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Thymic stromal lymphopoietin (TSLP) is a pleotropic cytokine highly implicated in the pathophysiology of asthma and allergic diseases. Although there are robust data regarding the associations of TSLP polymorphisms with the development of allergy and asthma, there is very little information on how these TSLP variants functionally affect downstream effector pathways and disease phenotype. The overall objective of this thesis was to investigate how TSLP polymorphisms are linked to alterations in TSLP secretion and subsequent downstream cellular events. Initially, we investigated the influence of innate and adaptive stimuli on epithelial-derived TSLP expression and secretion, including effects on dendritic cells (DC). We show that polyinosinic:polycytidylic acid (polyI:C) and allergen-specific T cells induced enhanced TSLP secretion from asthmatic bronchial epithelial cells (BEC) compared to non-asthmatic BEC. Furthermore, activated-BEC culture supernatants induced TSLP-dependent CCL17 production from monocyte-derived DC in relation to clinical asthmatic status (Chapter 2). Next, we examined effects of TSLP on hemopoietic progenitor eosinophil-basophil (Eo/B) differentiation, demonstrating enhanced TSLP-mediated hemopoiesis ex vivo in relation to clinical atopic status. We further demonstrated p38MAPK-dependent autocrine signaling by TNFα in TSLP-mediated human Eo/B differentiation ex vivo (Chapter 3). Lastly, to explore the potential functional consequences of a key variant of the TSLP gene, we investigated associations between the rs1837253 TSLP variant and ex vivo production of TSLP in nasal epithelial cells (NEC). We showed that NEC derived from individuals with the “protective” minor allele have diminished TSLP secretion, which suggests that this rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion (Chapter 4). The novel work presented herein provides further evidence for TSLP regulation of distinct immunological pathways in allergic immune inflammatory airway responses initiated at the epithelial surface, and thus (by implication) of allergic disease. These observations support the concept that TSLP is potentially an important biomarker and therapeutic target for allergic diseases characterized by increased Th2 and/or eosinophilic-basophilic inflammation. Continued investigations into the functional mechanisms linking TSLP variants to allergic disease phenotype are of critical importance. / Dissertation / Doctor of Science (PhD)

[Truncated abstract] The dramatic increase in the expression of allergic diseases such as asthma and allergy over the last 20-30 years has highlighted the urgent need to identify causative factors. It was hypothesised that direct immune interactions between mother and fetus contribute to the cytokine milieu of pregnancy, thus influencing immune maturation after birth. Further it was speculated that the cytokine responses produced as a result of maternalfetal interactions are Th-2 skewed in women allergic disease, which programmes their offspring towards developing an allergic phenotype after birth. To test this hypothesis a cohort of 169 pregnant women were recruited at 20 weeks gestation and defined as allergic or non-allergic based on both clinical history and skin prick test sensitisation. These women and their infants were followed up throughout pregnancy (20 weeks, 30 weeks, 36 weeks gestation and 6 weeks post-partum) and up to 2.5 years of age. Mixed lymphocyte reactions (MLR) were used to measure maternal cytokine (IL-6, IL-10, IL-13 and IFN-) and lymphoproliferative responses to fetal alloantigens at each pregnancy time-point. Human leukocyte antigen (HLA) typing of mothers and infants were performed to assess the effect of HLA mismatch on maternal MLR responses to their fetus. After delivery, mononuclear cells (MNC) were isolated from cord blood (CB) and stimulated with allergens, mitogen and toll-like receptor (TLR) ligands. .... As IL-6 also participates in adaptive immunity by promoting Th-2 differentiation it is proposed that the production of IL-6 as a results of maternal encounters with paternal antigens during pregnancy, contribute to the Th-2 skewed responses observed universally in most infants at birth. Associations between maternal-fetal interaction and clinical outcomes in infancy: Although clinical signs of allergy in infancy were not the main outcome measure of this thesis, there were interesting, yet complex relationships between the production of these maternal cytokines towards the fetus and allergic disease at infant follow-ups. Increased maternal IFN-¿ to fetal alloantigen was associated with asthma at 2.5 years and a trend towards recurrent wheeze at 12 months. In contrast decreased maternal IL-13 production was associated with IgE mediated food allergy at 12 months. Adjusting for maternal allergy and other potential confounders including infant gender, method of delivery, HLA mismatch, and paternal allergy did not account for these relationships. Further follow-ups of these infants are required to determine if these relationship last in to early childhood. In conclusion, the findings of this thesis provides further support for the hypothesis that immune responses at birth are programmed prenatally, and that this programming has implications later in life. Importantly, the placenta is the immunologically active interface between mother and fetus during pregnancy. Therefore it is emphasised that there is a crucial need for future research to focus on early immune programming at the placental level before the aetiological pathways of immune mediated diseases can be fully elucidated.

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Background It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing incidence of allergic disease. The advent of powerful, cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts. Objective We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development. Methods Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool samples at 1 week, 1 month, and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age (ClinicalTrials.gov ID NCT01285830). Results Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month (P = .004) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month (P = .02 and P = .01) and the phylum Proteobacteria at 12 months of age (P = .02). The microbiota was less uniform at 1 month than at 12 months of age, with a high interindividual variability. At 12 months, when the microbiota had stabilized, Proteobacteria, comprising gram-negative organisms, were more abundant in infants without allergic manifestation (Empirical Analysis of Digital Gene Expression in R [edgeR] test: P = .008, q = 0.02). Conclusion Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema. / <p>Funding Agencies|BioGaia AB, Stockholm, Sweden||Ekhaga Foundation, the Heart and Lung foundation||Research Council for the South-East Sweden|F2000-106|Olle Engqvist Foundation||Swedish Asthma and Allergy Association||Swedish Research Council||University Hospital of Linkoping||Soderberg Foundation||Vardal Foundation for Health Care Science and Allergy Research, Sweden||BioGaia AB||</p>

Objectifs L'objectif de la thèse est de caractériser par PCR quantitative en temps réel (QPCR) l'environnement fongique, bactérien ainsi que l'exposition à d'autres organismes allergisants (acariens et animaux de compagnie). Cette caractérisation des logements a pour but de mieux comprendre les interactions entre les différents micro-organismes de l'environnement intérieur et leurs relations aux maladies allergiques, dans le cadre d'une étude de grande cohorte. L'objectif secondaire est la mise en place de nouvelles QPCR dans d'autres circonstances sanitaires (infections, PHS) afin de mieux caractériser l'impact des microorganismes de l'environnement. L'étude EBRA-ELFE L'étude ELFE incluant 18 319 enfants est la première cohorte française qui s'intéresse au développement des enfants de la naissance à leur majorité dans une approche multi­disciplinaire. Une étude nichée EBRA (Environnement microBiologique et Risque Allergique) est centrée sur l'étude microbiologique des poussières dans les chambres d'enfant. Le mode d'échantillonnage (par capteur électrostatique à poussière, EDC) et d'analyse (QPCR) ont été validés et optimisés pour garantir l'acceptabilité du dispositif et la qualité des quantifications. Un panel de 10 cibles (moisissures, acariens, bactéries) sélectionnées pour leur caractère allergisant, toxique, infectieux ou potentiellement protecteur vis-à-vis des maladies allergiques a été initialement utilisé. Ainsi lors de la première collecte à la naissance des enfants en 2011, 3217 CEP ont été quantifiés par QPCR. Les concentrations de six moisissures (Aspergillus fumigatus, Aspergillus versicolor, Alternaria alternata, Cladosporium sphaerospermum, Penicillium chrysogenum, Stachybotrys chartarum), trois groupes de bactéries (Enterobacteriaceae, Mycobacteria et Streptomyces) et un acarien (Dermatophagoïdes pteronissynus) de l'environnement immédiat du nouveau-né ont été obtenues. Ces données ont permis d'identifier six profils de logements différents avec un gradient géographique E-O recouvrant la distribution des sifflements de l'asthme en France. Un deuxième panel de 10 cibles a été choisi et documenté. Il inclut entre autres des cibles « chien » et « chat » pour proposer un test complet comprenant les allergènes principaux des logements. La collaboration avec le groupe ELFE continue et un projet pour une deuxième campagne d'échantillonnage à 5 ans se met en place. L'utilisation de la QPCR pour caractériser d'autres situations à risque. La QPCR est un outil de quantification standardisé et reproductible et ses applications sont multiples. Au cours de ce travail de thèse, elle a été utilisée pour caractériser d'autres situations à risque : quantifier la présence de Thermoactinomyces vulgaris dans les aérosols des stations de compostages, détecter la présence d'Aspergillus fumigatus dans des environnements pouvant recevoir des patients immunodéprimés, mettre en évidence la présence d'ADN d' Aspergillus fumigatus ou de mucorales dans le sérum de patients immunodéprimés. Conclusion Les outils développés et les résultats obtenus pendant la thèse représentent une avancée pour une meilleure connaissance du monde microbien qui nous entoure et contribueront à mieux comprendre les mécanismes de développement des maladies allergiques / Objectives The aim of the study is to characterize by quantitative real-time PCR (QPCR) fungal, bacterial environment as well as exposure to other allergenic organisms (mites and pets). This characterization of dwellings aims to better understand the interactions between the different micro-organisms of the indoor environment and their relation to allergie diseases. The secondary aim is the use of other QPCRs in other health circumstances (infections, ABPA) te better characterize the impact of environmental microorganisms. The EBRA-ELFE study The ELFE study, which includes 18,319 children, is the first French cohort to study the development of children from birth to majority in a multi-disciplinary approach. A nested study EBRA (MicroBiological Environment and Allergie Risk) focuses on the microbiological compositior of dust in children's rooms. The electrostatic dust collector (EDC) sampling and analysis mode has been validated to guarantee an acceptable system (in terms of cost and constraints for the participants) and to optimize the quality of QPCR quantification. A panel of 10 targets (molds, mites, bacteria) selected for their allergenic, taxie, infectious or potentially protective effect against allergie diseases was initially used. Thus during the first sampling at birth of children in 2011, 3217 EDC were quantified by QPCR. The concentrations of six molds (Aspergillus fumigatus, Aspergillus versicolor, Alternaria alternata, Cladosporium sphaerospermum, Penicillium chrysogenum, Stachybotrys chartarum), three groups of bacteria (Enterobacteriaceae, Mycobacteria and Streptomyces) and one mite (Dermatophagoides pteronissynus) of the immediate environment of the new have been obtained. These data made it possible to identify six different dwelling profiles A second panel of 10 targets was chosen and documented. It includes "dog" and "cat" targets te propose a complete test including the main allergens of the dwellings. The collaboration with thE ELFE group continues and a project for a second 5-year sampling campaign is set up.The use of QPCR for the use of QPCR other risk situations The QPCR is a standardized tool, reproducible, allowing quantification and its applications are multiple. During this work, it was used to characterize other risk situations: presence of Thermoactinomyces vulgaris in the aerosols of composting stations, presence of Aspergillus fumigatus in environments that could receive immunocompromised patients , the presence of Aspergillus fumigatus DNA or mucorales in the serum of immunocompromised patients. Conclusion Tools developed and the results obtained during the study represent a step forward for a better knowledge of the microbial envrionnement and will contribute to a better understanding of the mechanisms of development of allergie diseases