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Autoimmune haemolytic anaemia provides an opportunity to characterise the T-cell response to an autoantigen of known pathological relevance. In most cases, AIHA is characterised by the production of autoantibodies to the Rh proteins. The aims of this work were to confirm that human AIHA is T-helper cell dependent and whether specific immunotherapy could be developed to target the T-helper cell response. Peripheral blood mononuclear cells (PBMC) were isolated from patients with either primary AIHA and stimulated in vitro with a panel of 42 15-mer peptides with 5 mer overlaps spanning the entire sequence of the RhD and CE proteins. PBMC with 22/27 patients proliferate in response to stimulation with at least one of these peptides compared to only 4/14 healthy donors. The proliferating cells were identified as T-helper cells by flow cytometry analysis and abrogation of the response using MHC class II blocking antibodies. There is a predominance of HLA-DRB*1501 and HLA-DQB*06 haplotypes whilst the HLA-DRB1*07 haplotype is under represented amongst the panel of primary AIHA patients. Antibodies directed against HLA-DR and HLA-DQ can inhibit the T-cell response to peptides from the Rh proteins (anti-HLA-DR>anti-HLA-DQ) suggesting that these MHC class I molecules play an important role in presenting the synthetic Rh peptides. The pathogenic T-helper cell response to RhD protein in vivo, may depend upon the balance of pathogenic and regulatory epitopes that are processed and presented by antigen presenting cells.

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Comment réalisons-nous des mouvements volontaires ? Quels mécanismes nous permettent de saisir des objets ou de s’orienter dans un environnement ? Certains travaux suggèrent que des représentations au sein du système nerveux central sont à la base d’actions banales telles que des mouvements d’atteinte manuelle vers un objet ou de la mémorisation de la disposition d’un centre commercial. Cependant, la nature de ces représentations reste à clarifier. Pour ce qui concerne le contrôle des mouvements du membre supérieur, deux principaux types de représentations du mouvement ont été proposés avec des représentations selon un système de coordonnées extrinsèque (représentations référées dans un espace normé, droite/gauche ; haut/bas…) et un système intrinsèque (représentations référées aux muscles et articulations, flexion/extension ; abduction/adduction…). Pour ce qui concerne la représentation de l’espace, deux systèmes de coordonnées pourraient être utilisés : un système allocentré (représentations référées dans un espace normé, cartésien ou polaire) et un système égocentré (représentations référées son propre corps). L’objectif de cette thèse était de clarifier la nature des représentations utilisées pour le contrôle sensorimoteur et la cognition spatiale. Nous nous sommes également intéressés aux modalités sensorielles impactant à la fois le contrôle sensorimoteur et la cognition spatiale, en se concentrant sur la vision et la proprioception. / How do we achieve voluntary movements? What mechanisms allow us to grasp objects or orient ourselves in an environment? Previous work suggests that representations within the central nervous system underlie trivial actions such as reaching movements toward an object or memorizing the layout of a shopping center. However, the nature of these representations remains unclear. Regarding the control of upper limb movements, two main types of movement representations have been proposed, with representations according to an extrinsic coordinate system (representations referred to a normed space, right/left, up/down...) and an intrinsic system (representations referred to muscles and joints, flexion/extension, abduction/adduction...). With respect to the spatial representation of an environment such as a park, two coordinate systems could be used: an allocentric system (with references between landmarks, in a cartesian or polar space) and an egocentric system (with references to its own body). The aim of this thesis was to clarify the nature of the representations used for sensorimotor control and spatial cognition. We were also interested in how sensory modalities impact both sensorimotor control and spatial cognition, and we specifically focused on vision and proprioception.

Au cours de la neurogenèse post-natale, des cellules souches prédéterminées résidant dans la zone ventriculo-subventriculaire génèrent continuellement des progéniteurs qui migrent à travers le flux migratoire rostral, se différencient et s'intègrent dans le bulbe olfactif (BO). Dans mon travail de thèse, j’ai démontré que le facteur de transcription bHLH NeuroD6 est spécifiquement et transitoirement exprimé dans le lignage neurogenique dorsal qui génère les cellules juxtaglomérulaires (CJGs) glutamatergiques pour le bulbe. J'ai apporté de nouvelles connaissances sur la période de génération des CJGs glutamatergiques, ainsi que sur leur morphologie et connectivité. J'ai cherché à élucider leur rôle dans le circuit neuronal du BO. Dans une première approche, j'ai soumis ces neurones à une privation sensorielle et je les ai suivis au cours du temps par imagerie in vivo. J'ai trouvé que, contrairement aux interneurones GABAergiques du BO, les CJG glutamatergiques survivent dans ces conditions difficiles, suggérant un équilibre homéostatique et dynamique entre excitation et inhibition dans ce système. Dans une deuxième approche, j'ai caractérisé les profils de réponse olfactive des CJG glutamatergiques à l'aide de souris GCaMP6s, pour examiner l'activité neuronale. J'ai découvert que ces neurones présentent un ensemble diversifié de réponses excitatrices, inhibitrices et mixtes avec différents degrés d'homo- et d'hétérogénéité dans les glomérules individuels. Ces résultats représentent les premières données in vivo sur la réponse olfactive disponibles pour les CJG glutamatergiques et renforcent l'idée que ces neurones agissent comme amplificateurs du signal sensoriel. / During postnatal OB neurogenesis, predetermined stem cells residing in the ventricular-subventricular zone continuously generate progenitors that migrate through the rostral migratory stream and integrate into the OB. Although the vast majority of these postnatally generated interneurons are inhibitory, a sub-fraction represents glutamatergic interneurons that integrate into the superficial glomerular layer. I have thus set out to study excitatory juxtaglomerular cells (JGCs) in more detail. In the following work I demonstrate that the bHLH transcription factor NeuroD6 is specifically and transitorily expressed in the dorsal neurogenic lineage that generates glutamatergic JGCs for the OB. I provide new insight into timing of generation, morphology and connectivity of glutamatergic JGCs. Further, I sought to elucidate their role in the OB circuit. In a first approach, I subjected these neurons to sensory deprivation and followed them over time using chronic in vivo imaging. Interestingly, I found that, contrary to GABAergic OB interneurons, glutamatergic JGCs survive under these conditions, pointing to a possible homeostatic balance between excitation and inhibition. In a second approach, I characterized odor-evoked response profiles of glutamatergic JGCs using GCaMP6s mice to monitor neuronal activity. I found that these neurons display a diverse set of excitatory, inhibitory and mixed responses with different degrees of homo- and heterogeneity across individual glomeruli. These results represent the first in vivo data on odor-response available for glutamatergic JGCs and strengthen the notion that these neurons act as signal amplifiers to gate glomerular output.

Operating in a hot environment when wearing clothing that is moisture vapour restrictive and thermally insulative, such as chemical and biological (CB) protective equipment, places a thermal burden on the wearer. The first two experiments addressed the general aim of this thesis, which was to quantify the thermoregulatory strain associated with wearing chemical, biological, radiological and nuclear (CBRN) individual protective equipment (IPE). CBRN IPE comprises of a suit (material of a low air permeability) and moisture vapour impermeable (MVIP) ancillary items such as a respirator, gloves and overboots, which increase insulation and impede evaporative cooling. The thermal burden associated with wearing military body armour (BA) was also quantified. Subsequent aims to investigate thermoregulatory control were explored in the third and fourth experiments. This thesis tested the general hypothesis that: improving the moisture vapour permeability (MVP) of CBRN ancillary items would alleviate thermoregulatory strain when worn in a hot, desert-like environment, and assessed whether a reduced thermoregulatory strain would be equal between the improved items. The aim of the first study was to quantify the thermal burden imposed by each MVIP ancillary IPE, and that of the MVIP BA during exercise and recovery in a hot and dry environment. The thermal burden of each item was quantified by the measured reduction to thermoregulatory strain (internal and surface body temperature, heart rate, whole body sudomotor response and perceptual measures) when the item was not worn, thereby simulating the idealistic situation of a 100 % MVP material. To isolate only the thermal burden of the items, and not the metabolic cost associated with wearing the items, when an item was not worn a weight equivalent to the mass of the item was secured to the area from where the item had been removed. During the first experiment, at the sponsor’s request, the thermal burden of items were assessed cumulatively such that items were progressively not worn and the thermal load on the wearer gradually lessened as fewer items were worn over the different conditions. It was found that not wearing any one of the MVIP ancillary items decreased thermoregulatory strain, perception of thermoregulatory strain or both. The BA, represented by a soft armour liner (BAL) with a mass of 170 g reflecting the shape and impermeability of BA but without the weight, alleviated the greatest thermoregulatory strain on participants when not worn. This was evident by a 16.1 % (p < 0.001) improvement to the rate of whole body sweat evaporation and an enhanced rate of cooling of rectal temperature (T_re) by 0.31 °C.hr^-1 (p < 0.05) during the 20-minute recovery period at the end of the protocol compared to the adjacent condition when the BAL was worn. Participants also felt less hot and less uncomfortable at some points during the protocol when the BAL was not worn. The least improvement to thermoregulatory strain occurred when the overboots were not worn as the only measure to be improved was a 35.2 minute (14.8 %, p < 0.05) increase to the predicted tolerance time (TT) to a T_re of 40 °C, or 28.5 minute (13.7 %, p < 0.05) improvement to a T_reof 39.5 °C. Improving the MVP of the gloves or respirator also improved whole body physiological and perceptual thermoregulatory measures to a greater degree than improving the MVP of the overboots, but to a lesser degree than the BAL. The aim of the second study was to again quantify the thermal burden associated with each item but individually, not in a cumulative order, to obtain the true thermal burden of the item that was unaffected by reducing the overall thermal load placed on the body during later conditions, as in the first study. It was found that not wearing the gloves best alleviated thermoregulatory strain on participants, attenuating the rate of rise of T_re during continuous work by 0.37 °C.hr^-1 (20.3 %, p < 0.001) culminating in an extended TT during continuous work by 9.2 minutes (21.3 %) in a 60-minute period (p < 0.05) compared to when the gloves were worn during the fully encapsulated condition. Perceptually, participants also felt less uncomfortable at some time points when the hands were exposed. Again, not wearing the overboots minimally reduced thermoregulatory strain. Improving the MVP of the BAL or respirator also reduced whole body thermoregulatory strain to a greater degree than improving the MVP of the overboots, but to a lesser degree than the gloves. Compared to the second study, underestimations of the thermal burden of the last items not to be worn during the first study (gloves and overboots) occurred during exercise, most likely because these items had less of a thermal load over which to demonstrate an improvement in the first study. The first two studies highlighted that whole body thermoregulatory strain could be reduced during exercise-induced hyperthermia when wearing CBRN IPE, when only small body surface areas, such as the hands or face, were exposed, and might have influenced whole body thermoregulatory responses such as sweat rate or skin blood flow (SkBF). Thus, the aim of the third study was to determine whether exposing either the hands or the head to a hot, desert-like environment would result in the greatest change to local sweat rate (LSR) and SkBF at the torso, forearm and thigh, as well as whole body thermal perception during exercise. To isolate the influence of temperature perturbations only at the treated sites (the head or hands) on thermoregulatory responses, measures were analysed at the same mean body temperature (T̅_b) during each condition. Thus, the influence of skin temperature (T_sk) from the untreated tissues (i.e. not the head or hands) on the changes to LSR and SkBF was minimal between conditions, and any differences would then be attributable to the perturbed local Tsk at the treated sites. However, no significant differences in LSR or SkBF at the torso, forearm or thigh, or whole body perceptual measures when T̅_b was 37.5 °C during exercise, were identified during exposure of either the head or hands. The lack of significant findings was attributed to either thermal sensitivity being altered with the introduction of exercise or the methodological shortcomings of the study such as: the magnitude of the stimulus not being sufficient to elicit a measurable response; the equipment not being sensitive to detect small differences; or the day-to-day variations in the thermoregulatory response outweighing any measurable differences. During the third study it was noted that post-exercise, SkBF declined at all sites and LSR declined at all sites except the chest, even though T̅_b remained elevated and these areas covered. Therefore, the aim of the fourth study was to determine the influence of non-thermal mechanisms on LSR and SkBF responses post-exercise, and whether any of these mechanisms could result in the regional variations seen in the third study. It was found that as there was a homogenous sweat pattern response at regional sites (chest, back, forearm and thigh), the mechanism governing the sudomotor response was most likely systemic and was influenced by oesophageal temperature (T_oe), exercise and/or posture. The regional LSR responses identified in the third study might have been due to an artifact of the confounding effects of clothing and/or mechanical pressure imposed on the sweat capsules. Further research was necessary, that standardized the duration of exercise pre-posture and clamped T_oe post-exercise, to investigate the finding that the greatest decrease to LSR was during standing and sitting with the magnitude of the response being less during lying (lateral, prone and supine). In conclusion, efficient thermoregulation is compromised in the encapsulated environment but can be improved by reducing the thermal burden of any of the ancillary items but particularly the MVIP gloves. To the sponsor, this might pose an attractive avenue for future improvements as air permeable prototype gloves have already gone through the initial product development and human testing phase as annexed in this thesis. / Overall, the general null hypothesis was rejected and the experimental hypothesis was accepted that improving the MVP of CBRN ancillary items alleviated thermoregulatory strain when exercising in a hot, desert-like environment, and that the reduced thermoregulatory strain was not equal between items.

Recent evidence suggests heat acclimation (HA) may improve exercise performance under cooler conditions and that combined-stressor approaches might optimise HA. Accordingly, the studies presented in this thesis examined strategies for optimising HA in well-trained athletes through the use of combined-stressor approaches and the subsequent effects on exercise in a temperate environment (cross-stressor). The first two studies examined the effect of dehydration in combination with exercise-heat stress on HA over the short- and longer-term and its subsequent decay, as well as investigating thermoregulation, parameters related to endurance performance and performance, in temperate conditions. Study three examined the addition of an overnight hypoxic stressor on short- and longer-term HA and endurance exercise performance in a temperate environment, after HA and following a 2-week decay. The final study comprehensively explored the ergogenic potential of heat acclimation for endurance performance in a temperate environment, relative to a cool exercise control group. Together these studies demonstrated that the majority of the alterations associated with HA are rapidly induced (5-days) but longer programmes (10-days) are necessary to optimise these adaptations; they are well maintained over a short decay period (7-days). Combined stressor approaches (addition of dehydration or hypoxia) did not meaningfully affect the rate or magnitude of the induction of HA. Finally, HA did not induce any greater ergogenic benefit than a cool exertion matched exercise programme in a temperate environment. In conclusion, HA is rapidly induced, robust, and the HA phenotype is minimally influenced by combined stressors (dehydration or hypoxia) when thermal strain is clamped. Moreover, when compared to an ecologically valid control, HA does not notably influence endurance performance or its related parameters in a temperate environment. These extensive findings provide useful guidance for athletes utilising environmental stressors in preparation for competition in various conditions.