Etude de la réponse lymphocytaire T dans l'allergie de l'enfant, au diagnostic et au cours de la désensibilisation

Les maladies allergiques sont de plus en plus fréquentent. Elles atteignent souvent l enfant jeune chez qui l allergie respiratoire et l allergie alimentaire sont les principales pathologies. L unique traitement curatif est l immunothérapie spécifique d antigène (ITA), largement développée dans l allergie respiratoire et encore à ses débuts dans l allergie alimentaire. Pour adapter au mieux la prise en charge du patient, le diagnostic précis de l allergie est indispensable et il n existe actuellement pas d examen biologique totalement fiable. Seul, la présence d IgE spécifiques permet de diagnostiquer une sensibilisation à un allergène mais pas une allergie cliniquement symptomatique. Dans une première partie, nous avons étudié l intérêt d un test fonctionnel, l ELISpot (Enzyme-linked immunosorbent spot), dans le diagnostic de l allergie aux acariens chez l enfant asthmatique. Le nombre de lymphocytes T circulants spécifiques d acariens sécréteur d interleukine (IL)-4 ou d IL-13 était associé à la présence d une allergie symptomatique, indépendamment des IgE spécifiques. Il était plus élevé dans le cas d une rhinite allergique sévère et plus faible dans le cas d une rhinite allergique légère. De plus, il variait au cours de l année en fonction des saisons avec un pic en automne et un pic en début de printemps. Dans une deuxième partie, nous avons étudié l intérêt de l ELISpot dans le diagnostic de l allergie au lait de vache chez l enfant, confirmée par un test de provocation orale en double aveugle. Nous avons décrit que le nombre de lymphocytes T spécifiques de la caséine et sécréteurs d IL-4 et d IL-13 était associé à l allergie au lait de vache avec une sensibilité de 100%. Par ailleurs, le nombre de lymphocytes T spécifiques de la caséine était également associé à la dose maximale de lait tolérée par l enfant.Enfin, dans une troisième partie, nous avons étudié la réponse lymphocytaire T au cours d une ITA sub-linguale (SLIT) d une part et sous-cutanée (SCIT) d autre part, chez des enfants asthmatiques allergiques aux acariens suivis pendant une année. Nous avons décrit une diminution des lymphocytes Th2 (sécréteurs d IL-4 et IL-13) spécifiques d acariens après 12 mois de SLIT associée à une augmentation des cellules sécrétrices d IL-10 (Tr1) spécifiques d acariens après 6 mois de SLIT. De plus, les lymphocytes T régulateurs (CD4+CD25hiCD127loFoxp3+) étaient augmentés après 12 mois de SCIT. Nous n avons pas retrouvé de production accrue d interféron g (IFNg) par les lymphocytes T spécifiques d acariens au cours de la désensibilisation.Au total, ce travail nous a permis de décrire qu un test fonctionnel, l ELISpot, permet de réaliser un diagnostic fiable de l allergie aux acariens et de l allergie au lait de vache chez l enfant. Par ailleurs, l ITA induit une diminution des cellules Th2 et une augmentation des cellules Tr1 par voie sub-linguale ainsi qu une augmentation des Treg Foxp3+ par voie sous-cutanée sans immunodéviation Th2/Th1, chez l enfant allergique aux acariens.Allergic diseases are steadily increasing steadily and especially in children. Allergen specific immunotherapy (desensitization) is the only curative treatment for which accurate diagnosis of allergy is essential. Currently, the presence of specific IgE diagnoses a sensitization to an allergen but not a clinically symptomatic allergy. In a first part, we studied the value of a functional test, the ELISpot (Enzyme-linked immunosorbent spot) in the diagnosis of allergy to house dust mites (HDM). The number of circulating HDM-specific IL-4 and IL-13 secreting T cells was associated with the presence of symptoms, regardless of specific IgE and was higher in severe rhinitis than in mild rhinitis. In addition, it varied according to the season with a peak in autumn and a peak in early spring (wet periods with greater allergen exposure). In a second part, we studied the value of ELISpot for the diagnosis of cow's milk allergy in children, confirmed by double blind placebo control food challenge. We found that the number of casein-specific IL-4 and IL -13 secreting T-cells was associated with allergy to cow's milk. It was also inversely correlated to the cow s milk tolerated cumulative dose. Receiver-operating characteristic (ROC) curve of combined IL-4 and IL-13 analysis was generated. AUC was 0,98 (95% CI 0.90-1.06). For a cut-off of 10 IL-4- and 12 IL-13 secreting T-cells, sensitivity and negative predictive value were 100%.Finally, in the third part, we monitored antigen specific T-cell response in HDM allergic children treated with sublingual ITA (SLIT) on the one hand and subcutaneous ITA (SCIT) on the other hand, during one year. We found a decrease in HDM specific Th2 cells after 12 months of SLIT associated with an increase in HDM specific IL-10 secreting T-cells after 6 months of SLIT. In addition, regulatory T cells (CD4 + CD25hiCD127loFoxp3+) were increased after 12 months of SCIT. In conclusion, this work has allowed us to describe a functional test, the ELISpot, as a reliable tool for the diagnosis of mite allergy and cow's milk allergy in children. In addition, in HDM allergic children, a decrease of Th2 cells and an increase of IL-10 secreting T-cells was found in children treated with SLIT to HDM as well as an increase in Foxp3+ Treg in children treated with SCIT.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

An EAACI “European Survey on Adverse Systemic Reactions in Allergen Immunotherapy (EASSI)”: the methodology:the methodology

At present, there is no European report on clinically relevant systemic reactions due to the regular use of allergen immunotherapy (AIT), administered either subcutaneously or sublingually (SCIT and SLIT, respectively) outside clinical trials. Using an electronic survey and a “harmonised terminology” according to MedDRA, we aimed to prospectively collect systemic adverse reactions due to AIT from real life clinical settings. Under the framework of the EAACI, a team of European specialists in AIT, pharmacovigilance, epidemiology and drugs regulation set up a web-based prospective pilot survey to be conducted in three European countries (France, Germany and Spain). A designated “national coordinator” was responsible for following ethics requirements relative to each country and to select at least 30 doctors per country. Patients were recruited the same day they received their first dose of either SCIT or SLIT. Patient inclusion criteria were: adults and children, with IgE mediated pollen, house dust mite, Alternaria, and/or animal dander respiratory allergies who will initiate AIT. A list of 31 symptoms terms were extracted from the MedDRA (Medical Dictionary for Regulatory Activities) dictionary to harmonize the reporting of all adverse systemic reactions in this survey. The SurveyMonkey® online instrument was used by participant doctors to submit information directly to a blinded central database. Three questionnaires were generated: i) the Doctor Questionnaire, ii) the Patient Questionnaire and iii) the Adverse Reaction Questionnaire. A handbook and a mistake report form were given to each doctor. In this paper, we describe the methodology followed

Proteinase 3 mRNA expression is induced in monocytes but not in neutrophils of patients with cystic fibrosis

AbstractProteinase 3 (PR3), a serine proteinase which can degrade lung tissue, is present in the cystic fibrosis (CF) sputum. In the present study, PR3 protein and mRNA expression was determined in circulating neutrophils and monocytes. CF neutrophils contained similar PR3 concentrations as healthy controls and poorly expressed PR3 mRNA. In contrast, CF monocytes showed significantly higher PR3 concentrations than controls, together with an upregulation of PR3 mRNA expression especially during pulmonary exacerbation. Interestingly, antibiotic treatment fully abrogated PR3 mRNA expression and decreased PR3 protein in monocytes. Our findings highlight a potential role of monocyte-derived PR3 in CF-associated airway inflammation

Formaldehyde Exposure and Lower Respiratory Infections in Infants: Findings from the PARIS Cohort Study

Background: Certain chemical pollutants can exacerbate lower respiratory tract infections (LRIs), a common childhood ailment. Although formaldehyde (FA) is one of the most common air pollutants found in indoor environments, its impact on infant health is uncertain

Eur Respir J

Omalizumab is a monoclonal anti-IgE antibody used to treat severe allergic asthma (SAA). The aim of the STELLAIR study was to determine the importance of pre-treatment blood eosinophil count as a predictive measure for response to omalizumab.This retrospective real-life study was conducted in France between December 2015 and September 2016 using medical records of SAA omalizumab-treated patients. Response to omalizumab was assessed by three criteria: physician evaluation, reduction of >/=40% in annual exacerbation rate and a combination of both. Response rate was calculated according to blood eosinophil count measured in the year prior to omalizumab initiation.872 SAA omalizumab-treated patients were included by 78 physicians (723 adults (age >/=18 years) and 149 minors (age 6-17 years)). Blood eosinophil count was >/=300 cells.microL(-1) in 52.1% of adults and 73.8% of minors. By physician evaluation, 67.2% of adults and 77.2% of minors were responders and 71.1% adults and 78.5% minors had a >/=40% reduction in the exacerbation rate. In adults, the response rate for combined criteria was 58.4% (95% CI 53.2-63.4%) for blood eosinophils >/=300 cells.microL(-1) (n=377) and 58.1% (95% CI 52.7-63.4%) for blood eosinophils /=300 cells.microL(-1), and suggests that omalizumab effectiveness is similar in "high" and "low" eosinophil subgroups

Development of algorithms for the diagnosis and management of acute allergy in primary practice

Most patients presenting with allergies are first seen in the primary care setting. However, inadequacies in training and available guidance for general practitioners (GP) have been identified as significantly impacting the quality of care for these patients, resulting in inefficient use of healthcare resources. To address the lack of available guidance, a working group of French allergists has developed a series of online tools aimed at GPs. The expert panel developed algorithms for the diagnosis and treatment of common allergies by incorporating deliberations based on clinical guidelines and experience. In addition, they developed tables of common symptoms and detailed clinical cases that guide GPs through the typical decisions they are faced with in line with current best practice. These tools translate evidence-based recommendations from international clinical guidelines, outlining the key steps involved and assisting the physician in making decisions at each step. In addition to targeting improvements in diagnosis and standard of primary care, the tools also aim to reduce the burden on specialist allergy services by enabling GPs to diagnose and treat mild and moderate allergies, referring only severe and/or atypical cases to secondary care. The tools are adapted to the high primary care workload, enabling the physician to access essential information rapidly without unnecessary referrals to specialist allergy services. Keywords: Allergy, Primary care, Diagnosi

Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study

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The emerging landscape of dynamic DNA methylation in early childhood

Background: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood. Results: By analysing 538 paired DNA blood samples from children at birth and at 4-5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of rho <1.14x10(-7). Genes with an increase in age-differential methylation were enriched in pathways related to 'development', and were more often located in bivalent transcription start site (TSS) regions, which can silence or activate expression of developmental genes. Genes with a decrease in age-differential methylation were involved in cell signalling, and enriched on H3K27ac, which can predict developmental state. Maternal smoking tended to decrease methylation levels at the identified da-DMSs. We also found 101 a-DMSs (0.71%) that were regulated by genetic variants using cis-differential Methylation Quantitative Trait Locus (cis-dMeQTL) mapping. Moreover, a-DMS-associated genes during early development were significantly more likely to be linked with disease. Conclusion: Our study provides new insights into the dynamic epigenetic landscape of the first 8 years of life.Peer reviewe

Google Trends terms reporting rhinitis and related topics differ in European countries

Google Trends (GT) searches trends of specific queries in Google and reflects the real-life epidemiology of allergic rhinitis. We compared Google Trends terms related to allergy and rhinitis in all European Union countries, Norway and Switzerland from 1 January 2011 to 20 December 2016. The aim was to assesswhether the same terms could be used to report the seasonal variations of allergic diseases. Using the Google Trend 5-year graph, an annual and clear seasonality of queries was found in all countries apart from Cyprus, Estonia, Latvia, Lithuania and Malta. Different terms were found to demonstrate seasonality depending on the country - namely 'hay fever', 'allergy' and 'pollen' - showing cultural differences. A single set of terms cannot be used across all European countries, but allergy seasonality can be compared across Europe providing the above three terms are used. Using longitudinal data in different countries and multiple terms, we identified an awareness-related spike of searches (December 2016)