Oligomerization and Nitration of the Grass Pollen Allergen Phl p 5 by Ozone, Nitrogen Dioxide, and Peroxynitrite: Reaction Products, Kinetics, and Health Effects.

The allergenic and inflammatory potential of proteins can be enhanced by chemical modification upon exposure to atmospheric or physiological oxidants. The molecular mechanisms and kinetics of such modifications, however, have not yet been fully resolved. We investigated the oligomerization and nitration of the grass pollen allergen Phl p 5 by ozone (O3), nitrogen dioxide (NO2), and peroxynitrite (ONOO-). Within several hours of exposure to atmospherically relevant concentration levels of O3 and NO2, up to 50% of Phl p 5 were converted into protein oligomers, likely by formation of dityrosine cross-links. Assuming that tyrosine residues are the preferential site of nitration, up to 10% of the 12 tyrosine residues per protein monomer were nitrated. For the reaction with peroxynitrite, the largest oligomer mass fractions (up to 50%) were found for equimolar concentrations of peroxynitrite over tyrosine residues. With excess peroxynitrite, the nitration degrees increased up to 40% whereas the oligomer mass fractions decreased to 20%. Our results suggest that protein oligomerization and nitration are competing processes, which is consistent with a two-step mechanism involving a reactive oxygen intermediate (ROI), as observed for other proteins. The modified proteins can promote pro-inflammatory cellular signaling that may contribute to chronic inflammation and allergies in response to air pollution.

Depletion of CD56+CD3+ invariant natural killer T cells prevents allergen-induced inflammation in humanized mice.

BACKGROUND: CD56-expressing natural killer (NK) cells as well as invariant NK T (iNKT) cells have been shown to either promote or inhibit allergic immune responses. OBJECTIVE: The aim of the present study was to investigate the impact of these cells in a recently developed humanized mouse model of allergen-induced IgE-dependent gut and lung inflammation. METHODS: Nonobese diabetic-severe combined immunodeficiency γ-chain knockout mice were injected intraperitoneally with human PBMCs or CD56-depleted (CD56neg) PBMCs from highly sensitized donors with birch or grass pollen allergy together with the respective allergen or with NaCl as a control. Three weeks later, the mice were challenged with the allergen rectally and gut inflammation was monitored by video miniendoscopy and by histology. Furthermore, airway inflammation was measured after an additional intranasal allergen challenge. RESULTS: Allergen-specific human IgE in mouse sera, detectable only after coinjection of the respective allergen, was reduced in mice being injected with CD56neg PBMCs compared with in mice receiving nondepleted PBMCs. Consequently, allergen-induced IgE-dependent colitis, airway hyperreactivity, and mucus-producing goblet cells were significantly inhibited in these mice. Interestingly, reconstitution of CD56neg PBMCs with nondepleted CD56+ cells and with CD56+CD3+ iNKT cells restored gut as well as lung inflammation, whereas addition of CD3-depleted CD56+ cells did not. CONCLUSION: These results demonstrate that allergen-specific gut and lung inflammation in PBMC-engrafted humanized mice is promoted by CD56+CD3+ iNKT cells, which opens new possibilities of therapeutic intervention in allergic diseases.

Outdoor pollen-related changes in lung function and markers of airway inflammation: A systematic review and meta-analysis.

BACKGROUND: Experimental challenge studies have shown that pollen can have early and delayed effects on the lungs and airways. Here, we qualitatively and quantitatively synthesize the evidence of outdoor pollen exposure on various lung function and airway inflammation markers in community-based studies. METHODS: Four online databases were searched: Medline, Web of Science, CINAHL and Google Scholar. The search strategy included terms relating to both exposure and outcomes. Inclusion criteria were human-based studies published in English that were representative of the community. Additionally, we only considered cross-sectional or short-term longitudinal studies which investigated pollen exposure by levels or season. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was conducted using random-effects models. RESULTS: We included 27 of 6551 studies identified from the search. Qualitative synthesis indicated associations between pollen exposure and predominantly type-2 inflammation in both the upper and lower airways, but little evidence for lung function changes. People with ever asthma and/or seasonal allergic rhinitis (SAR) were at higher risk of such airway inflammation. Meta-analysis confirmed a positive relationship between pollen season, eosinophilia and eosinophil cationic protein (ECP) in people with ever SAR but the results between studies were highly variable. Heterogeneity was reduced after further subgrouping by age, and the forest plots indicated that eosinophilic airway inflammation to outdoor pollen exposure increased with age. CONCLUSION: Among people with ever asthma and ever SAR, exposure to increased ambient pollen triggers type-2 upper and lower airway inflammation rather than a non-specific or innate inflammation. These findings can lead to the formulation of specific pollen immunotherapy for susceptible individuals. Future research should be directed towards investigating lagged associations and effect modifications using larger and more generalized populations. SYSTEMATIC REVIEW REGISTRATION: CRD42020146981 (PROSPERO).

Effect of perennial dust mites allergy on symptom severity of autumn allergic rhinitis in adults.

Background: Multiple immunoglobulin E (IgE) mediated sensitizations and/or allergies often coexist in patients with allergic rhinitis (AR). Several simultaneous allergen exposures in multiple IgE-mediated sensitizations and/or allergies may increase the allergen load and be related to disease severity. No study has verified whether positive allergen serum IgE levels and allergen categories together are associated with AR severity in adults. Objective: To investigate the effects of perennial dust mites (DMs) allergy and multiple serum sIgE-mediated autumn pollen allergy coexistence on symptom severity in adult patients with AR in autumn. Methods: In total, 153 patients with AR and with autumn pollen allergy (Artemisia argyi, ragweed, and hop) with or without DMs allergy were recruited in the autumn pollen season. Symptom severity was assessed by using the Chinese version of the visual analog scale (VAS): four rhinitis symptoms (sneezing, rhinorrhea, nasal pruritus, and nasal congestion) and two ocular symptoms (ocular itching and/or grittiness and/or redness, and ocular tearing) were scored at approximately the same period. We measured allergen serum sIgE levels for the inhaled allergens. The effects of DMs allergy and multiple autumn pollen allergy coexistence on symptom severity were analyzed. Results: Neither the sum of the autumn pollen allergens categories (total number of positive autumn pollen allergens, i.e., Artemisia argyi or ragweed or hop positive: 1; Artemisia argyi and ragweed positive: 2; Artemisia argyi, ragweed, and hop positive: 3) nor serum sIgE levels( total sIgE levels of positive autumn pollen allergens) exerted any influence on the severity of nasal and ocular symptoms (p > 0.05). When the concomitant DMs allergy status was considered, the sum of the positive autumn pollen allergen categories and accumulated positive autumn pollen and DMs serum sIgE levels (total levels of serum sIgE of positive autumn pollen allergens plus the levels of serum sIgE of DMs) had no influence on patients' symptom severity (p > 0.05). Conclusion: The coexistence of perennial DMs allergy and multiple autumn pollen allergy did not affect the severity of symptoms among adult patients with AR and with autumn pollen allergy in autumn.

Eicosanoids seasonally impact pulmonary function in asthmatic patients with Japanese cedar pollinosis.

BACKGROUND: Condition of asthma in patients with asthma and concomitant seasonal allergic rhinitis (SAR) deteriorates during the Japanese cedar pollen (JCP) season. However, the underlying mechanisms remain unclear. METHODS: We analyzed seasonal variations in eicosanoid levels in the airways of patients with asthma and concomitant SAR sensitized to JCP (N = 29, BA-SAR-JCP group) and those not sensitized (N = 13, BA-AR-non-JCP group) during the JCP season. The association between changes in eicosanoid concentrations and pulmonary function was assessed. Exhaled breath condensate (EBC) was collected, and pulmonary function tests were performed during the JCP and non-JCP seasons. The cysteinyl leukotriene (CysLT), thromboxane B2 (TXB2), prostaglandin D2-methoxime (PGD2-MOX), and leukotriene B4 (LTB4) levels in the collected EBC were measured via enzyme-linked immunosorbent immunoassays. RESULTS: The log CysLT levels significantly increased in the BA-SAR-JCP group during the JCP season compared with the non-JCP season (1.78 ± 0.55, 1.39 ± 0.63 pg/mL, mean ± standard deviation, respectively, p = 0.01) and those in the BA-AR-non-JCP group during the JCP season (1.39 ± 0.38 pg/mL, p = 0.04). Moreover, the log TXB2 levels seemed to increase. However, the log LTB4 and log PGD2-MOX levels did not increase. The changes in the log CysLT levels during the two seasons were negatively correlated to forced expiratory volume in one second (FEV1) in the BA-SAR-JCP group (r = -0.52, p < 0.01). CONCLUSIONS: In the BA-SAR-JCP group, seasonal increases in eicosanoid levels in the airway likely promoted deterioration in pulmonary function despite optimal maintenance treatment.

Tree pollen exposure is associated with reduced lung function in children.

BACKGROUND: Allergic disease is a recognized global epidemic and a significant cause of ill health and poor quality of life. The prevalence of pollen allergy is high throughout the world, and pollen exposure itself plays a role in emergency department presentations and hospitalizations for asthma. Lung function and airway inflammation are important measures of asthma activity and control. OBJECTIVE: To examine associations between exposure to multiple pollen types and lung function and markers of airway inflammation at 8 and 14 years of age, and to explore potential modification by residential greenness. METHODS: A cohort of high-risk children living in Sydney, Australia had spirometry and fractional exhaled nitric oxide (FeNO) measured at 8 and 14 years of age. Ambient pollen concentration on the day of lung function measurement and up to three days prior was used as the exposure measure. Residential greenness was derived from satellite imagery. We modelled the association between six pollen types and lung function and FeNO. We also assessed modifying effects of residential greenness. RESULTS: Casuarina, cypress and Pinus pollen in the air the day before measurement and 3 days prior respectively, were associated with reduced lung function in 8-year-olds. The pollen exposures were associated with decreases in FEV1 and FVC; however, the FEV1 /FVC ratio was not affected. Effect modification by greenness was not observed due to loss of power. CONCLUSIONS & CLINICAL RELEVANCE: Airborne tree pollen of cypress, Casuarina and Pinus and not grass in some regions may be detrimental to childhood lung function.

Effects of a probiotic treatment (Enterococcus faecalis) and open-label placebo on symptoms of allergic rhinitis: study protocol for a randomised controlled trial.

INTRODUCTION: Several studies suggest that gut microbiota may play an important role in allergic diseases. The present trial aims to examine effects of the probiotic Enterococcus faecalis on symptoms of allergic rhinitis in patients. Effects of this probiotic on the immune system have been reported by several studies, but the majority of the previous trials were animal studies. In addition, it is well known that symptoms in allergic rhinitis are prone to exhibit high placebo responses. Moreover, recent studies report that even placebos without deception (open-label placebos) are highly effective in reducing symptoms of allergic rhinitis. Our study design combines both new approaches to assess effects on allergic symptoms in patients. The objective of this study is to compare the effects of a probiotic treatment (E. faecalis) with effects seen by open-label placebo, concealed placebo treatment and no treatment control. METHODS AND ANALYSIS: A total of 120 patients with allergic rhinitis will be randomly assigned to one of four different groups: a double-blind probiotic/placebo group (groups 1 and 2), an open-label placebo group (group 3) and a no-treatment group (group 4) to control for spontaneous variation of symptoms. The primary outcome is the evaluation of allergic symptoms using the Combined Symptoms Medication Score. Furthermore, health-related quality of life is examined (Rhinitis Quality of Life Questionnaire). Secondary outcomes include a visual analogue scale on allergic burden and a second quality of life questionnaire. This report describes the study design of the randomised controlled trial. ETHICS AND DISSEMINATION: The study design was approved by the ethical committee of the UKT Department of Psychosomatic Medicine and Psychotherapy, Tübingen, Germany. The trial is registered at the German Clinical Trials Register (www.drks.de, DRKS00015804). The trial results will be published in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: German Clinical Trials Register (www.drks.de, DRKS00015804); Pre-results.

Pollen-Food Allergy Syndrome: A not so Rare Disease in Childhood.

Seasonal allergic rhinoconjunctivitis (SAR) affects millions of people worldwide, particularly in childhood and adolescence. Pollen food allergy syndrome (PFAS) is a common adverse reaction occurring few minutes after the consumption of vegetable foods in patients with pollen-induced SAR. PFAS has rarely been investigated in the pediatric population, as it has been mainly examined as an adult disease. Recent studies suggested that PFAS might be more frequent in childhood than previously recognized. The present review aims to give an overview of the epidemiology, pathophysiology, diagnosis, management and prognosis of PFAS in children with SAR-induced by pollens.

Analysis of the Serum Cytokine Profile in Allergic Patients Opens a Way to Personalized Treatment of Allergy.

Plant lipid transfer proteins and homologues of the main birch pollen allergen Bet v 1 are involved in the development of allergic reactions of varying severity to plant foods and pollen. In this study, the sera from patients with tree and weed pollen allergies in the Moscow region were examined. The levels of IL-4, IL-5, IL-9, IL-10, IL-13, IL-17A, IFNγ, TNFα, and TNFß cytokines were determined in the sera of patients with specific IgE antibodies to Bet v 1 and Pru p 3 allergens. It was confirmed that patients with pollen allergy are often characterized by Th2 response of the immune system, though other mechanisms of allergy development occurred in some cases. The data obtained demonstrate the necessity of detailed analysis of the individual mechanism of allergic reactions and patient-centered approach to the personalized allergy treatment.

New findings, pathophysiology, and antigen analysis in pollen-food allergy syndrome.

PURPOSE OF REVIEW: PFAS shows various cross-reactivities with antigens because of the area in which the patient resides and dietary habits, and progress in component allergen analysis in recent years has clarified the pathogenesis. This review describes newly identified findings for antigens involved in PFAS. RECENT FINDINGS: We describe recent findings for PR-10 family, profilin and LTP, as known major antigens for PFAS. Microarrays of allergen components have significantly improved the ability to describe IgE profiles. In addition, we describe a new antigen, GRP, in the fruit pulp of recently identified fruit. SUMMARY: PFAS is a food allergy based on the cross-reactivity of pollen antigens and food antigens. Symptoms induced by sensitization differ depending on the specific antigen. The functions of each antigen are diverse, and even the same antigen can cause different symptoms. As analytical techniques progress, the findings will help to establish treatments, such as specific immunotherapy.

Bioinformatics-Based Approaches Predict That MIR-17-5P Functions in the Pathogenesis of Seasonal Allergic Rhinitis Through Regulating ABCA1 and CD69.

OBJECTIVE: As the most prevalent type of rhinitis, allergic rhinitis is consisted of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis. This study is carried out for revealing the mechanisms of SAR. METHODS: Microarray data set GSE43523 (including 7 SAR nasal epithelial cells and 5 nonallergic control nasal epithelial cells) was extracted from Gene Expression Omnibus database. Based on limma package, differential expression analysis for the 2 groups was performed to obtain differentially expressed genes (DEGs). Using Multifaceted Analysis Tool for Human Transcriptome online tool, the functions involving the DEGs were predicted by enrichment analysis. Combined with Cytoscape software, protein-protein interaction (PPI) network was built and a significant network module was acquired. In addition, transcription factor (TF)-target and miRNA-target pairs were predicted using WebGestalt tool, and then TF-miRNA-target regulatory network was built by Cytoscape software. RESULTS: There were 274 DEGs between rhinitis and control samples, including 144 upregulated genes and 130 downregulated genes. After PPI for the DEGs was built, a significant network module was identified. In the TF-miRNA-target regulatory network, ABCA1, CPEB4, CD69, MIR-17-5P, and CREB had higher degrees. Furthermore, both ABCA1 and CD69 were targeted by MIR-17-5P in the regulatory network. CONCLUSION: CPEB4 and CREB might be implicated in the pathogenesis of SAR. Besides, MIR-17-5P might also act in SAR via targeting ABCA1 and CD69.

Japanese Cedar Pollen-Specific IgA in Nasal Secretions and Nasal Allergy Symptoms.

OBJECTIVE:: IgA-dependent degranulation of eosinophils and positive correlation between IgA and eosinophil cytotoxic protein levels in nasal secretions have been reported. However, the association between IgA and allergic reactions remains unclear. Therefore, we evaluated the changes in Japanese cedar-specific IgA levels and allergy symptoms after Japanese cedar pollen scattering in symptomatic and asymptomatic individuals sensitized to Japanese cedar pollen. METHODS:: Nasal secretion and serum samples were collected from 31 participants (21 symptomatic and 10 asymptomatic participants) in January (preseason) and March (peak season). Japanese cedar-specific IgA or IgE levels were measured using ELISA with diamond-like carbon-coated chips. RESULTS:: The ratio of Japanese cedar pollen-specific IgA to total IgA (rIgA) in the nasal secretions of symptomatic participants increased significantly in March compared with that in January ( P < .01); however, the ratio of specific IgE to total IgE (rIgE) in nasal secretions did not. rIgA in nasal secretions among asymptomatic participants also did not increase during pollen season. rIgA in nasal secretions was significantly correlated with nasal allergic symptoms (r = 0.82; P < .0001) with no significant correlation between rIgE and symptoms. CONCLUSIONS:: To our knowledge, this is the first study to show an association between nasal symptoms and rIgA in nasal secretions, suggesting that rIgA is useful as an antigen-specific biomarker for allergic rhinitis or pollinosis. Furthermore, rIgA values in nasal secretions do not increase in asymptomatic participants sensitized to Japanese cedar during the pollen season.

Impaired sports performance of athletes suffering from pollen-induced allergic rhinitis: a cross-sectional, observational survey in German athletes.

BACKGROUND: Allergic rhinitis has major impacts on sports performance of athletes. The present study aimed at determining the frequency of seasonal pollen allergy and analyzing the impacts of pollen allergy, the choice of allergy treatments and their benefits for sports performance in a group of professional and recreational athletes. METHODS: The study was conducted as a self-reported questionnaire survey. Subjects were recruited from the German Sport University and the Cologne Marathon 2014 during the peak pollen season of 2014. RESULTS: Athletes returned 636 completed questionnaires, 42.6% of participants reported suffering from a pollen allergy and 30.2% also suffered from asthma. Performance impairments were reported in more than 80% of allergic subjects. In all, 82.2% of subjects used symptomatic medications, 32.3% alternative therapies, and 47.6% allergen immunotherapy. Subjects who used immunotherapy had fewer impaired training bouts than those who used symptomatic and alternative therapies. The majority of subjects had concerns about allergy treatment such as side effects, negative impacts on sports performance and lack of long-term effects. CONCLUSIONS: This study confirmed a high prevalence of pollen allergy among German athletes. The majority of allergic rhinitis athletes were undertreated, and the reason could be their reservations about allergy treatments. Pollen allergy tremendously reduced sports performance of athletes during the pollen season. This impact can be lessened with proper treatment such as immunotherapy. Better understanding of available treatment modalities should be provided to patients and physicians to improve sports performance of athletes suffering from pollen allergy.

A Specifically Designed Multispecies Probiotic Supplement Relieves Seasonal Allergic Rhinitis Symptoms.

BACKGROUND: Probiotics are purported to reduce symptoms of allergic rhinitis. This study sought to determine the proportion of participants with an improvement in the mini Rhinoconjunctivitis Quality of Life Questionnaire (mRQLQ) in response to a multispecies probiotic supplement with a Simon Two-Stage design. METHODS: This study was based on a Simon Two-Stage Design for p1-p0 = 0.18 to account for seasonal variation in symptoms. Under this design, ≥10 patients are required to exhibit an improvement in quality-of-life scores to determine that there was sufficient activity for the supplement to be considered effective. Participants consumed a probiotic supplement (Ecologic® AllergyCare; probiotik®pur) twice daily for 8 weeks. The primary outcome measure was based on a change in mRQLQ scores following supplementation. Secondary outcomes include assessment of change in symptoms and medication usage with a twice-weekly symptom and medication diary, nasal congestion by rhinomanometry, and total serum Immunoglobulin E (IgE) and specific IgE for Bermuda grass. RESULTS: A total of 40 participants completed the study. A total of 25 participants (63%, 49-76%, p < 0.001; mean, 95% confidence interval, p-value) out of 40 participants had a clinically meaningful response to treatment based on assessment of mRQLQ. On average, mRQLQ scores changed from 2.83 ± 1.51 at baseline to 1.66 ± 1.36 at week 4 and 1. 38 ± 1.13 at week 8 (p < 0.01) (mean ± SD, p-value). Sum of individual symptom scores and overall symptom scores over the course of treatment was significantly reduced (p = 0.036 and p = 0.039, respectively). A moderate reduction in frequency of allergy-related medication use in the final 4 weeks of supplementation period was observed (52.5% weeks 0-4 to 41.4% weeks 4-8; average proportion of total diary responses, p = 0.085). The supplement was largely well tolerated by participants at the dose provided. CONCLUSIONS: The proportion of participants exhibiting improvement in quality-of-life metrics warrants continued investigation in the form of a phase III placebo-controlled trial.

The burden of allergic rhinitis and allergic rhinoconjunctivitis on adolescents: A literature review.

OBJECTIVE: To evaluate the literature regarding the burden of allergic rhinitis (AR) and allergic rhinoconjunctivitis (ARC) in adolescents (aged 10-19 years). DATA SOURCES: Searches were performed in MEDLINE, Embase, Health Technology Assessment Database, and National Health Service Economic Evaluation Database for studies that evaluated concepts of symptoms, quality of life (QOL), daily activities, sleep, examination performance, school absenteeism and presenteeism, and treatment burden in adolescents with AR or ARC. STUDY SELECTIONS: English-language journal articles indexed in the last 15 years describing noninterventional, population-based studies. Records were assessed by 2 independent reviewers. RESULTS: A total of 27 articles were identified; outcomes evaluated were symptoms (n = 6 studies), QOL (n = 9), daily activities (n = 5), emotional aspects (n = 3), sleep (n = 6), education (n = 7), and treatment burden (n = 2). AR symptoms rated most bothersome were rhinorrhea, nasal congestion, and itchy eyes. QOL was worse in adolescents with AR vs controls regardless of QOL instrument used. Nasal symptoms and nasal obstruction were more likely to be associated with poor QOL in adolescents than in adults or younger children, respectively. Daily functioning and sleep were also negatively affected by AR. In addition, a detrimental effect on absenteeism, school productivity, and academic performance was reported. CONCLUSION: Although AR and ARC are sometimes perceived as trivial conditions, this review indicates that their effect on adolescent life is negative and far-reaching. It is critical that clinicians gain a greater understanding of the unique burden of AR and ARC in adolescents to ensure they receive prompt and appropriate care and treatment to improve clinical and academic outcomes.

Repeatability of nasal allergen challenge results: Further validation of the allergic rhinitis clinical investigator collaborative protocols.

BACKGROUND: Nasal allergen challenge (NAC) models have been used to study allergic rhinitis and new therapies. Symptoms and biological samples can be evaluated at time points after allergen exposure. OBJECTIVE: To verify protocol repeatability and adequate interval between allergen exposures. METHODS: Ten ragweed allergic participants were exposed to incrementally increasing dosages of ragweed allergen intranasally until they achieved a total nasal symptom score (TNSS) of 8 of 12 and a peak nasal inspiratory flow (PNIF) of 50% reduction or more from baseline. Three weeks later, participants were challenged with a cumulative dose equal to the sum of all the allergen doses received at screening. TNSS and PNIF were recorded at regular intervals, including a 24-hour assessment. A subsequent visit was conducted after a further 3 weeks. Nasal secretion samples were collected for cytokine and eosinophil quantification. RESULTS: Nine participants completed all visits. TNSS and PNIF responses followed previous patterns, with an initial peak at 30 minutes followed by a gradual decline. Most participants reported similar patterns at both NAC visits, although some did not demonstrate the same phenotype at both visits. Some experienced a secondary symptom increase 24 hours after NAC. Eosinophil and cytokine sections followed a similar pattern at both NAC visits. CONCLUSION: NAC is an adequate method for modeling AR in humans, demonstrating appropriate repeatability of symptoms, nasal mucosal eosinophil, and cytokines. The 24-hour time point, previously not studied in our model, may be beneficial in evaluation of long-acting medications. This three-week interval NAC model will be beneficial for studies in which before and after treatment comparisons are desired.