Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-01-28T09:47:26Z No. of bitstreams: 2 Tese - Bruna Daniella de Souza Silva - 2015.pdf: 3849700 bytes, checksum: 267d28b0d91fc274ddb5bfd83ed08e5b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-01-28T09:49:33Z (GMT) No. of bitstreams: 2 Tese - Bruna Daniella de Souza Silva - 2015.pdf: 3849700 bytes, checksum: 267d28b0d91fc274ddb5bfd83ed08e5b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-01-28T09:49:33Z (GMT). No. of bitstreams: 2 Tese - Bruna Daniella de Souza Silva - 2015.pdf: 3849700 bytes, checksum: 267d28b0d91fc274ddb5bfd83ed08e5b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-02-13 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Millions of people die every year due to tuberculosis (TB), an infectious disease that have effective treatment, can be prevented and is curable. One of the greatest problems faced by this disease is the latent infection (LTBI), where individuals do not manifest clinical symptoms, is a reservoir of the causing agent, Mycobacterium tuberculosis (Mtb), and can reactive the disease at any time during their life span. Moreover, TB can affect any organ in the body, such as the skin, causing extrapulmonary TB, a rare form of TB, the TB skin. Some of these forms may be more severe than pulmonary TB, causing serious consequences to the patient, contributing to the high mortality rate of this disease. In this context, understanding the immunological events related to the interaction between pathogen and host the development of active disease or latent infection is a crucial point that can contribute to the control of TB. Thus, the objectives of this study were to evaluate the specific immune response of CD8+ T cells and cytokines in cutaneous tuberculosis, latent and active pulmonary TB. Thirty six patients with pulmonary TB, one patient with cutaneous TB and 36 healthy controls, classified as LTBI (N = 13) or negative (TST-, N = 23) by the tuberculin skin test were recruited and the peripheral blood mononuclear cells, plasma and sera from those individuals were collected to perform flow cytometry, ELISA and multiplex bead array analysis. It was observed that patients with active pulmonary TB presented TCD8+ cells with a regulatory profile, expressing IL-10 and TGF-β in a direct relation to the bacillary load. The same profile was observed in the individual with cutaneous TB, an extra-pulmonary form of TB. The findings observed in this studyco nclude that Mtb can modulate CD8+ T cell response in lung and skin tuberculosis, demonstrating the importance of studies assessing the immune interaction between the pathogen and the host. / A tuberculose (TB) é uma doença causada por Mycobacterium tuberculosis, principal agente etiológico da TB humana. Milhões de pessoas morrem todo ano em decorrência da TB, doença infecciosa que tem prevenção, tratamento e cura. Um dos maiores problemas enfrentados com essa doença é a infecção latente (TBIL), onde o indivíduo não manifesta os sintomas clínicos e constitui um reservatório da bactéria, podendo desenvolver a doença ativa em qualquer momento. Além disso, a TB pode afetar qualquer órgão do corpo, como por exemplo, a pele, causando uma forma rara de TB extrapulmonar, a TB cutânea. Algumas dessas formas podem ser mais severas que a TB pulmonar, trazendo consequências graves ao paciente, contribuindo para o alto índice de mortalidade dessa enfermidade. Nesse contexto, entender os eventos imunológicos relacionados à interação entre patógeno e o hospedeiro no desenvolvimento da doença ativa ou da infecção latente é um ponto crucial que pode contribuir para o controle da TB. Diante disso, os objetivos desse trabalho foram avaliar a resposta imune específica de células TCD8+ e citocinas na tuberculose cutânea, latente e pulmonar ativa. Para isso, foram recrutados 36 pacientes com TB pulmonar ativa, 01 paciente com TB cutânea e 36 controles sadios classificados quanto à prova tuberculínica em indivíduos com infecção latente (TBIL = 13) ou não (PT-=23). Foram obtidas, de todos os pacientes, as células mononucleares do sangue periférico, o plasma e o soro para realização dos ensaios de citometria de fluxo e ELISA. Foi observado que os pacientes com TB pulmonar ativa apresentam um perfil regulador de células TCD8+ específicas, com expressão de IL-10 e TGF-β relacionados com a carga bacilar quando comparado aos indivíduos com TBIL e controles sadios PT negativa. Esse mesmo perfil também foi observado e descrito no caso clínico do paciente com TB cutânea. Diante de todos os achados observados nesse trabalho podemos concluir que Mtb pode modular a resposta de células TCD8+ na tuberculose pulmonar e cutânea, demonstrando a importância de estudos que avaliem a interação imunológica entre o patógeno e o hospedeiro tais como este.

Le FcRn ou récepteur néonatal du Fc des IgG est un récepteur " clé " qui prolonge la demi-vie des IgG et de l’albumine et assure leur biodistribution. Récemment, son rôle s'est étendu à la réponse immunitaire humorale et anti-tumorale. Par ailleurs, certains travaux indiquent que le niveau d’expression du FcRn dans les différents tissus pourrait être à l’origine d’une modulation de ses fonctions. Dans ce contexte, nous avons démontré que l’expression du FcRn était diminuée dans le tissu cancéreux par rapport au tissu sain, chez des patients atteints du cancer du poumon et que cet effet était corrélé à leur pronostic. Afin de comprendre les répercussions de cette diminution sur la tumorigenèse, nous avons mis en place le modèle murin de métastases pulmonaires B16F10, chez les souris FcRn-/-. L'absence de FcRn influence la réponse anti-tumorale, en altérant le nombre de cellules dendritiques et des TCD8+. Pour la première fois, nous avons montré que l'absence du FcRn influençait le développement/maturation et fonctions des cellules NK, fragilisant ainsi encore plus l'immunosurveillance antitumorale. Ces résultats mettent en avant un nouveau rôle du FcRn dans la biologie des cellules NK. Les mécanismes à l’origine de cet effet restent à élucider. / FcRn or neonatal receptor for the Fc portion of IgG is a "key" receptor since it extends the half-life of IgGs and albumin and ensures their biodistribution. Recently, its role has been extended to the humoral and anti-tumor immune. Moreover, some studies indicate that the expression level of FcRn in the different tissues may modulate its functions. In this context, we showed that the expression of FcRn was decreased in lung cancer tissue compared to healthy tissue, in patients with NSLC. This decreased expression is correlated with the prognosis of the patients. In order to understand the impact of the reduced FcRn expression on tumorigenesis, we implemented a murine model of lung metastases, implanting B16F10 cells in FcRn deficient mice. The absence of FcRn influences the anti-tumor response, by altering the number of dendritic cells and TCD8+ cells. We showed for the first time that the lack of FcRn altered the development / maturation and the functional activity of NK cells, thus weakening even more anti-tumor immunosurveillance. These new results on NK highlight a new role of FcRn in the biology of NK cells. The mechanisms underlying this effect need to be elucidated.