ED Sciences de la Vie et de la Santé
CHARACTERIZATION OF HUMAN GUT-DERIVED T FOLLICULAR HELPER CELLS IN HEALTH TO COMPREHEND THEIR RELEVANCE IN AUTOIMMUNITY.
by Iris HASANTARI (Immunologie Conceptuelle, Expérimentale et Translationnelle)
The defense will take place at 14h00 - Salle de conferences, CARF CARF - Université de Bordeaux Campus Carreire, 46, rue Léo Saignat 33076 Bordeaux Cedex
in front of the jury composed of
- Nathalie SCHMITT - Chargée de recherche - Université de Bordeaux - CNRS UMR5164 - Directeur de these
- Luis GRACA - Professeur des universités - Universidade de Lisboa- Instituto de Medicina Molecular João Lobo Antunes - Rapporteur
- Arsène MEKINIAN - Professeur des universités - praticien hospitalier - Department of Internal Medicine, Saint-Antoine Hospital, APHP, Sorbonne University, - Rapporteur
- Carole LE COZ - Chargée de recherche - Institut Toulousain des Maladies Infectieuses et Inflammatoires CHU Purpan - Examinateur
- Helena PAIDASSI - Chargée de recherche - Université Claude Bernard Lyon 1, Bâtiment Rosalind Franklin - Examinateur
- Thierry NOEL - Professeur des universités - Université de Bordeaux - UMR MFP - Examinateur
Over the past two decades, studies in human and animal models have highlighted the impact of the composition of the gut microbiota on the physiopathology of multiple diseases including autoimmune diseases (AID). The gut microbiota influences health and disease through different pathways including bacterial metabolites, neural signals but also through its impact on the properties of gut immune cells. In mouse models of AID, several studies have shown that the composition of the gut microbiota can alter the properties of gut immune cells which can in turn migrate to different target organs and affect the diseases susceptibility and/or course. These studies raised a broader question about the role of gut-derived immune cells in the pathogenesis of human AID whether or not associated to dysbiosis. T follicular helper (Tfh) cells are a CD4+ T cell subset specialized in helping B cells. They provide B cells with signals required for the generation of antibody-secreting long-lived plasma cells and memory B cells. Due to their specialization in providing help to B cells, Tfh cells play a central role in the pathogenesis of AID. We hypothesize that gut-derived Tfh cells could be relevant in an AID context, yet their characteristics, including under physiological conditions, remain poorly defined. The aim of this PhD is therefore to characterize phenotypically and functionally human gut-derived Tfh cells in a physiological context to better understand their role in the pathogenesis of AIDs.
Social emotional profile and circuits in two mouse strains expressing alpha5 nicotinic receptor mutations linked to alcohol abuse
by Cécile PAGEZE (Institut de neurosciences cognitives et intégratives d'Aquitaine)
The defense will take place at 14h00 - Amphithéâtre du BBS Batiment BBS, 2 Rue Hoffman Martinot, 33000 Bordeaux
in front of the jury composed of
- Vincent DAVID - Chargé de recherche - Université de Bordeaux - Directeur de these
- Mickaël NAASSILA - Professeur des universités - Université de Picardie Jules Verne - Rapporteur
- Elodie EY - Chargée de recherche - Université de Strasbourg - Rapporteur
- Liana FATTORE - Directrice de recherche - University of Cagliari - Examinateur
- Francesco PAPALEO - Full professor - Instituto Italiano di Tecnologia, Genova - Examinateur
- Jacques BARIK - Professeur des universités - Université Côte d'Azur - Examinateur
Genetic association studies have identified single nucleotide polymorphisms (SNPs) in the CHRNA5 gene, which encodes the α5 subunit of nicotinic acetylcholine receptors (α5-nAChRs), as factors of increased vulnerability to alcohol use disorders (AUD). To investigate the functional implications of this genetic risk, two transgenic mouse models were studied: one expressing a human variant of the α5 SNP (α5KI mice), and the other carrying a complete deletion of the α5 subunit (α5KO mice). It has previously been demonstrated that both lines recapitulate behavioural phenotypes characteristic of AUD, including excessive alcohol consumption, while exhibiting opposing pre-consumption profiles (anxiety vs impulsivity), reflecting distinct clinical subtypes observed in patients. Beyond these behavioral alterations, impairments in social emotional processing are now recognized as central features of AUD. However, the underlying neurobiological mechanisms, as well as the status of these impairments, whether as cause or consequence of the disorder, remain poorly understood. In this context, the present thesis aimed to characterize the ability to discriminate affective states and its neuronal correlates in α5KI and α5KO mice, both before and after chronic alcohol exposure, and to determine the involvement of the projection from the basolateral amygdala (BLA) to the ventral hippocampus (vCA1) in these processes. The results reveal marked deficits in emotion recognition in both mutant lines. Moreover, chronic alcohol exposure induces alterations in social emotional behavior, with sex-specific effects, highlighting the critical role of biological sex as a key variable in the study of social dysfunctions associated with AUD. By combining complementary experimental approaches of fiber photometry, in vivo electrophysiology, and optogenetics, this work identifies the BLA–vCA1 projection as a key circuit involved in the discrimination of affective states. These findings underscore the central role of α5-nAChRs in the modulation of emotional recognition processes and position the BLA-vCA1 pathway as a previously underexplored neural substrate in the context of addictive disorders.