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Biomarqueurs endotypiques et réponses immunitaires aux infections respiratoires au cours d’une exacerbation sévère chez l’enfant asthmatique

Abstract : During the first years of life, the lung and airway grows and the immune system, immature at birth, develops. Innate immunity, as the first line of host defense, plays a key role and contributes to the imbalance of the neonatal adaptive response, characterized by an inherent bias against anti-infectious immunity that facilitates an allergic response. The hygiene hypothesis suggests that the development of asthma is, in part at least, attributable to immune dysregulation due to lack of exposure to certain microorganisms.Asthma, the most frequent chronic disease in children, is favored by genetic, epigenetic, and environmental risk factors. Different evolutionary patterns have been described, and the factors likely to influence the natural history of asthma are multiple. In terms of structural damage, remodeling appears early in the natural history of asthma, probably between 3 and 6 years of age. The preschool age could therefore constitute a window of opportunity to characterize severe asthma and to prevent irreversible lesions. Several approaches have made it possible to categorize asthma patients, either by identifying their specific clinical characteristics, named “phenotype”, or by the underlying pathophysiological process leading to inflammation, named “endotype”. Exacerbations are a particular event, frequent in young children, which is conducive to the study of the inflammatory response.Hypothesis: The heterogeneity of asthma phenotypes in children is the result of inter-individual variability of the bronchial mucosa immune response, partly determined by genetic factors, and partly influenced by environmental, among which microbial exposures. A better understanding of childhood asthma, taking into account its mechanisms, could lead to improved treatment to prevent functional impairment and anatomical damage. Objectives and main results of the PhD thesis:1/ To describe factors associated with severity in asthmatic children.The analysis of data from the French national CobraPed cohort suggests that factors influencing asthma severity may differ according to age: exposure to tobacco and/or molds is associated with severity at preschool age, whereas atopic diseases are associated with severity at school age.2/ To correlate endotypes and phenotypes at preschool age. The analysis of the immune response during respiratory infections (VIRASTHMA 2) showed in the most severe children, prone to exacerbations, lower systemic levels of Th1 and Th2, pro- and anti-inflammatory cytokines and antiviral responses during a severe virus-induced exacerbation.3/ To correlate endotypes and evolutionary phenotypes. The analysis of the immune response in parallel with the clinical evolutionary profile at one year in school-age children (VIRASTHMA) did not display a relationship between the cytokine profile at the time of exacerbation and future risk of poor asthma control and/or recurrence of exacerbations.4/ To generate hypotheses on the interactions between microbiota and atopy. The analysis of untargeted profiling of the plasma metabolome from children from the VIRASTHMA 1 and 2 cohorts allowed to identify a defect in secondary bile acids associated with atopy, suggesting that these metabolites, known to be generated by the intestinal microbiota and with immunomodulatory functions, could play a key role in tolerance during childhood. In conclusion, this thesis confirms the utility of phenotyping asthmatic children and describing their environment. Prone to exacerbation phenotype could correspond to a distinct endotype, characterized by a defect of the anti-infectious response. The microbiota also plays a key role in the development of atopy and the perpetuation of asthma.
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Submitted on : Wednesday, November 3, 2021 - 11:35:14 AM
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Stéphanie Lejeune. Biomarqueurs endotypiques et réponses immunitaires aux infections respiratoires au cours d’une exacerbation sévère chez l’enfant asthmatique. Médecine humaine et pathologie. Université de Lille, 2021. Français. ⟨NNT : 2021LILUS017⟩. ⟨tel-03412701⟩

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