Regulation of IgE activity in inhalational tolerance via formation of IgG anti-IgE/IgE immune complexes

Background

Allergic asthma is an inflammatory disorder of the airways that results from inappropriate production of IgE against harmless, environmental antigens. Sequestration of free IgE using humanized IgG anti-IgE is an effective therapy for asthma and other atopic disorders. However, the status of free IgE in subjects who have naturally developed immune tolerance to inhaled antigens has not been well studied.

Methods

C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) for 7 days to induce allergic airway disease (AAD) or 6 weeks to induce a state of local inhalational tolerance (LIT). Serum from AAD or LIT mice, diluted to achieve equivalent levels of total OVA-specific IgE, was used to sensitize rat basophil leukemia cells for allergen-mediated degranulation. Levels of degranulation were measured in relation to serum concentrations of free IgE and IgG anti-IgE/IgE immune complexes.

Results

Serum from AAD animals induced a greater degree of basophil degranulation than serum from LIT animals. These results correlated with higher levels of free IgE in AAD animals, whereas LIT mice demonstrated a significant increase in IgG anti-IgE/IgE immune complexes relative to their diseased counterparts.

Conclusions

Sequestration of free IgE by naturally occurring IgG anti-IgE may aid in the development of immune tolerance against inhaled allergens. The decrease in bioavailability of free IgE may, in turn, contribute to the overall reduction of asthma symptoms via a mechanism that mimics the therapeutic effects of humanized IgG anti-IgE.

     

Effects of specific allergen immunotherapy on biological markers and clinical parameters in asthmatic children: a controlled-real life study

Background

Allergen-specific immunotherapy (AIT) is the only treatment able to change the natural course of allergic diseases. We aimed at investigating the clinical efficacy of SLITOR (Serbian registered vaccine for sublingual allergen specific immunotherapy).

Methods

7–18 years old children with allergic asthma and rhinitis were enrolled and addressed to the active (AIT plus pharmacological treatment) or control (standard pharmacological treatment only) group. Clinical and medications scores, lung function and exhaled FeNO were measured at baseline and at every follow-up.

Results

There was a significant improvement in both nasal and asthma symptom scores as well as in medication score in SLIT group. SLIT showed an important influence on lung function and airway inflammation.

Conclusions

Our data showed that SLITOR was effective not only in terms of patient reported outcomes but an improvement of pulmonary function and decrease of lower airway inflammation were also observed.

     

Survey on the impact of comorbid allergic rhinitis in patients with asthma

Background

Allergic rhinitis (AR) and asthma are inflammatory conditions of the airways that often occur concomitantly. This global survey was undertaken to understand patient perspectives regarding symptoms, treatments, and the impact on their well-being of comorbid AR and asthma.

Methods

Survey participants were adults with asthma (n = 813) and parents of children with asthma (n = 806) from four countries each in the Asia-Pacific region and Europe. Patients included in the survey also had self-reported, concomitant AR symptoms. Patients and parents were recruited by telephone interview or by direct interview.

Results

Most patients (73%) had pre-existing symptoms of AR when their asthma was first diagnosed. Shortness of breath (21%) was the most troublesome symptom for adults, and wheezing (17%) and coughing (17%) the most troublesome for children. Patients used different medications for treating asthma (most commonly short-acting β-agonists and inhaled corticosteroids) and for treating AR (most commonly oral antihistamines). The concomitant presence of AR and asthma disrupted the ability to get a good night's sleep (79%), to participate in leisure and sports activities (75%), to concentrate at work or school (69% of adults, 73% of children), and to enjoy social activities (57% of adults, 51% of children). Most patients (79%) reported worsening asthma symptoms when AR symptoms flared up. Many (56%) avoided the outdoors during the allergy season because of worsening asthma symptoms. Many (60%) indicated difficulty in effectively treating both conditions, and 72% were concerned about using excessive medication. In general, respondents from the Asia-Pacific region reported more disruption of activities caused by symptoms and more concerns and difficulties with medications than did those from Europe. Differences between the two regions in medication use included more common use of inhaled corticosteroids in Europe and more common use of Chinese herbal remedies in the Asia-Pacific region.

Conclusion

Results of this survey suggest that comorbid asthma and AR substantially impact patient well-being and that the worsening of AR symptoms in patients with asthma can be associated with worsening asthma symptoms. These findings underscore the need for physicians who treat patients with asthma to evaluate treatment options for improving symptoms of both AR and asthma when present concomitantly.

     

Allergic rhinitis and asthma: inflammation in a one-airway condition

Background

Allergic rhinitis and asthma are conditions of airway inflammation that often coexist.

Discussion

In susceptible individuals, exposure of the nose and lungs to allergen elicits early phase and late phase responses. Contact with antigen by mast cells results in their degranulation, the release of selected mediators, and the subsequent recruitment of other inflammatory cell phenotypes. Additional proinflammatory mediators are released, including histamine, prostaglandins, cysteinyl leukotrienes, proteases, and a variety of cytokines, chemokines, and growth factors. Nasal biopsies in allergic rhinitis demonstrate accumulations of mast cells, eosinophils, and basophils in the epithelium and accumulations of eosinophils in the deeper subepithelium (that is, lamina propria). Examination of bronchial tissue, even in mild asthma, shows lymphocytic inflammation enriched by eosinophils. In severe asthma, the predominant pattern of inflammation changes, with increases in the numbers of neutrophils and, in many, an extension of the changes to involve smaller airways (that is, bronchioli). Structural alterations (that is, remodeling) of bronchi in mild asthma include epithelial fragility and thickening of its reticular basement membrane. With increasing severity of asthma there may be increases in airway smooth muscle mass, vascularity, interstitial collagen, and mucus-secreting glands. Remodeling in the nose is less extensive than that of the lower airways, but the epithelial reticular basement membrane may be slightly but significantly thickened.

Conclusion

Inflammation is a key feature of both allergic rhinitis and asthma. There are therefore potential benefits for application of anti-inflammatory strategies that target both these anatomic sites.

     

A critical appraisal on AIT in childhood asthma

Abstract

Allergen immunotherapy (AIT) is the only disease-modifying treatment approved for allergic rhinitis and allergic asthma and represents a suitable therapeutic option, especially in childhood, to modify the progression of respiratory allergic diseases. Starting from the previous “generic class effect” evaluation, as testified by the numerous meta analyses, AIT is now considered a product-specific pathogenic-oriented treatment.

Background

AIT was empirically proposed more than one century ago in the subcutaneous form (SCIT), but the IgE-mediated mechanism of allergy was elucidated only after 50 years of clinical use of the treatment. The sublingual administration (SLIT) was developed during the 1980 ties, to achieve an improvement in safety and convenience. While SCIT is approved in the United States for the treatment of asthmatic patients with more than 12 years, so far few trials evaluated the clinical efficacy and safety of SLIT in children with allergic asthma, although the indications and some aspects remain unclear. Certainly, due to compliance problems, the age below 3 years may be reasonably considered a practical contraindication.

Conclusions

Given that some specific AIT products are effective and approved as drugs (AIFA, EMA, FDA), the use in children is still debated. Some aspects still need robust confirm: (a) the safety of AIT in asthma; (b) the optimal regimen of administration; (c) the role of AIT as preventative treatment for asthma development.

     

Selecting optimal second-generation antihistamines for allergic rhinitis and urticaria in Asia

Background

Allergic diseases are on the rise in many parts of the world, including the Asia–Pacific (APAC) region. Second-generation antihistamines are the first-line treatment option in the management of allergic rhinitis and urticaria. International guidelines describe the management of these conditions; however, clinicians perceive the additional need to tailor treatment according to patient profiles. This study serves as a consensus of experts from several countries in APAC (Hong Kong, Malaysia, the Philippines, Singapore, Thailand, Vietnam), which aims to describe the unmet needs, practical considerations, challenges, and key decision factors when determining optimal second-generation antihistamines for patients with allergic rhinitis and/or urticaria.

Methods

Specialists from allergology, dermatology, and otorhinolaryngology were surveyed on practical considerations and key decision points when treating patients with allergic rhinitis and/or urticaria.

Results

Clinicians felt the need for additional tools for diagnosis of these diseases and a single drug with all preferred features of an antihistamine. Challenges in treatment include lack of clinician and patient awareness and compliance, financial constraints, and treatment for special patient populations such as those with concomitant disease. Selection of optimal second-generation antihistamines depends on many factors, particularly drug safety and efficacy, impact on psychomotor abilities, and sedation. Country-specific considerations include drug availability and cost-effectiveness. Survey results reveal bilastine as a preferred choice due to its high efficacy and safety, suitability for special patient populations, and the lack of sedative effects.

Conclusions

Compliance to the international guidelines is present among allergists, dermatologists and otorhinolaryngologists; however, this is lower amongst general practitioners (GPs). To increase awareness, allergy education programs targeted at GPs and patients may be beneficial. Updates to the existing international guidelines are suggested in APAC to reflect appropriate management for different patient profiles and varying symptoms of allergic rhinitis and urticaria.

     

Asthma out of control? A structured review of recent patient surveys

Background

An understanding of the needs and behaviors of asthma patients is important in developing an asthma-related healthcare policy. The primary goal of the present review was to assess patient perspectives on key issues in asthma and its management, as captured in patient surveys.

Methods

Local, national, and multinational asthma surveys were reviewed to assess patient perspectives, and where possible healthcare provider (HCP) perspectives, on key issues, including diagnosis, treatment, control, quality of life, and other patient-centered outcomes. Twenty-four surveys, conducted or published between 1997 and 2003 in Europe and North America, were included in this review. Substantial differences among studies prevented a formal meta-analysis; instead, data were pooled to allow for general comparisons and qualitative analysis.

Results

The results indicate that patients' knowledge of the underlying causes of asthma and treatment options remains inadequate. Moreover, patients often tolerate poor symptom control, possess meager knowledge of correct drug usage, and display insufficient adherence to therapy. Many patients have a low expectation of receiving an appropriate therapy or of having a positive encounter with the HCP. Among HCPs, there is evidence of inadequate understanding of disease etiology and poor or unstructured communication with patients, resulting often in inaccurate assessment of disease severity. Moreover, patients often underreport their symptoms and severity, which in turn could lead to misclassification and undertreatment.

Conclusion

Improving patient education about the importance of achieving optimal asthma control, along with improved communication between patients and HCPs, emphasizing treatment options and optimal treatment of inflammation, may lead to better outcomes and improved asthma management in daily practice.

     

Association between HMGB1 and asthma: a literature review

Background

Recently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders. Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated to airway hyper-responsiveness and airway inflammation.

Objective

This literature review aims to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma.

Methods

We reviewed experimental studies that investigated the pathogenetic role of HMGB in bronchial airway hyper-responsiveness, inflammation and the correlation between HMGB1 level and asthma.

Results

A total of 19 studies assessing the association between HMGB1 and asthma were identified.

Conclusions

What emerged from this literature review was the confirmation of HMGB-1 involvement in diseases characterised by chronic inflammation, especially in pulmonary pathologies. Findings reported suggest a potential role of the alarmin in being a stadiation method and a marker of therapeutic efficacy; finally, inhibiting HMGB1 in humans in order to contrast inflammation should be the aim for future further studies.

     

Breaking new ground: challenging existing asthma guidelines

Background

While we have international guidelines and various national guidelines for asthma diagnosis and management, asthma remains poorly controlled in many children and adults. In this paper we review the limitations of current asthma guidelines and describe important issues and remaining questions regarding asthma guidelines for use, particularly in primary care.

Discussion

Clinical practice guidelines based on evidence from randomized controlled trials are considered the most rigorous and accurate. Current evidence-based guidelines are written predominantly from the perspective of the patient with a clear-cut asthma diagnosis, however, and tend not to consider the heterogeneity of asthma or to accommodate individual patient variations in response to treatment or their needs, differences in practice settings, or local differences in availability and cost of therapies. The results of randomized controlled trials, which are designed to establish efficacy of treatment under ideal conditions, may not apply to 'real-world' clinical practice, where patients are unselected, monitoring is less frequent, and effectiveness – the benefit of treatment in routine clinical practice – is the most relevant outcome. Moreover, most guidelines see asthma in isolation rather than considering other factors that may impact on asthma and response to asthma therapy, particularly age, allergic rhinitis, cigarette smoking, adherence, and genetic factors. When these links are recognized, guidelines rarely provide practical recommendations for treatment in these scenarios. Finally, there is some evidence that general practitioners are not convinced of the applicability of asthma guidelines to their practice settings, especially when those writing the guidelines principally work in specialist practice.

Conclusion

Developing country-specific guidelines or, ideally, local guidelines could provide more practical solutions for asthma care and could account for regional factors that influence patient choice and adherence to therapy. Pragmatic clinical trials and well-designed observational trials are needed in addition to randomized controlled trials to assess real-world effectiveness of therapies, and such evidence needs also to be considered by guideline writers. Finally, practical tools to facilitate the diagnosis and assessment of asthma and factors responsible for poor control, such as associated allergic rhinitis, limited adherence, and smoking behavior, are needed to supplement treatment information provided in clinical practice guidelines for asthma.

     

Roles of Bronchopulmonary C-fibers in airway Hyperresponsiveness and airway remodeling induced by house dust mite

Background

Asthma is characterized by chronic airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling. While exposure of house dust mites (HDM) is a common cause of asthma, the pathogenesis of the HDM-induced asthma is not fully understood. Bronchopulmonary C-fibers (PCFs) contribute to the neurogenic inflammation, viral infection induced-persistent AHR, and ovalbumin induced collagen deposition largely via releasing neuropeptides, such as substance P (SP). However, PCF roles in the pathogenesis of the HDM-induced asthma remain unexplored. The goal of this study was to determine what role PCFs played in generating these characteristics.

Methods

We compared the following variables among the PCF-intact and -degenerated BALB/c mice with and without chronic HDM exposure (four groups): 1) AHR and pulmonary SP; 2) airway smooth muscle (ASM) mass; 3) pulmonary inflammatory cells; and 4) epithelium thickening and mucus secretion.

Results

We found that HDM evoked AHR associated with upregulation of pulmonary SP and inflammation, ASM mass increase, epithelium thickenings, and mucus hypersecretion. PCF degeneration decreased the HDM-induced changes in AHR, pulmonary SP and inflammation, and ASM mass, but failed to significantly affect the epithelium thickening and mucus hypersecretion.

Conclusion

Our data suggest an involvement of PCFs in the mechanisms by which HDM induces allergic asthma via airway inflammation, AHR, and airway remodeling.

     

Prediction of missing common genes for disease pairs using network based module separation on incomplete human interactome

Background

Identification of common genes associated with comorbid diseases can be critical in understanding their pathobiological mechanism. This work presents a novel method to predict missing common genes associated with a disease pair. Searching for missing common genes is formulated as an optimization problem to minimize network based module separation from two subgraphs produced by mapping genes associated with disease onto the interactome.

Results

Using cross validation on more than 600 disease pairs, our method achieves significantly higher average receiver operating characteristic ROC Score of 0.95 compared to a baseline ROC score 0.60 using randomized data.

Conclusion

Missing common genes prediction is aimed to complete gene set associated with comorbid disease for better understanding of biological intervention. It will also be useful for gene targeted therapeutics related to comorbid diseases. This method can be further considered for prediction of missing edges to complete the subgraph associated with disease pair.

     

Markers of atopic dermatitis,allergic rhinitis and bronchial asthma in pediatric patients: correlation with filaggrin,eosinophil major basic protein and immunoglobulin E

Background

Allergic reactions have been implicated as contributions in a number of atopic disorders, including atopic dermatitis (AD), allergic rhinitis (AR) and bronchial asthma (BA). However, the potential for filaggrin protein, eosinophil major basic protein (MBP) and immunoglobulin E (IgE) to elicit allergic response or to contribute to atopic disorders remains largely unexplored in pediatric patients. This study was undertaken to investigate the status and contribution of filaggrin protein, eosinophil MBP and total IgE in pediatric patients with AD, AR and BA.

Methods

Sera from 395 pediatric patients of AD, AR or BA with varying levels of disease activity according to the disease activity index and 410 age-matched non-atopic healthy controls were evaluated for serum levels of atopic markers, including filaggrin, eosinophil MBP and IgE.

Results

Serum analysis showed that filaggrin levels were remarkably high in pediatric patients with AD, followed by BA and AR, whereas its levels were low in non-atopic pediatric controls. Eosinophil MBP levels in sera of atopic patients were significantly high as compared with their respective controls, but its levels were highest in AR patients, followed by AD and BA. Total IgE in sera of AD patients was markedly high, followed by AR and BA patients, whereas its levels were low in non-atopic pediatric controls. Interestingly, not only was an increased number of subjects positive for filaggrin protein, eosinophil MBP or total IgE, but also their levels were statistically significantly higher among those atopic patients whose disease activity scores were higher as compared with atopic patients with lower disease activity scores.

Conclusions

These findings strongly support a role of filaggrin protein, eosinophil MBP and IgE in the onset of allergic reactions in pediatric patients with AD, AR and BA. The data suggest that filaggrin, eosinophil MBP or IgE might be useful in evaluating the progression of AD, AR or BA and in elucidating the mechanisms involved in the pathogenesis of these pediatric disorders.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

The effect of 1,25-dihydroxyvitamin D<Subscript>3</Subscript> on TSLP,IL-33 and IL-25 expression in respiratory epithelium

Background

Airway epithelium is an active and important component of the immunological response in the pathophysiology of obstructive lung diseases. Recent studies suggest an important role for vitamin D₃ in asthma severity and treatment response.

Objective

Our study evaluated the influence of an active form of vitamin D₃ on the expression of selected mediators of allergic inflammation in the respiratory epithelium.

Material and Methods

Primary nasal and bronchial epithelial cells were exposed to1,25D₃ for 1 hour and were then stimulated or not with IL-4, TNF-α, LPS, and poly I:C. After 24 hours TSLP, IL-33, and IL-25 protein levels were measured in culture supernatants usingELISAandmRNAlevels in cells by real time PCR.

Results

1,25D₃ increased TSLP concentration in unstimulated nasal epithelial cells, but did not influence IL-33 and IL-25 expression. In IL-4-stimulated epithelial cell cultures 1,25D₃ mostly inhibited TSLP and IL-33 expression. In LPS-treated cultures 1,25D₃ decreased IL-33 expression. Simultaneously 1,25D₃ augmented IL-25 production in the same model of stimulation.

Conclusion

Our study revealed the dual nature of vitamin D₃ manifested in both pro- and anti-inflammatory properties observed in airway epithelial cells.

     

A case of atopic dermatitis caused by <Emphasis Type="Italic">Ascaris lumbricoides</Emphasis> infection

Background

Parasite infections stimulate total and specific IgE production that, in the case of Toxocara canis infection, corresponds to chronic allergic symptoms. There may also be other infections which have similar symptoms, such as Ascaris lumbricoides infection. Ascaris lumbricoides is a large nematode that causes abdominal pain, nausea, vomiting, bloating, anorexia and intermittent diarrhoea. Patients with ascaridiasis and high IgE levels may also have allergy-like symptoms such as asthma, urticaria and atopic dermatitis.

Case presentation

We report a case of atopic dermatitis caused by Ascaris lumbricoides which shows the important role of parasitic infection in patients with long-lasting dermatitis. The patient was a 12-year old female suffering since early infancy from atopic dermatitis and asthma. She was treated for dermatitis with oral bethametasone and topical pimecrolimus with little benefit. After two cycles of mebendazole therapy, the patient showed progressive improvement of symptoms.

Conclusions

In patients with dermatitis, Ascaris lumbricoides infection should be not excluded: adequate anthelmintic treatment may result in complete regression from the disease.

     

Amelioration of patients with chronic spontaneous urticaria in treatment with vitamin D supplement

Background

Spontaneous urticaria is a common allergic skin condition affecting 0.5–1% of individuals and may burden on health care expenditure or may be associated with remarkable morbidity.

Aim

In this study, we measured the effect of vitamin D supplementation in patients with a diagnosis of CSU. Furthermore, quality of life and cytokine changes were evaluated.

Methods

The clinical trial was conducted on 20 patients with idiopathic chronic urticaria. Vitamin D was administered orally for 8 weeks and disease activity was measured pre- and post-treatment using USS and DLQI. On the other hand expressions of IL-17, IL-10, Foxp3, and TGF-β by Real-time RT-PCR were assessed.

Results

USS questionnaire showed that severity of idiopathic urticaria after the intervention, which compared with the first day reached a significant 55% reduction. The DLQI quality of life questionnaire 2 months after treatment showed 55% improvement. Along with the significant improvement of clinical symptoms, use of vitamin D increase FOXP3 gene expression and downregulation of IL-10, TGF-B, and FOXP3, IL-17, but these changes were not statistically significant.

Limitation

These might happen due to lack of enrolled population in the investigation.

Conclusion

Vitamin D can be used along with standard medical care and it’s a safe and cost-effective method for the treatment of chronic urticaria with deficiency of vitamin D.

     

A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it

Introduction

Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.

Objectives

(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.

Methods

A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.

Results

Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.

Conclusion

Further efforts are required to improve data sharing in metabolomics.

     

The involvement of osmolarity in the safety of contrast media

Background

New non-ionic contrast agents, classified into low osmolar agents and iso-osmolar agents, present different biochemical characteristics that may influence the allergic reactions they cause. The aim of our study was to evaluate how osmolarity may affect safety in the use of contrast agents.

Case presentation

Six patients with a positive history for reaction to contrast agent were included in this study. Only one patient prick and intradermal skin test was positive. However, in 5 cases, patients presented an immediate reaction after administration of contrast agent that was not IgE mediated.

Conclusions

In this study, we focused on iodixanol, an iso-osmolar contrast agent, finding good safety of this product in patients with previous hypersensitivity reactions to contrast agent.