Introdução: O pênfigo foliáceo endêmico (PFE) ou Fogo Selvagem (FS) é uma dermatose bolhosa autoimune com auto-anticorpos IgG patogênicos, principalmente da subclasse IgG4, direcionados contra epítopos da desmogleína 1 (Dsg1), uma glicoproteína desmossômica que desempenha papel na adesão celular da epiderme. Os auto-anticorpos ligam-se a domínios específicos da Dsg1, gerando acantólise (perda da adesão celular) através de mecanismos diversos, tais como sinalização intracelular de moléculas e impedimento estérico. A etiopatogenia do FS é multifatorial, apresentando interações entre fatores imunológicos, genéticos e ambientais. Em algumas regiões do Brasil, detectou-se alta prevalência de FS (3%), sugerindo importante participação de fatores ambientais como desencadeantes da resposta autoimune. Indivíduos saudáveis de áreas endêmicas de FS reconhecem epítopos não-patogênicos da Dsg1, e exposição a insetos hematófagos é um fator de risco para FS. FS e doença de Chagas compartilham algumas regiões geográficas, e anticorpos anti- Dsg1 foram detectados em doentes de Chagas. Na reserva indígena Terena (Limão Verde), onde a prevalência de FS é alta, a população está exposta a picadas de simulídeos, cimecídeos e reduvídeos. Estes insetos podem atuar como vetores de doenças, bem como na imunomodulação do processo autoimune do FS. Objetivos: Nosso estudo teve como objetivos: 1- avaliar a frequência de anticorpos anti-Trypanosoma cruzi em doentes de FS e na população saudável da área de alto risco para FS, habitantes da aldeia indígena de Limão Verde, Mato Grosso do Sul, Brasil; 2- avaliar a reatividade concomitante contra Dsg1 e T. cruzi nessa população de alto risco para FS. Métodos: Realizamos ensaio sorológico de ELISA (enzyme linked immunosorbent assay) para reatividade contra Dsg1 e contra T. cruzi em 40 doentes de FS e em 150 indivíduos saudáveis da reserva indígena Terena. Adicionalmente, todos os soros foram analisados através da técnica de imunofluorescência indireta (IFI) para doença de Chagas. Nas reações positivas por ELISA e IFI para Chagas, TESA (trypomastigoste extracted/secreted antigens) immunobloting foi realizado como teste confirmatório para doença de Chagas. Resultados: A forma indeterminada da doença de Chagas foi identificada através da reação contra o T. cruzi por ELISA, IFI e TESA-BLOT em cinco indivíduos de Limão Verde, que não apresentavam FS. Nenhum doente de FS da região estudada apresentou reatividade contra T. cruzi. O perfil de anticorpos anti-Dsg1 evidenciou resultado positivo em 15 dos 40 doentes de FS e em 33 dos 150 soros de indivíduos saudáveis da região endêmica de FS. Não se observou reação cruzada entre doença de Chagas e FS. Conclusões: 1-Nosso estudo revelou pela primeira vez a ocorrência de doença de Chagas, forma indeterminada, em uma população ameríndia Terena da aldeia de Limão Verde, uma área endêmica de fogo selvagem; 2-Nenhum doente de fogo selvagem da reserva indígena Terena de Limão Verde, Aquidauana (MS) apresentou reatividade contra o Trypanosoma cruzi; 3-A resposta antidesmogleína 1 nos doentes de fogo selvagem foi encontrada em 37,5% (15/40) dos pacientes. Auto-anticorpos anti-desmogleína 1 nos indivíduos sadios (sem fogo selvagem) foram encontrados em 22% (33/150) dos casos. 4-Não houve concomitância de doença de Chagas e fogo selvagem na amostra populacional estudada de Limão Verde / Introduction: Endemic pemphigus foliaceus (EPF) or Fogo Selvagem (FS) is an autoimmune blistering disorder with pathogenic IgG autoantibodies, mainly of the IgG4 subclass, that recognize desmoglein 1 (Dsg1), a desmossomal glycoprotein that plays a role in epidermal cell adhesion. Autoantibodies binding to specific domains of Dsg1 lead to acantholysis through different mechanisms, such as intracellular molecular signaling and steric hindrance. Etiopathogenesis of FS is multifactorial, with the interaction of immunological, genetic and environmental factors. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting an important role for environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize non-pathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Interestingly, FS and Chagas disease share some geographic sites, and anti- Dsg1 has been detected in Chagas patients. In the Terena reservation of Limao Verde, where FS prevalence is high, the population is prone to insect bites (Simulium, Cimex and Triatoma). Those insects may play a role as disease vectors or exert modulation of the autoimmune process in FS. Aims: Our study aimed: 1-To evaluate the frequency of antibodies anti- Trypanosoma cruzi in FS patients and in a healthy population living in a highrisk area for FS, a native Brazilian reservation of Limão Verde, Mato Grosso, Brazil; 2-.To analyze the concomitant reactivity against Dsg1 and T. cruzi in a high-risk population for FS. Methods: We performed ELISA (enzyme linked immunosorbent assay) for Dsg1 and T. cruzi in forty FS patients and 150 healthy individuals living in the Terena reservation. All sera were also analyzed by indirect immunofluorescence (IIF) for Chagas disease. In those seropositive reactions for T. cruzi, TESA (trypomastigoste extracted/secreted antigens) immunoblotting was performed as a confirmatory test for Chagas disease. Results: Indeterminate Chagas disease was identified utilizing ELISA, IIF and TESA-BLOT for T. cruzi in five non-FS individuals from Limão Verde. In counterpart, none of the FS patients living in the same geographic region showed reactivity against Trypanosoma cruzi. Anti-Dsg1 antibodies were present in 15 out of 40 FS sera and in 33 out of 150 sera from healthy individuals from endemic FS site. No cross-reactivity between Chagas disease and FS was observed. Conclusions: 1- Our study revealed, for the first time, the occurrence of indetermined Chagas disease in an Amerindian Terena population of Limão Verde, Aquidauana, an endemic area of Fogo Selvagem; 2-None of the FS patients from the present endemic focus of Limao Verde, Aquidauana (MS) showed reactivity against Trypanosoma cruzi; 3-The anti-Dsg1 response in FS patients of this focus was detected in 37.5% (15/40) of the patients. In non-FS controls, autoantibodies anti-Dsg 1 were detected in 22% (33/150) of the sera; 4-There was no concomitance of Chagas disease and fogo selvagem in the analyzed population of Limão Verde

Introdução: O pênfigo foliáceo endêmico (PFE) ou Fogo Selvagem (FS) é uma dermatose bolhosa autoimune com auto-anticorpos IgG patogênicos, principalmente da subclasse IgG4, direcionados contra epítopos da desmogleína 1 (Dsg1), uma glicoproteína desmossômica que desempenha papel na adesão celular da epiderme. Os auto-anticorpos ligam-se a domínios específicos da Dsg1, gerando acantólise (perda da adesão celular) através de mecanismos diversos, tais como sinalização intracelular de moléculas e impedimento estérico. A etiopatogenia do FS é multifatorial, apresentando interações entre fatores imunológicos, genéticos e ambientais. Em algumas regiões do Brasil, detectou-se alta prevalência de FS (3%), sugerindo importante participação de fatores ambientais como desencadeantes da resposta autoimune. Indivíduos saudáveis de áreas endêmicas de FS reconhecem epítopos não-patogênicos da Dsg1, e exposição a insetos hematófagos é um fator de risco para FS. FS e doença de Chagas compartilham algumas regiões geográficas, e anticorpos anti- Dsg1 foram detectados em doentes de Chagas. Na reserva indígena Terena (Limão Verde), onde a prevalência de FS é alta, a população está exposta a picadas de simulídeos, cimecídeos e reduvídeos. Estes insetos podem atuar como vetores de doenças, bem como na imunomodulação do processo autoimune do FS. Objetivos: Nosso estudo teve como objetivos: 1- avaliar a frequência de anticorpos anti-Trypanosoma cruzi em doentes de FS e na população saudável da área de alto risco para FS, habitantes da aldeia indígena de Limão Verde, Mato Grosso do Sul, Brasil; 2- avaliar a reatividade concomitante contra Dsg1 e T. cruzi nessa população de alto risco para FS. Métodos: Realizamos ensaio sorológico de ELISA (enzyme linked immunosorbent assay) para reatividade contra Dsg1 e contra T. cruzi em 40 doentes de FS e em 150 indivíduos saudáveis da reserva indígena Terena. Adicionalmente, todos os soros foram analisados através da técnica de imunofluorescência indireta (IFI) para doença de Chagas. Nas reações positivas por ELISA e IFI para Chagas, TESA (trypomastigoste extracted/secreted antigens) immunobloting foi realizado como teste confirmatório para doença de Chagas. Resultados: A forma indeterminada da doença de Chagas foi identificada através da reação contra o T. cruzi por ELISA, IFI e TESA-BLOT em cinco indivíduos de Limão Verde, que não apresentavam FS. Nenhum doente de FS da região estudada apresentou reatividade contra T. cruzi. O perfil de anticorpos anti-Dsg1 evidenciou resultado positivo em 15 dos 40 doentes de FS e em 33 dos 150 soros de indivíduos saudáveis da região endêmica de FS. Não se observou reação cruzada entre doença de Chagas e FS. Conclusões: 1-Nosso estudo revelou pela primeira vez a ocorrência de doença de Chagas, forma indeterminada, em uma população ameríndia Terena da aldeia de Limão Verde, uma área endêmica de fogo selvagem; 2-Nenhum doente de fogo selvagem da reserva indígena Terena de Limão Verde, Aquidauana (MS) apresentou reatividade contra o Trypanosoma cruzi; 3-A resposta antidesmogleína 1 nos doentes de fogo selvagem foi encontrada em 37,5% (15/40) dos pacientes. Auto-anticorpos anti-desmogleína 1 nos indivíduos sadios (sem fogo selvagem) foram encontrados em 22% (33/150) dos casos. 4-Não houve concomitância de doença de Chagas e fogo selvagem na amostra populacional estudada de Limão Verde / Introduction: Endemic pemphigus foliaceus (EPF) or Fogo Selvagem (FS) is an autoimmune blistering disorder with pathogenic IgG autoantibodies, mainly of the IgG4 subclass, that recognize desmoglein 1 (Dsg1), a desmossomal glycoprotein that plays a role in epidermal cell adhesion. Autoantibodies binding to specific domains of Dsg1 lead to acantholysis through different mechanisms, such as intracellular molecular signaling and steric hindrance. Etiopathogenesis of FS is multifactorial, with the interaction of immunological, genetic and environmental factors. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting an important role for environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize non-pathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Interestingly, FS and Chagas disease share some geographic sites, and anti- Dsg1 has been detected in Chagas patients. In the Terena reservation of Limao Verde, where FS prevalence is high, the population is prone to insect bites (Simulium, Cimex and Triatoma). Those insects may play a role as disease vectors or exert modulation of the autoimmune process in FS. Aims: Our study aimed: 1-To evaluate the frequency of antibodies anti- Trypanosoma cruzi in FS patients and in a healthy population living in a highrisk area for FS, a native Brazilian reservation of Limão Verde, Mato Grosso, Brazil; 2-.To analyze the concomitant reactivity against Dsg1 and T. cruzi in a high-risk population for FS. Methods: We performed ELISA (enzyme linked immunosorbent assay) for Dsg1 and T. cruzi in forty FS patients and 150 healthy individuals living in the Terena reservation. All sera were also analyzed by indirect immunofluorescence (IIF) for Chagas disease. In those seropositive reactions for T. cruzi, TESA (trypomastigoste extracted/secreted antigens) immunoblotting was performed as a confirmatory test for Chagas disease. Results: Indeterminate Chagas disease was identified utilizing ELISA, IIF and TESA-BLOT for T. cruzi in five non-FS individuals from Limão Verde. In counterpart, none of the FS patients living in the same geographic region showed reactivity against Trypanosoma cruzi. Anti-Dsg1 antibodies were present in 15 out of 40 FS sera and in 33 out of 150 sera from healthy individuals from endemic FS site. No cross-reactivity between Chagas disease and FS was observed. Conclusions: 1- Our study revealed, for the first time, the occurrence of indetermined Chagas disease in an Amerindian Terena population of Limão Verde, Aquidauana, an endemic area of Fogo Selvagem; 2-None of the FS patients from the present endemic focus of Limao Verde, Aquidauana (MS) showed reactivity against Trypanosoma cruzi; 3-The anti-Dsg1 response in FS patients of this focus was detected in 37.5% (15/40) of the patients. In non-FS controls, autoantibodies anti-Dsg 1 were detected in 22% (33/150) of the sera; 4-There was no concomitance of Chagas disease and fogo selvagem in the analyzed population of Limão Verde

Le canal sodique épithélial sensible à l'amiloride (ENaC) est une protéine composée de trois sous unités similaires [alpha][bêta][gamma] codées par trois gènes distincts et associées en un complexe hétérotétramérique [alpha]2[bêta][gamma]. ENaC est localisée au niveau de la membrane apicale des cellules épithéliales à jonctions serrées. C'est une protéine clé de la réabsorption du sodium au niveau du néphron distal, des voies aériennes supérieures et du colon distal. Son rôle dans la régulation du volume extracellulaire et la pression sanguine a été renforcé par la découverte de deux maladies génétiques humaines liées à la fonction du canal : le syndrome de Liddle et le pseudoaldostéronisme de type I (PHA I) due respectivement à un gain et une perte de fonction du canal. L'activité et l'expression de ce dernier sont finement régulées. Sa régulation par les sérines protéases et le sodium extracellulaire (auto-inhibition) a été mis en évidence par Chraïbi et collaborateurs en 1997, mais peu de choses sont connues sur les mécanismes et le rôle fonctionnel de la boucle extracellulaire dans ces différentes voies de régulation. Notre objectif est d'identifier les sites potentiels impliqués dans ces différentes voies de régulation. Pour ce faire, des mutations au niveau de la partie terminale de la boucle extracellulaire des sous unités [alpha], [bêta] et [gamma] du canal ont été réalisées par mutagenèse dirigée et l'effet des sérines protéases et du sodium extracellulaire a été étudié. Nos résultats, obtenus par la technique de voltage-clamp à deux électrodes, montrent que le domaine WPS (un domaine conservé dans les trois sous unités des différentes espèces et situé au niveau de la partie terminale de la boucle extracellulaire du canal) est impliqué dans la régulation d'ENaC par les sérines protéases et le sodium extracellulaire. Nous avons montré plus particulièrement que le tryptophane [alpha]W453 a un rôle fonctionnel majeur dans ces deux voies de régulation. Sa substitution par une arginine au niveau de la sous unité [alpha] rend ENaC résistant à la trypsine et abolit totalement l'inactivation du canal par le sodium extracellulaire. Par contre, la même mutation au niveau de la sous unité [gamma] ne change ni la réponse du canal à la trypsine ni sa sensibilité au sodium extracellulaire, alors que les canaux portant la mutation W/R au niveau de la sous unité [bêta] ont une sensibilité intermédiaire. L'ensemble de ces résultats montre le rôle fonctionnel de la boucle extracellulaire d'ENaC dans la régulation du canal par les sérine-protéases et le sodium extracellulaire.

Cooking is mind, body, spirit work. What’s possible when we ‘drop in’ to our bodies when cooking? We begin noticing what we are energetically bringing to the food we make. This creative project practices a pedagogy that works with food to create healing space. Healing, as it is defined here, is not void of discomfort nor is it happiness all the time. Who haunts your domestic space? Who is at your back when you cook? This project finds information and sacred knowledge in the food we cook and eat; it reflects back to us deeply buried truths regarding our traumas, joys, and subjectivity. This pedagogy holds the potential for participants to bring “new meanings” to food, and thereby, be activated as cultural producers cooking up the next chapter in our peoples’ creation stories (Anzaldúa 103). This project is documented as an auto-ethnographic tale from the perspective of the practitioner, using erotic storytelling to keep fire in the pages and a methodology of refusal to “determine the length of the [academy’s] gaze” (Tuck and Ree 640).

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Il existe peu d’études qui ont exploré différentes approches pédagogiques traitant de la simulation notamment dans un contexte de formation collégiale en soins infirmiers et ce, malgré leur implantation grandissante dans ces programmes de formation. Aucun instrument de mesure au sujet de l’auto-efficacité provenant de la théorie développée par Bandura (1977 a ou b, 1986) dans ce contexte n’a été identifié. But : Explorer l’ajout de la simulation haute-fidélité (SHF) à l’examen clinique objectif structuré (ECOS) sur l’auto-efficacité, l’anxiété et la performance en situation d’apprentissage d’étudiantes de niveau collégial en soins infirmiers. Afin d’atteindre ce but, cinq objectifs ont été proposés, répartis en trois phases. Méthodes : Un comité d’experts a participé au développement du questionnaire traitant de l’auto-efficacité perçue suivi d’une validation auprès d’étudiantes en soins infirmiers et d’une analyse factorielle exploratoire (n=221). Par la suite, une étude pilote a été réalisée auprès d’étudiantes en soins infirmiers (n=20) réparties dans un groupe expérimental (ECOS suivi de SHF) et un groupe témoin (ECOS seulement). Deux questionnaires autoadministrés et une grille d’observation ont été utilisés en pré et post-test pour toutes les participantes des deux groupes, suivis d’entretiens individuels semi-dirigés auprès de volontaires (n=19). Enfin, des entretiens individuels semi-dirigés ont été réalisés auprès de candidates à l’exercice de la profession infirmière (n=14) en complément aux données recueillies lors de l’étude pilote. Résultats : Cette étude a permis de créer un nouvel instrument de mesure en langue française. Les résultats quantitatifs collectés lors de l’étude pilote permettent de constater que les deux groupes se comportent de la même façon soit par une diminution significative de l’anxiété après simulation ainsi qu’une performance moyenne de 7/10. Celle-ci étant supérieure après la réalisation d’ECOS seulement, comparativement aux ECOS suivi de la SHF. Ces résultats appuient les propos recueillis des participantes suggérant ainsi d’utiliser les deux types de simulations en complémentarité. Forces et limites : Cette étude utilise des instruments de mesure validés avec de bonnes qualités métrologiques (α > 0,80). Les limites sont principalement liées aux difficultés de recrutement. Conclusions : Cette étude contribue à une meilleure connaissance de la valeur ajoutée d’une deuxième approche pédagogique par simulation sur l’auto-efficacité, l’anxiété et la performance d’étudiantes de niveau collégial en soins infirmiers. Cette connaissance pourrait permettre de mieux préparer les futures infirmières au niveau de la pratique clinique et de favoriser la recherche dans ce domaine encore peu exploré.

Objetivos: Determinar las medidas de autocuidado que tienen los pacientes que asisten a la ESN-PCT del Centro de Salud Conde de la Vega Baja. Material y método: El presente estudio es de enfoque cuantitativo, tipo descriptivo, de corte transversal, nivel aplicativo. Población: La población de estudio estuvo conformada por 30 pacientes con diagnóstico de tuberculosis que reciben el tratamiento de Esquema I y 10 pacientes en tratamiento Multidrogoresistente (MDR) que asisten al Centro de Salud Conde de la Vega Baja. Técnica e instrumento: La técnica fue la entrevista, y el instrumento un cuestionario. Resultados: Los resultados fueron que 25 pacientes (62.5%) realiza medidas de autocuidado adecuadas y 15 pacientes (37.5%) tiene medidas de autocuidado inadecuadas. Respecto a la alimentación, 14 pacientes (35%) consume 5 comidas durante el día; 9 pacientes (22.5%) ingiere una alimentación balanceada; 7 pacientes (17.5%) toma 5-7 vasos de agua diario; 33 pacientes (82.5%) come las principales comidas en el hogar. En relación al descanso y sueño, 28 pacientes (70 %) duerme de 6 a 8 horas diarias; en cuanto a medidas higiénicas, 28 pacientes (70%) se baña diario; 18 pacientes (45%) tiene habitación privada; 34 pacientes (85%) tiene ventilación e iluminación en el hogar; 26 pacientes (65%) refiere tener ventanas en el dormitorio; 10 pacientes (25%) tiene el habito de lavado de manos; 19 pacientes (47.5%) usa papel desechable cubriéndose la boca y nariz. En cuanto a la práctica de hábitos nocivos 15 pacientes (37.5%) toma alcohol; 9 pacientes (22.5%) consume cigarrillos; y 3 pacientes (7.5%) consume drogas; 11 pacientes (27.5%) asiste a reuniones sociales, fiestas; Respecto a control y tratamiento de la enfermedad, 34 pacientes (85%) asiste al tratamiento; 24 pacientes (60%) refiere que acude a la consulta con el médico; Respecto a ejercicio y recreación, 29 pacientes (72.5%) ve televisión; 13 pacientes (32.5%) practica ejercicios; 11 pacientes (27.5%) sale con su familia; 9 pacientes (22.5%) acudeal internet. Respecto a cuidado emocional, social y espiritual; 32 pacientes (80%) cuenta con una red social, 3 pacientes (7.5%) siente rechazo de las personas; 13 pacientes (32.5%) asiste a la iglesia, 17 pacientes (42.5%) busca la armonía con Dios y su ser. Conclusiones: La mayoría de los pacientes con tuberculosis realiza medidas de autocuidado adecuadas respecto a descanso y sueño, control y tratamiento de la enfermedad, hábitos nocivos, cuidado emocional, social, sin embargo un porcentaje significativo tiene medidas de autocuidado inadecuadas respecto a alimentación, medidas higiénicas, ejercicio y recreación, cuidado espiritual. -- PALABRAS CLAVES: MEDIDAS DE AUTOCUIDADO, PACIENTES CON TUBERCULOSIS EN LA ESN-PCT / -- Objectives: To determine the measures of self-care that patients have attending ESN-PCT Health Center Count of Vega Baja. Materials and Methods: This study is a quantitative approach, descriptive, cross-sectional, application level. Population: The study population consisted of 30 patients diagnosed with tuberculosis who are treated Scheme I and 10 patients treated Multidrogoresistente (MDR) attending the Health Centre Count of Vega Baja. . Technical and instrument: The technique was the interview, and a questionnaire instrument. Results: The results were that 25 patients (62.5%) perform appropriate self-care measures and 15 patients (37.5%) have inadequate self-care measures.With regard to food, 14 patients (35%) consume 5 meals throughout the day, 9 patients (22.5%) eat a balanced diet, 7 patients (17.5%) takes 5-7 glasses of water daily, 33 patients (82.5%) eating the main meal at home.In relation to rest and sleep, 28 patients (70%) sleep of 6-8 hours per day, in terms of hygiene, 28 patients (70%) bathes daily, 18 patients (45%) have private room, 34 patients (85%) have ventilation and lighting in the home, 26 patients (65%) reports having windows in the bedroom and 10 (25%) have the habit of washing hands, 19 patients (47.5%) use disposable paper covering his mouth and nose. As for the practice of harmful habits 15 patients (37.5%) drink alcohol, 9 patients (22.5%) consumed cigarettes, and 3 patients (7.5%) using drugs, 11 patients (27.5%) attending social gatherings, parties, respect to control and treatment of disease, 34 patients (85%) attending treatment, 24 patients (60%) states that goes to the consultation with the doctor; As for exercise and recreation, 29 patients (72.5%) watch television and 13 patients (32.5%) practice exercises, 11 patients (27.5%) out with his family, 9 patients (22.5%) goes to the internet. Regarding emotional care, social and spiritual, 32 patients (80%) have a social network, 3 patients (7.5%) people feel rejection and 13 patients (32.5%) attend church, 17 patients (42.5%) seeks harmony with God and being.Conclusions: Most patients with tuberculosis takes appropriate self-care measures regarding rest and sleep, control and treatment of disease, bad habits, emotional care, social, however a significant percentage have inadequate selfcare measures regarding food, measures hygiene, exercise and recreation, spiritual care. -- KEYWORDS: MEASURES OF SELF, TUBERCULOSIS IN PATIENTS WITH ESN-PCT

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Les lymphocytes T (LT) sont des cellules essentielles du système immunitaire. Elles expriment à leur surface un récepteur, le TCR, qui a la capacité de reconnaître des peptides issus de la dégradation de protéines provenant d'agent infectieux associés aux molécules du complexe majeur d'histocompatibilité. Cette reconnaissance conduit à l'activation de signaux intracellulaires dans les LT propagés grâce à la coordination fine de molécules de signalisations cytosoliques ou membranaires qui agissent de concert pour entraîner des réponses cellulaires adaptées au type d'agent infectieux et permettre le développement d'une réponse immunitaire efficace. Au cours de ce travail de thèse, j'ai étudié deux protéines impliquées dans ces processus, CD5 et Themis1. Les protéines CD5 sont des co-récepteurs des LT capables d'inhiber la signalisation transmise par les TCR. Ils contribuent à réguler le répertoire des TCR en modulant finement les processus de sélection dans le thymus. Le rôle de ces co-récepteurs dans les LT périphériques et les mécanismes moléculaires par lesquels ils opèrent restent mal compris. Pour essayer d'élucider ces mécanismes, j'ai analysé l'interactome de CD5 dans les LT par spectrométrie de masse. J'ai montré que l'engagement des TCR entraîne le recrutement par CD5 d'un complexe moléculaire formé des protéines c-Cbl, Sts-2, SHIP, CIN85, CrkL et Pi3K. L'analyse de l'interactome de CD5 dans les LT c-cbl-/- suggère que c-CBL agit comme une protéine adaptatrice au sein de ce complexe qui relie CD5 aux autres protéines de signalisation. J'ai montré qu'une tyrosine, localisée en position 429 sur la région intracytoplasmique de CD5, était nécessaire à la formation de ce signalosome. L'analyse de la signalisation des TCR dans les LT provenant de souris contenant une mutation invalidante de la tyrosine 429 montre que ce complexe moléculaire régule négativement la phosphorylation de protéines telles que ZAP-70, SLP-76 et ERK et diminue la capacité des lymphocytes T à proliférer en réponse à l'engagement des TCR. CD5 réprime parallèlement l'activité des protéines Foxo1 en facilitant l'activation d'Akt et diminue ainsi la différentiation des LT naïfs en LT régulateurs (Treg) dans les organes lymphoïdes périphériques. Nos résultats suggèrent que CD5 pourrait faciliter le développement de réponses immunitaires efficaces en bloquant la différentiation de Treg dirigés contre des antigènes étrangers. La protéine Themis1 a été découverte récemment et joue un rôle essentiel dans le développement des LT en inhibant l'activité catalytique des tyrosines phosphatases SHP-1 et SHP-2. Les fonctions moléculaires et cellulaires régulées par Themis1 dans les LT périphériques sont inconnues. Au cours de ma thèse, j'ai étudié un nouveau modèle murin sélectivement déficient pour Themis1 dans les LT périphériques après leur développement dans le thymus. Des analyses in vitro montrent que Themis1 augmente les seuils de signalisation des TCR nécessaire pour activer les LT et réprime sélectivement la production d'IFNƴ dans des cellules polarisées Th1. In vivo, l'expression de Themis1 augmente la susceptibilité au développement d'Encephalomyélite Autoimmune Expérimental (EAE), un modèle murin de sclérose en plaques. Des résultats préliminaires obtenus dans ce modèle suggèrent de façon inattendue que Themis1 favorise la différentiation des LT encephalitogènes producteurs d'IFNƴet de GM-CSF. Themis1 pourrait agir in vivo en réprimant l'activité des co-récepteurs inhibiteurs tels que PD-1 et CTLA-4 qui recrutent des phosphatases à domaines SH2. / T-cells play a key role in immune responses. Each T-cell expresses a unique TCR (T-cell receptor) which specifically recognises a microbial-derived antigen presented by MHC molecules (major histocompatibility complex) on the surfaces of host cells. This interaction leads to the activation of T-cells via highly regulated intracellular signalling pathways using numerous membrane-bound and cytoplasmic proteins. These complex signals are responsible for the development of a customised immune response specifically directed against the invading pathogen. This thesis examines the role of two proteins involved in TCR signalling, CD5 and Themis1. CD5 proteins are TCR-associated co-receptors which exhibit inhibitory activity on TCR signalling. They modulate the variability of the TCR repertoire by finely regulating positive and negative selection in the thymus. However, their role in peripheral T-cells and the underlying molecular mechanisms by which they act is poorly understood. To answer this question, the CD5 interactome in peripheral T-cells was determined by mass spectrometry. Analysis of the interactome shows that, upon TCR engagement, CD5 recruits several proteins in a molecular complex referred to hereafter as "CD5 signalosome", namely: c-Cbl, Sts-2, SHIP, CIN85, CrkL and Pi3K. The same interactome analysis in c-Cbl deficient T-cells proves that c-Cbl acts as an adaptor necessary for the interaction between CD5 and the other proteins of the CD5 signalosome. These data have also demonstrated the necessity of a specific tyrosine for signalosome recruitment, located in position 429 within the intracytoplasmic domain of CD5. Analysis of TCR signalling in T-cells harbouring an invalidating Tyr429 mutation reveals that the CD5 signalosome downregulates phosphorylation of key proteins such as ZAP-70, ERK1/2 and SLP-76 and decreases T-cell auto-amplification upon stimulation. In parallel, CD5 also inhibits activity of Foxo1 protein by facilitating Akt recruitment, thereby reducing regulatory T-cell (Treg) generation in secondary lymphoid organs. Altogether, our data suggest that the CD5 co-receptor could promote a specifically adapted immune response against exogenous antigens by limitation of Treg differentiation. In 2009, our team identified a previously unknown signalling protein called Themis1 (THymocyte-Express Molecule Important for Selection) that is essential for T-cell development. The role of Themis1 has been extensively studied in thymocytes and recent data show that Themis enhances TCR signalling by selective inhibition of SHP-1 and SPH-2 phosphatases in these cells. However, its role in peripheral T-cells remains elusive. To study the post-thymic role of Themis1, we generated a new mouse model selectively deficient for Themis1 in peripheral T-cells but not in thymocytes. My in vitro analyses show that Themis1 enhances the TCR signalling threshold necessary to activate T-cells and selectively represses IFNƴ production in Th1 polarised T-cells. In vivo, Themis1 expression increases susceptibility to experimental autoimmune encephalomyelitis (EAE, multiple Sclerosis mouse model). Surprisingly, preliminary results obtained in the same mouse model also suggest that Themis1 enhances differentiation of encephalitogenic T-cells producing IFNƴ and GM-CSF. We therefore hypothesise that Themis1 could act in vivo by repressing the activity of co-inhibitory receptors such as PD-1 or CTLA-4 by recruiting SH2 domain-containing phosphatases.