Allergen-specific IgE Research Articles

Influence of Porphyra-derived polysaccharides and oligosaccharides on attenuating food allergy and modulating enteric microflora in mice

ABSTRACT Recently, there have been reports on the immunomodulatory properties of polysaccharides (PP), oligosaccharides (PO), and mixtures of PO/PP derived from Porphyra. To explore their potential in alleviating allergic responses and enteric dysbiosis, this study delved deeper into their effects using a murine model of food allergy. Daily administration of Porphyra samples mitigated allergic diarrhea, enteritis, and allergen-specific IgE production. Moreover, Porphyra samples exerted a significant reduction in the secretion of IL-2, IL-4, IFN-γ, and IL-17A, along with an elevation in the IL-10/IL-4 ratio in splenocytes upon allergen stimulation. Similarly, expression of IL-4 and IFN-γ in the duodenum was suppressed. Notably, allergic mice displayed a distinct fecal microflora profile compared to that of normal mice. Interestingly, PP and PO treatments exhibited different effects on improving enteric dysbiosis. These findings collectively suggest the potential of PP and PO as functional food candidates for the management of allergic enteritis and dysbiosis.

Allergen Differences and Correlation Analysis in Siblings Diagnosed with Respiratory Allergic Diseases

Introduction: Many parents of children with allergies are worried whether their subsequent children will have allergic reactions to the same allergens. Much of the current research on sibling allergens has been focused on twins; however, in real life, very few children are twins. Our study provides an opportunity to initially explore the sensitivity to allergens in siblings diagnosed with respiratory allergic diseases. Methods: Siblings diagnosed with bronchial asthma and/or allergic rhinitis in the Outpatient Department of Allergy Department of Yantai Yuhuangding Hospital from January 2018 to December 2021 were selected. The siblings were divided into elder group and younger group. Data of gender, age, feeding history, serum total IgE (TIgE), absolute eosinophil counts, and allergen-specific IgE (sIgE) were collected and analyzed. The sIgEs of allergens were divided into six categories and analyzed. Results: A total of 98 sibling pairs of patients were included in this study. There were no differences in the positive rates of the different types of allergens, TIgE values, and the absolute eosinophil values between the elder and younger groups and between different genders. Logistic regression analysis indicated that the elder siblings allergic to dust mites, fungi, weed pollens, or food had a statistically significant increased risk of having their younger sibling sensitive to these types of allergens (all p <0.05), and the risk of allergy to dust mites, weed pollens, and tree pollens of younger group increased with age (all p <0.05). Except for the sIgE values of dust mites, the sIgE values of the other allergens were significantly correlated between the two groups (all p <0.05). Conclusion: The positive rates of different allergens were similar between siblings. Elder siblings with dust mites, fungi, weed pollen, or food allergen positivity will have younger siblings sensitive to the same types of allergens.

Characterization of clinical features of monosensitized and polysensitized allergic rhinitis patients with pollen allergy

Objectives: The present study evaluates the prevalence of monosensitization and polysensitization in patients with pollen-hypersensitive moderate-to-severe persistent allergic rhinitis (AR), and determines the clinical characteristics of the two phenotypes. Methods: This retrospective cohort study included 160 patients with moderate-to-severe persistent AR among the 3,699 patients who presented to allergy outpatient clinics who were found to have hypersensitivity to pollen based on a skin prick test and/or allergen-specific IgE positivity. The patients were divided into two groups: monosensitized (hypersensitivity to pollen alone), and polysensitized (hypersensitivity to pollen and other allergens). Both groups were evaluated for allergen hypersensitivity, symptoms of AR, symptom frequency and comorbidities related to AR. Results: Of the 160 patients, 83 (51.9%) were monosensitized and 77 (48.1%) were polysensitized. The mean age was 29.5 ± 10.7 yeasrs and 28.3 ± 8.3 years, respectively and the female-to-male ratio was 42/41 and 47/30 in the two groups. Nasal congestion was remarkably more common in the polysensitized patients than in the monosensitized patients (p = 0.01). Hypersensitivity to weed mix and Cupressus arizonica pollen identified with a skin prick test was significantly more common in the polysensitized patients than in the monosensitized patients (p = 0.03 and p = 0.01, respectively). The two groups were similar in terms of the prevalence of asthma and other comorbidities related to rhinitis (p = 0.78). Conclusions: In this single-center study, the rates of monosensitization and polysensitization were found to be similar in patients with pollen-hypersensitive moderate-to-severe AR, and the clinical characteristics of the polysensitized phenotype were different from those of the monosensitized phenotype.

Comparison of Skin Prick Tests (SPT), Intradermal Tests (IDT) and In Vitro Tests in the Characterization of Insect Bite Hypersensitivity (IBH) in a Population of Lusitano Horses: Contribution for Future Implementation of SPT in IBH Diagnosis.

Thirty controls (C) and 30 IBH-affected (T) Lusitano horses were evaluated. T horses were included based on anamnesis and physical examination, supported by questionnaires. All horses were submitted to skin tests, Intrademal (IDT) and Skin Prick Tests (SPT), on the neck with 14 specific allergens, 13 recombinant proteins (r-proteins) from Culicoides nubeculosus (Cul n) and Culicoides obsoletus (Cul o) salivary glands and Culicoides nubeculosus Whole Body Extract (Cul n WBE). Addicionally, a cluster of six T and six C horses were also tested with Cul n 3 and Cul n 4 produced in insect cells and barley, as well as E. coli produced Cul o 3 and Cul o WBE. Allergen concentrations were 10 µg/mL for IDT and 100 µg/mL for SPT, and wheal diameters assessed at 20 min, 6 and 48 h. IDTs were considered positive when wheal diameter was ≥50% of the histamine wheal and SPT's ≥ 0.9 cm. In vitro tests, allergen-specific serum IgE and sulfidoleukotriene (sLT) release assay were also carried out. Results showed that Cul n WBE, Cul n 7, 8, 9, Cul o1P and Cul o 2P were the best performing allergens for SPTs (p ≤ 0.0001) for the 1st allergen panel and Cul o WBE, Cul n 3 Bar and Cul n 4 Bac (p ≤ 0.05) for the 2nd, presenting a higher discriminatory diagnostic potential than IDTs, at a concentration of 100 µg/mL, with readings assessed at 20 min. Regarding in vitro tests overall, the sLT release assay performed best.

Differential changes in the gut microbiota between extrinsic and intrinsic atopic dermatitis

Elevated serum level of total and (or) allergen-specific IgE is one of the key features of atopic dermatitis (AD). Previous studies have shown that the gut microbiome mediates interactions between external exposures and the immune system in AD; however, the relationship between the gut microbiota and IgE remains unclear. In the present study, analyses of environmental exposures for 250 AD patients and 138 healthy volunteers revealed an association between hygiene levels in the residential environment and the occurrence of AD and the IgE level. Metagenomic sequencing of the gut microbiota from 68 AD patients and 77 healthy controls showed that AD patients had a distinct gut microbiota composition; moreover, while L-histidine degradation was enriched in healthy controls, L-histidine biosynthesis was enriched in AD patients. Extrinsic and intrinsic AD showed different enrichment patterns of specific microbes and differential associations of functional pathways. Our study indicated that elevated levels of IgE in AD were related to specific microbes in the gut microbiota, which showed extensive interactions with environmental factors.

Higher House Dust Mite-Specific IgE Levels among Chronic Spontaneous Urticaria Patients May Implicate Higher Basophil Reactivity

Introduction: Allergen-specific IgE (sIgE) sensitization exists in a considerable fraction of chronic spontaneous urticaria (CSU) patients. Basophils have been implicated in the pathogenesis of CSU. This paper aimed to explore the relationship between allergic sensitization and basophil reactivity in CSU and the possible underlying mechanism. Methods: Basophil-enriched leukocytes were isolated from the peripheral blood of 76 CSU patients and 9 healthy controls. Basophil CD63 and FcεRIα (the alpha subunit of the high-affinity IgE receptor) expression in the blood samples with various house dust mite (HDM)-sIgE levels were determined by flow cytometry. Basophil reactivity and SHIP-1 (a molecule related to the IgE/FcεRI signaling pathway) expression were analyzed after stimulation with an HDM allergen or other stimuli. Results: HDM-sIgEstrong positive (≥3.5 kU/L) CSU patients had a significantly higher mean percentage of basophil CD63 and higher baseline levels of FcεRIα expressed by basophils than HDM-sIgEnormal (<0.35 kU/L) CSU patients and healthy controls; the same went for total serum IgE. After stimulation with Dermatophagoides pteronyssinus peptidase 1 (Derp1) alone or together with Derp1-sIgE, the stimulation index of CD63 and levels of FcεRIα expressed by basophils in HDM-sIgEstrong positive CSU patients were significantly higher than those in HDM-sIgEnormal CSU patients and healthy controls. Significantly more SHIP-1 mRNA expression in HDM-sIgEstrong positive CSU patients was induced after the combined stimulation in comparison to other subjects. Conclusion: CSU patients with higher HDM-sIgE levels (≥3.5 kU/L) may have higher CD63 and FcεRIα expression on peripheral blood basophils. Peripheral blood basophils in these CSU patients are more responsive to HDM allergen stimulation. Higher HDM-sIgE levels among CSU patients may implicate higher basophil reactivity.

Airway epithelium IgE-FcεRI cross-link induces epithelial barrier disruption in severe T2-high asthma

Although high-affinity immunoglobulin (Ig)E receptor (FcεRI) expression is upregulated in type 2 (T2)-high asthmatic airway epithelium, its functional role in airway epithelial dysfunction has not been elucidated. Here we report the upregulated expression of FcεRI and p-EGFR (Epidermal Growth Factor Receptor), associated with decreased expression of E-cadherin and claudin-18 in bronchial biopsies of severe T2-high asthmatics compared to mild allergic asthmatics and non-T2 asthmatics. Monomeric IgE (mIgE) decreased the expression of junction proteins, E-cadherin, claudin-18, and ZO-1, and increased alarmin messenger RNA and protein expression in cultured primary bronchial epithelial cells from T2-high asthmatics. Epithelial FcεRI ligation with mIgE decreased transepithelial electric resistance in air-liquid interface cultured epithelial cells. FcεRI ligation with mIgE or IgE- Dinitrophenyl or serum of high-level allergen-specific IgE activated EGFR and Akt via activation of Src family kinases, mediating alarmin expression, junctional protein loss, and increased epithelial permeability. Furthermore, tracheal instillation of mIgE in house dust mite-sensitized mice induced airway hyper-responsiveness, junction protein loss, epithelial cell shedding, and increased epithelial permeability. Thus, our results suggest that IgE-FcεRI cross-linking in the airway epithelium is a potential and unnoticed mechanism for impaired barrier function, increased mucosal permeability, and EGFR-mediated alarmin production in T2-high asthma.

The combination of Ara h 2-sIgE and basophil activation test could be an alternative to oral food challenge in cases of suspected peanut allergy.

Most children with peanut sensitisation do not have a clinical peanut allergy (PA). Oral food challenge (OFC) is then necessary to diagnose PA and assess the reactive dose of the allergen. However, OFC is laborious to perform, expensive and stressful. We evaluated whether in vitro tests, such as basophil activation test (BAT), allergen-specific IgE (sIgE) and their combination, could be used to replace OFC for the diagnosis of PA in children. Ninety-one patients aged 6 months to 18 years with suspected PA were prospectively recruited. These patients then underwent an OFC to assess PA. Whole peanut-sIgE, Ara h 2-sIgE, Ara h 8-sIgE and %CD63+ basophils (CCR3+ /SCClow ) to peanut measured by BAT were investigated for PA diagnosis. Forty-one patients had a positive peanut OFC, and the remaining 50 were only sensitised. All patients with Ara h 2-sIgE >7 kUA /L were allergic to peanut. A threshold of 6% for activated basophils yielded a sensitivity of 95% and a specificity of 54%. All patients with Ara h 2-sIgE ≤7 kUA /L and BAT ≤6% (n = 22) had a negative OFC except for one who presented an oral syndrome due to PR-10 sensitisation. We have shown that Ara h 2-sIgE >7 kUA/L is a discriminating threshold for the diagnosis of PA. Furthermore, when Ara h 2-sIgE ≤7 kUA/L and BAT ≤6%, patients do not need to adjust their diet and, thus, do not need an OFC.

Associations between HLA class II alleles and IgE sensitization to allergens in the Qatar Biobank cohort.

Allergic disorders are the consequence of IgE sensitization to allergens. Population studies have shown that certain human leukocyte antigen (HLA) alleles are associated with increased or decreased risk of developing allergy. We aimed to characterize the relationship between HLA class II allelic diversity and IgE sensitization in an understudied Arab population. We explored associations between IgE sensitization to 7 allergen mixes and mesquite (comprising 41 food or aeroallergens) and 45 common classical HLA class II alleles in a well-defined cohort of 797 individuals representing the general adult population of Qatari nationals and long-term residents. To do so, we performed HLA calling from whole genome sequencing data at 2-field resolution using 2 independent algorithms. We then applied 3 different regression models to assess either each allergen mix independently, in the context of IgE sensitization to other allergens tested, or polysensitization. More than half (n= 447) of the study participants showed IgE sensitization to at least 1 allergen, most of them (n= 400) to aeroallergens (Phadiatop). We identified statistically significant negative and positive associations with 24 HLA class II alleles. These have been reported to confer risk or protection from variety of diseases; however, only a few have previously been associated with allergy in other populations. Our study reveals several new risk and protective genetic markers for allergen-specific IgE sensitization. This is a first and essential step toward a better understanding of theorigins of allergic diseases in this understudied population.

Effects of the immunoglobulin/histamine complex on panic disorder concurrent with chronic spontaneous urticaria: a case report

BackgroundPanic disorder and panic attacks are two of the most common problems in psychiatry. A psychoimmunological correlation between allergic diseases and panic disorder has been strongly suggested. Histamine H1 receptor antagonists have been suggested as alternative drugs for the treatment of panic disorder. Chronic spontaneous urticaria (CSU) and panic disorder improved simultaneously with selective serotonin reuptake inhibitor antidepressants. Panic disorder has also been treated with the antihistamine chlorpheniramine. The immunoglobulin/histamine complex is a histamine-fixed immunoglobulin preparation that was reported to be effective in treating CSU. This case report describes the successful treatment of a patient with concomitant panic disorder and CSU for 23 years using immunoglobulin/histamine complex therapy.Case presentationThis report describes a 52-year-old female Korean patient who suffered from CSU with panic disorder for 23 years. Basic allergy tests (blood tests and skin prick tests) were conducted before and after treatment for the evaluation of allergic conditions. A multiple allergosorbent test (MAST) for the detection of allergen-specific IgE levels was also performed. The clinical severity of CSU was evaluated using the urticaria severity score system. Diagnostic interviews systematically assessed the diagnostic criteria outlined by the DSM-V, and the patient was evaluated before, during and after treatment using the Beck Depression Inventory (BDI-2) for depression, the State-Trait Anxiety Inventory (STAI) for anxiety and the Beck Hopelessness Score (BHS) for hopelessness. The patient received 2 ml of Histobulin™ (12 mg human immunoglobulin/0.15 µg histamine complex) once a week by subcutaneous injection for the treatment of CSU. Initial improvement of CSU was achieved after the third injection. After the twenty-seventh injection of Histobulin™, she showed no symptoms or signs and ceased allergic medication use. With the remission of CSU, allergic rhinitis was also completely resolved. The frequency of the common cold was significantly decreased during and after treatment. The medication frequency and development of clinical manifestations of panic disorder changed in parallel with the clinical severity of CSU. Moreover, the patient exhibited no clinical manifestations and ceased medication for panic disorder and sleeping pills for insomnia simultaneously with the remission of CSU. In the psychological evaluation, the BDI, STAI and BHS scores improved accordingly.ConclusionsThe immunoglobulin/histamine complex was effective in treating CSU and concomitant panic disorder in this patient and could be effective in treating some types of panic disorder. Considering the mechanisms of action of histamine and the immunoglobulin/histamine complex together with the patient’s clinical progress, histamine seemed to be related to panic disorder in this case. The concept of histamine-mediated syndromes, including allergies and psychiatric disorders, shows that a wider disease identity may be needed. Further studies on the immunopathogenesis of panic disorder and the mechanisms of action of the immunoglobulin/histamine complex are necessary.

Investigation of Serum allergen-specific IgE concentrations in feline asthma: a clinical experience

The aim of this study is to investigate allergen agents by allergen-specific serum IgE analysis in domestic cats diagnosed with feline asthma (FA). A total of 21 cats (16 FA and 5 control cats) were included in the study. Allergen-specific serum IgE levels were measured in cats diagnosed with feline asthma and in the control group. Allergen levels were classified as negative, weak, moderate and strong. The difference between the two groups was compared statistically. While the mean age of the cats in the FA group was 3.9kg ±2.4 years, the mean age of the cats in the control group was 3.4±2.2 years. The most common clinical manifestations in cats with FA were cough, sneezing, wheezing, and acute dyspnea, respectively. Allergen-specific IgE levels tested for 20 different allergens showed that 14 out of 16 cats developed a reaction to more than one allergen. The vast majority of cats with FA had a moderate or strong positive reaction to house dust mites. In conclusion, FA is an important and common chronic lower respiratory tract disease of feline patients and allergen-specific serum IgE levels can be easily used in clinical practice to guide the selection of allergens in the treatment of this disease and adjust for the quality of life and well-being of cats.

K-means cluster analysis of characteristic patterns of allergen in different ages: Real life study.

Atopy varies in people of different ages owing to different physical conditions and exposure to allergens. We aimed to cluster ages based on atopic severity using K-means cluster analysis and identify atopic incidence, severity, as well as the association among peripheral eosinophils, IgE and sensitisation. Consecutive patients (n=7654) with allergic symptoms and undergoing allergen-specific IgE tests were included from 2013 to 2017. Age, sex, specific-IgE, peripheral eosinophil counts and total-IgE were collected. Five age categories were identified: 1-17, 18-36, 37-52, 53-69 and 70-100years. The incidences of atopy and poly-sensitisation decreased with increasing age. Similar trend was observed for aeroallergens, egg and milk but not for peanuts, soy or seafood. Dust mites remain the crucial factor bothering patients with allergic symptoms, especially for children and adolescents. In patients aged <52years, sensitisation to aeroallergens was more prevalent than food. In group 37-52years, incidence of females' atopy was higher than that of males. The overlap of atopy, high eosinophils, and high total-IgE was found in only 19.18% of patients. The trend of allergen-test positivity is not parallel to total IgE and peripheral eosinophil counts. Age-grouping based on cluster analysis helps to find the changes in atopic status and distribution of sensitised allergens with age. Allergen tests are still necessary in the clinical diagnosis and treatment. An innovative exploration of the influence of age and allergens on total-IgE and eosinophil counts is helpful for the development of bio-targeted precision therapy. ChiCTR2300067700.

The Danger of Disappearing Allergen Skin Test Substances

Allergic diseases affect approximately one-quarter to one-half of the average population under 50 years of age in Central Europe. Due to the high proportion of affected individuals, allergy testing needs to be performed on a large scale, with high sensitivity and specificity at a low cost. Skin tests are the most important diagnostic measure fulfilling these requirements: they can be performed immediately and, quite in contrast to laboratory tests, the results of skin prick tests for the diagnosis of immediate allergy (IgE-mediated: Type I) can be assessed, and discussed with the patients 15–20 minutes later. Patients do not need to be called in for a second appointment to discuss the results of serum-based determination of specific IgE. Recently, we demonstrated that the sensitivity of skin prick tests is superior to the measurement of allergen-specific IgE, even for modern molecular allergens. In T cell mediated allergy of the delayed type (contact dermatitis: Type IV), patch tests read after 48–72 hours are the only available diagnostic measure.

Vitamin D Role in Childhood Mite Allergy and Allergen Immunotherapy (AIT).

The post hoc analysis presented here aimed to address the influence of endogenous vitamin D in the immunological mechanism underlying effective mite allergoid immunotherapy (AIT). Previously, we have shown that in allergic children, after 12 months of this immunoactive treatment, functionally potentiated memory regulatory T cells are identified. Indeed, AIT is the only known treatment that is able to reshape the detrimental immune response against the allergen into a non-noxious one. Besides, VD is widely considered an immunoregulatory molecule that is endogenously produced and exogenously provided by foods and supplements that might interact with the AIT mechanism, thus affecting its outcome. Therefore, a post hoc analysis of the clinical and immunological data from three different cohorts of allergic patients was performed. One cohort (N = 70) was on a standard symptom-controlling pharmacological treatment, while the other two (N = 60 and N = 35) were treated with AIT for 12 months. In the first cohort, a lower mean endogenous VD level (<22 ng/mL) was observed along with worse symptoms and a greater use of medications. Remarkably, the comparison between two sub-cohorts of patients with a serum VD level above (N = 32) or below (N = 28) a cut-off value set at the mean value (27 ng/mL) revealed that optimal improvement of all clinical and immune parameters was achieved (as expected from effective AIT), irrespective of the VD level. Notably, the third analysis, carried out on one cohort of AIT patients that were also concomitantly taking VD3 as a food supplement (N = 19), was distinguished by an uppermost overall treatment outcome (the amelioration of symptoms, the lowest medication requirements, and a reduction in the total and allergen-specific IgE levels), as well as an increase in the allergen-specific tolerogenic memory T regulatory cells. These findings suggest that the endogenous VD level affects the allergy severity and allergen immunotherapy effectiveness. In addition, VD3 might be investigated as an add-on supplement to obtain the best out of immunotherapy in VD-deficient/-insufficient allergic patients. The immunogenic, but low-allergenic, mite allergoid used as the bioactive agent might have contributed to minimizing the allergic response and highlighting the immunological effects described here.

Exposure to violence and asthma in Puerto Rican youth with high Th2 immunity.

Little is known about the determinants of asthma among youth with high T helper 2 (Th2) immunity. We hypothesized that exposure to violence (ETV) and violence-related distress are associated with asthma in children and adolescents with high Th2 immunity. We analyzed data from Puerto Ricans with high Th2 immunity aged 9-20 years in the Puerto Rico Genetics of Asthma and Lifestyle (PR-GOAL) and the Epigenetic Variation of Childhood Asthma in Puerto Ricans (EVA-PR) studies, and in a prospective study (PROPRA). High Th2-immunity was defined as ≥1 positive allergen-specific IgE and/or a total IgE ≥ 100 IU/mL and/or an eosinophil count ≥ 150 cells/μL. Asthma was defined as physician-diagnosed asthma and current wheeze. ETV and violence-related distress were assessed with the validated ETV Scale and Checklist of Children's Distress Symptoms (CCDS) questionnaires, respectively. In multivariable analyses, each 1-point increment in ETV score was significantly associated with 1.13-1.17 times increased odds of asthma in PR-GOAL and in EVA-PR (both at p ≤ 0.01), and each 1-point increment in CCDS score was significantly associated with 1.53-1.54 increased odds of asthma in PR-GOAL and in EVA-PR (both at p ≤ 0.03). Further, a persistently high ETV score was significantly associated with asthma in PROPRA (odds ratio [OR] = 2.83, 95% confidence interval [CI] = 1.10-7.29). Similar results were obtained in a sensitivity analysis using an eosinophil count ≥ 300 cells/μL instead of ≥150 cells/μL to define high Th2 immunity. ETV during childhood is associated with increased risk of persistent or new-onset asthma in youth with high Th2 immunity.

The Very Low IgE Producer: Allergology, Genetics, Immunodeficiencies, and Oncology.

Opposite to other immunoglobulin (Ig) classes and subclasses, there is no consensus on the definition of normal levels of serum total IgE. However, longitudinal studies on birth cohorts produced growth charts of total IgE levels in helminth-free and never atopic children and defining the normal ranges of total serum IgE concentration at the individual, rather than population, level. Accordingly, very 'low IgE producers' (i.e., children whose tIgE level belong to the lowest percentiles) became atopic while keeping their total IgE levels in a range considered 'normal' if compared to the general age-matched population but 'abnormally high' if projected on the tIgE growth chart against the trajectory of that child's own percentile levels. In 'low IgE producers', the IgE-specific activity, i.e., the ratio between allergen-specific and total IgE, is more important than the absolute specific IgE levels to confirm causality between allergen exposure and allergic symptoms. Patients with allergic rhinitis or peanut anaphylaxis but low or undetectable allergen-specific IgE levels must therefore be reconsidered considering their total IgE levels. Low IgE producers have been also associated with common variable immunodeficiency, lung diseases, and malignancies. A few epidemiological studies have shown a higher risk of malignancies in very low IgE producers, leading to a debated hypothesis proposing a novel, evolutionistic-relevant function for IgE antibodies for antitumor immune surveillance.

Prophylactic and therapeutic potential of magnolol-loaded PLGA-PEG nanoparticles in a chronic murine model of allergic asthma.

Magnolol is a chemically defined and active polyphenol extracted from magnolia plants possessing anti-allergic activity, but its low solubility and rapid metabolism dramatically hinder its clinical application. To improve the therapeutic effects, magnolol-encapsulated polymeric poly (DL-lactide-co-glycolide)-poly (ethylene glycol) (PLGA-PEG) nanoparticles were constructed and characterized. The prophylactic and therapeutic efficacy in a chronic murine model of OVA-induced asthma and the mechanisms were investigated. The results showed that administration of magnolol-loaded PLGA-PEG nanoparticles significantly reduced airway hyperresponsiveness, lung tissue eosinophil infiltration, and levels of IL-4, IL-13, TGF-β1, IL-17A, and allergen-specific IgE and IgG1 in OVA-exposed mice compared to their empty nanoparticles-treated mouse counterparts. Magnolol-loaded PLGA-PEG nanoparticles also significantly prevented mouse chronic allergic airway mucus overproduction and collagen deposition. Moreover, magnolol-encapsulated PLGA-PEG nanoparticles showed better therapeutic effects on suppressing allergen-induced airway hyperactivity, airway eosinophilic inflammation, airway collagen deposition, and airway mucus hypersecretion, as compared with magnolol-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles or magnolol alone. These data demonstrate the protective effect of magnolol-loaded PLGA-PEG nanoparticles against the development of allergic phenotypes, implicating its potential usefulness for the asthma treatment.

D-2-hydroxyglutarate decreases allergic sensitization in asthma

Abstract Allergic asthma is a chronic inflammatory disease affecting the lungs which is mediated by allergen-specific IgE and type 2 cytokines. IgE and type 2 cytokine production require Tfh13 cell and Th2 cell polarization, respectively, which must first be primed by dendritic cells (DC). Recent studies demonstrate that cellular metabolic perturbations critically regulate DC activation and subsequent T cell priming. To characterize DC metabolic mechanisms which may regulate allergic sensitization, we analyzed GWAS data to identify metabolism-related genes that are associated with asthma risk. We identified 384 single nucleotide polymorphisms (SNPs) in the D2HGDHlocus that are significantly associated with childhood-onset asthma. Further, expression quantitative trait loci analysis of the 10 most significant SNPs revealed that these SNPs promote reduced expression of D2HGDHmRNA. D2HGDH is an enzyme which catalyzes the conversion of D-2-hydroxyglutarate (D-2HG) to α-ketoglutarate (aKG). D-2HG is a potent inhibitor of aKG-dependent epigenetic enzymes. Bone marrow-derived dendritic cells (BMDCs) stimulated with the fungal allergen Alternariaexhibited a significant increase in the ratio of aKG/D-2HG compared to mock or LPS treated BMDCs. Further, in vivostudies revealed that intranasal administration of cell-permeable D-2HG prior to intranasal exposure to Alternariasignificantly reduced Th2 and Tfh13 polarization, impaired IgE+ germinal center B cell differentiation, and induced T follicular regulatory cell polarization in mice. Our results suggest a mechanism whereby D-2HG suppresses epigenetic modifications in DCs, which are necessary for allergic sensitization and polarization of Th2 and Tfh13 cells. VCU CTSA UL1TR002649 as well as funding from NIAID R56AI139658

B cell intrinsic Toll-like receptor 9 signaling regulates class switching to IgE

Abstract Chronic allergic diseases such as allergic asthma are driven by excessive production of allergen specific IgE. B cells produce IgE by class switch recombination (CSR) in response to T cell help and Th2 cytokines. However, development of allergic diseases can also be influenced by factors such as early-life exposure to microbial products. In vivo, stimulation of Toll-like receptor 9 (TLR9) with microbial DNA reduces IgE levels, largely thought to be a response to Th1 cytokines. However, the directeffects of TLR9 signaling on B cell class switching to IgE remain unclear. To delineate the B cell intrinsic effects of TLR9 stimulation, we treated mouse splenic B cells in vitrowith IL-4 and anti-CD40 antibody with or without a synthetic TLR9 agonist, CpG oligodeoxynucleotides (CpG). Compared to stimulation with IL-4 and anti-CD40 alone, the addition of CpG decreased IgE production. Using B cells from reporter mice that track germline transcription, a prerequisite for CSR, we found that CpG inhibited Iɛ but increased Iγ1 germline transcription. By Western blot analyses, we probed the expression of transcription factors known to negatively regulate Iɛ and positively regulate Iγ1 transcription. These transcription factors were synergistically upregulated in the presence of CpG with IL-4 and anti-CD40. Together, these data illustrate a molecular mechanism by which microbial products directly perturb the production of IgE and influence the development of allergic disease. R01 HL165120

Dupilumab as Adjunct Treatment for Persistent Food Allergy in Adulthood

Atopic disease affects both immunocompetent and immunodeficient patients. Known risk factors for atopic disease, such as atopic dermatitis (AD) and IgE mediated food allergy, include impaired skin integrity, Th2 predominance, and altered T-regulatory activity. Food allergies in particular can be life-threatening and there is no known cure, although immunomodulatory (anti IL-4Rα/IL-13, anti IL-5, and anti IgE) trials for food allergy are underway. The allergen-specific IgE levels and skin prick tests of atopic dermatitis patients often decrease while on dupilumab (anti IL-4Rα/IL-13) therapy but the question remains: does dupilumab improve or eliminate food allergy? One case report has reported success with dupilumab in an adult woman. Here we describe the de-labeling of several allergenic foods in an adult patient being treated for AD with dupilumab.A 29-year-old man presented to our allergy clinic with a history of severe AD and multiple food allergies. His eczema had been recalcitrant to high-dose topical steroids, BB-UVB phototherapy, cyclosporine, methotrexate, and both intramuscular and intralesional Kenalog (ILK). He finally improved on weekly dupilumab dosing and did not have adverse effects from dupilumab therapy. His food allergies posed significant morbidity with multiple reactions requiring epinephrine as well as ongoing anxiety regarding cross-contact. His history is notable for childhood reactions to peanut, tree nuts, fish, and shellfish, with concordantly elevated skin prick and specific IgE levels. After dupilumab therapy, these reactions decreased, leading to a risk/benefit discussion and agreement to perform physician-guided oral food challenges in an effort to broaden his diet (Figure 1). The majority of challenges were passed and the patient has maintained those foods in his diet (Figure 2). In addition, the patient reports substantial improvement in his anxiety at work as well as in social interactions. In this case, dupilumab as an immodulatory agent for AD offered the additional benefit of decreasing morbidity from food allergies. Given the persistence of food allergy, further research into adjunctive therapeutic options is vital to improving patient quality of life. Unlike other therapies like JAKinhibitors and systemic steroids used for atopic dermatitis, anti-IL-4Rα/IL-13 therapy is not immunosuppressive and has a favorable side-effect profile for patients. [Display omitted] [Display omitted]