ANCA-induced granulomatosis and vasculitis outside the kidney has not been clarified. To investigate this, we used intravenous MPO-ANCA IgG in the same strain of mice to induce different patterns of lung disease mirroring patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Repeated intravenous MPO-ANCA IgG induced GPA with NCGN, lung capillaritis, arteritis and granulomatosis. Lung leukocyte phenotypes were evaluated by immunohistochemical image analysis and by flow cytometry. ANCA lung capillaritis and microabscesses began within one day and evolved into granulomas in under seven days. Influenza plus single dose MPO-ANCA IgG induced MPA with NCGN, lung capillaritis and arteritis, but no granulomatosis. Allergic airway disease caused by house dust mites or ovalbumin plus single dose intravenous MPO-ANCA IgG induced EGPA with eosinophilic bronchiolitis, NCGN, capillaritis, arteritis, and granulomatosis. Thus, our study shows that the occurrence and pattern of lung lesions are determined by the same ANCA IgG accompanied by different synergistic immune factors.

Non-invasive strategy: Developing a topical IL-4Rα-specific nanobody for the treatment of allergic airway diseases

Inhibiting IL-4 and IL-13 are critical cytokines that induce the pathogenic responses of allergic airway diseases. Currently, monoclonal antibodies targeting IL-4Rα are administered subcutaneously to treat eosinophilic rhinosinusitis and allergic asthma. However, these treatments have several drawbacks. To address these issues, we have developed a novel IL-4Rα-targeting nanobody designed for non-invasive delivery to local inflammatory sites in allergic airway diseases. H5, selected via the ribosomal display applied screening from synthetic nanobody library, underwent dimerization and in-silico affinity maturation using AlphaFold2 and GROMACS resulting in a substantial/dramatic enhancement of its binding affinity. H5 effectively controlled inflammatory markers such as MUC5AC, CCL26, and FOXJ1 in human nasal epithelial cells (HNECs) by inhibiting IL-4 and IL-13 signaling. The bivalent form of H5 showed efficacy in easily accessible cells, such as multi-ciliated cells, while the monovalent variant targeted hard-to-reach cells, such as basal cells of HNECs. In summary, we developed a nanobody that could effectively inhibit inflammatory signaling in HNECs via intranasal administration, showing promise as a non-invasive rhinitis treatment.

Potential Protective Factors for Allergic Rhinitis Patients Infected with COVID-19.

At the beginning of the 2019 coronavirus disease (COVID-19) pandemic, airway allergic diseases such as asthma and allergic rhinitis (AR) were considered as risk factors for COVID-19, as they would aggravate symptoms. With further research, more and more literature has shown that airway allergic disease may not be a high-risk factor, but may be a protective factor for COVID-19 infection, which is closely related to its low-level expression of the ACE2 receptor and the complex cytokines network as underlying molecular regulatory mechanisms. In addition, steroid hormones and age factors could not be ignored. In this review, we have summarized some current evidence on the relationship between COVID-19 and allergic rhinitis to highlight the underlying mechanisms of COVID-19 infection and provide novel insights for its prevention and treatment. The key findings show that allergic rhinitis and its related molecular mechanisms may have a protective effect against COVID-19 infection.

Altered ontogeny and transcriptomic signatures of tissue-resident pulmonary interstitial macrophages ameliorate allergic airway hyperresponsiveness.

Environmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen. We utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization. Our findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure. These results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.

Single-cell analysis in rheumatic and allergic diseases: insights for clinical practice.

Since the advent of single-cell RNA sequencing (scRNA-seq) methodology, single-cell analysis has become a powerful tool for exploration of cellular networks and dysregulated immune responses in disease pathogenesis. Advanced bioinformatics tools have enabled the combined analysis of scRNA-seq data and information on various cell properties, such as cell surface molecular profiles, chromatin accessibility and spatial information, leading to a deeper understanding of pathology. This Review provides an overview of the achievements in single-cell analysis applied to clinical samples of rheumatic and allergic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, allergic airway diseases and atopic dermatitis, with an expanded scope beyond peripheral blood cells to include local diseased tissues. Despite the valuable insights that single-cell analysis has provided into disease pathogenesis, challenges remain in translating single-cell findings into clinical practice and developing personalized treatment strategies. Beyond understanding the atlas of cellular diversity, we discuss the application of data obtained in each study to clinical practice, with a focus on identifying biomarkers and therapeutic targets.

Cross-domain microbiomes: the interaction of gut, lung and environmental microbiota in asthma pathogenesis.

Recent experimental and epidemiological studies underscore the vital interaction between the intestinal microbiota and the lungs, an interplay known as the "gut-lung axis". The significance of this axis has been further illuminated following the identification of intestinal microbial metabolites, such as short-chain fatty acids (SCFA), as key mediators in setting the tone of the immune system. Through the gut-lung axis, the gut microbiota and its metabolites, or allergens, are directly or indirectly involved in the immunomodulation of pulmonary diseases, thereby increasing susceptibility to allergic airway diseases such as asthma. Asthma is a complex outcome of the interplay between environmental factors and genetic predispositions. The concept of the gut-lung axis may offer new targets for the prevention and treatment of asthma. This review outlines the relationships between asthma and the respiratory microbiome, gut microbiome, and environmental microbiome. It also discusses the current advancements and applications of microbiomics, offering novel perspectives and strategies for the clinical management of chronic respiratory diseases like asthma.

Mononuclear phagocyte sub-types in vitro display diverse transcriptional responses to dust mite exposure

Mononuclear phagocytes (MNP), including macrophages and dendritic cells form an essential component of primary responses to environmental hazards and toxic exposures. This is particularly important in disease conditions such as asthma and allergic airway disease, where many different cell types are present. In this study, we differentiated CD34+ haematopoietic stem cells towards different populations of MNP in an effort to understand how different cell subtypes present in inflammatory disease microenvironments respond to the common allergen house dust mite (HDM). Using single cell mRNA sequencing, we demonstrate that macrophage subtypes MCSPP1+ and MLCMARCO+ display different patterns of gene expression after HDM challenge, noted especially for the chemokines CXCL5, CXCL8, CCL5 and CCL15. MLCCD206Hi alternatively activated macrophages displayed the greatest changes in expression, while neutrophil and monocyte populations did not respond. Further work investigated how pollutant diesel exhaust particles could modify these transcriptional responses and revealed that CXC but not CC type chemokines were further upregulated. Through the use of diesel particles with adsorbed material removed, we suggest that soluble pollutants on these particles are the active constituents responsible for the modifying effects on HDM. This study highlights that environmental exposures may influence tissue responses dependent on which MNP cell type is present, and that these should be considerations when modelling such events in vitro. Understanding the nuanced responsiveness of different immune cell types to allergen and pollutant exposure also contributes to a better understanding of how these exposures influence the development and exacerbation of human disease.

Exploring the Role of Lactoferrin in Managing Allergic Airway Diseases among Children: Unrevealing a Potential Breakthrough.

The prevalence of allergic diseases has dramatically increased among children in recent decades. These conditions significantly impact the quality of life of allergic children and their families. Lactoferrin, a multifunctional glycoprotein found in various biological fluids, is emerging as a promising immunomodulatory agent that can potentially alleviate allergic diseases in children. Lactoferrin's multifaceted properties make it a compelling candidate for managing these conditions. Firstly, lactoferrin exhibits potent anti-inflammatory and antioxidant activities, which can mitigate the chronic inflammation characteristic of allergic diseases. Secondly, its iron-binding capabilities may help regulate the iron balance in allergic children, potentially influencing the severity of their symptoms. Lactoferrin also demonstrates antimicrobial properties, making it beneficial in preventing secondary infections often associated with respiratory allergies. Furthermore, its ability to modulate the immune response and regulate inflammatory pathways suggests its potential as an immune-balancing agent. This review of the current literature emphasises the need for further research to elucidate the precise roles of lactoferrin in allergic diseases. Harnessing the immunomodulatory potential of lactoferrin could provide a novel add-on approach to managing allergic diseases in children, offering hope for improved outcomes and an enhanced quality of life for paediatric patients and their families. As lactoferrin continues to capture the attention of researchers, its properties and diverse applications make it an intriguing subject of study with a rich history and a promising future.

Flagellin conjugated Per a 10 and its T cell peptides attenuate airway inflammation and restore cellular function.

Adjuvants were used to modulate response towards relevant immune cells. The present study aims to investigate FlaA-conjugated Per a 10 and T cell peptides in amelioration of allergic airway disease in mice. Mice given Per a 10 showed allergic features with higher cellular infiltration, IgE, Th-2 cytokines and alarmins. Fusion protein treatment reduced lung inflammation (p < 0.0001) and cellular infiltrates (p < 0.001) with higher IgG2a/IgE indicating resolution of disease. Immunotherapy with FPT1 and FPT3 reduces IL-4, IL-5 and IL-13 levels (p < 0.0001) with a fourfold increase in IFN-γ secretion in BALF. FPT1- and FPT3-treated mice have increased IL-10 and TGF-β levels (p < 0.001) with CD4+Foxp3+ T cells (p < 0.01) indicating Treg response. There was enhanced expression of claudin-1 (1.7-fold) and occludin (fourfold) in lungs of FPT1- and FPT3-treated mice with reduced TSLP (p < 0.01) and IL-33 (p < 0.0001) secretion in BALF indicating recovery of epithelial function. Peptide-conjugated FlaA proteins showed protective immunity in mice and have potential for immunotherapy with restoration of cellular function.

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)-β 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.

Pathogenic role of different phenotypes of immune cells in airway allergic diseases: a study based on Mendelian randomization.

Airway allergic disease (AAD) is a class of autoimmune diseases with predominantly Th2-type inflammation, mainly including allergic rhinitis (AR), allergic asthma (AS), and chronic sinusitis (CRS). There are very complex regulatory mechanisms between immune cells and AAD; however, previous reports found that the functions of the same immune cells in AAD are not identical. The aim of this study was to explore the causal relationship between different phenotypic immune cells and their association with AAD. Utilizing the publicly available Genome-Wide Association Studies (GWAS) database, this study conducted a bidirectional Mendelian randomization (MR) to assess the causal relationship between immune cells of 731 different immunophenotypes and AAD. The primary assessment methods included inverse variance weighting, weighted median, and MR Egger. Additionally, sensitivity analyses such as MR-PRESSO, leave-one-out, and scatter plots were employed to eliminate the interference of heterogeneity and pleiotropy, ensuring the stability of the causal inference. A total of 38 immune cells with different immunophenotypes were found to be positively and causally associated with AR, of which 26 were protective factors and 12 were risk factors. Positive associations were found between 33 immune cells and AS, of which 14 were protective factors and 19 were risk factors, as well as between 39 immune cells and CRS, of which 22 were protective factors and 17 were risk factors. Finally, the results of all relevant immune cells for the three diseases were taken and intersected, and it was found that CD3 on CD39+-activated Treg (IVWAR = 0.001, IVWCRS = 0.043, IVWAS = 0.027) may be the key immune cell that inhibits the development of AAD (ORAR = 0.940, ORAS = 0.967, ORCRS = 0.976). This study reveals that different immune phenotypes of immune cells are closely related to AAD at the genetic level, which provides a theoretical basis for future clinical studies.