Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2015-10-22T13:46:44Z No. of bitstreams: 1 Jessica Dias Petrilli.Avaliação ... 2015.pdf: 2014197 bytes, checksum: 11dd7ed8b03eff8645c6f34b778cc32e (MD5) / Approved for entry into archive by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2015-10-26T11:29:00Z (GMT) No. of bitstreams: 1 Jessica Dias Petrilli.Avaliação ... 2015.pdf: 2014197 bytes, checksum: 11dd7ed8b03eff8645c6f34b778cc32e (MD5) / Made available in DSpace on 2015-10-26T11:29:00Z (GMT). No. of bitstreams: 1 Jessica Dias Petrilli.Avaliação ... 2015.pdf: 2014197 bytes, checksum: 11dd7ed8b03eff8645c6f34b778cc32e (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Os macrófagos são componentes importantes da resposta imune inata contra o Mycobaterium tuberculosis (Mtb) e podem desempenhar um papel importante na patogênese da tuberculose (TB). Macrófagos são derivados dos monócitos, os quais são classificados em subpopulações a partir da expressão da molécula de superfície CD14 e CD16. São denominados de clássicos, intermediários e não clássicos, e possuem diferenças funcionais e fenotípicas. Os fatores que levam ao desenvolvimento de TB ativa ainda não são claros. Um desequilíbrio entre subpopulações de monócitos circulantes pode estar envolvido na imunopatogênese da TB, uma vez que macrófagos são células importantes da resposta imune inicial da doença. Assim, neste estudo avaliou-se os subgrupos de monócitos em pacientes com TB ativa e latente (TBL). Voluntários com TB ativa, TBL e indivíduos saudáveis foram recrutados para avaliação de frequência, níveis de ativação e produção de citocinas dos subgrupos de monócitos circulantes e após a estimulação antigênica por citometria de fluxo. Nossos resultados não demonstraram diferenças significativas nas frequências, níveis de ativação e produções de citocinas das subpopulações de monócitos entre os grupos estudados. No entanto, pacientes com TB ativa tiveram um aumento na frequência dos monócitos clássicos ativados após estimulação antigênica comparados com os controles saudáveis. Não observou-se uma expansão das subpopulações CD16+ em pacientes TB. Por outro lado, se observou uma expansão dos monócitos CD16- e maior ativação dessa subpopulação após estimulação antigênica em indivíduos TB e TBL. Diante disso, os monócitos clássicos parecem desempenhar algum papel na infecção da TB, uma vez que esta subpopulação se expande e apresenta-se mais ativada após estimulação antigênica principalmente em resposta a Mce1A. Entretanto, esta expansão de monócitos clássicos na TB ainda precisa ser avaliada / Macrophages are important components of the innate immune response against Mycobacterium tuberculosis (Mtb) and may play an important role in the pathogenesis of tuberculosis (TB). Macrophages are derived from monocytes, which are classified into subpopulations from the expression of CD14 and CD16 surface molecule. They are denominated classics, intermediate and non-classical, and have functional and phenotypic differences. The factors that lead to the development of active tuberculosis are not clear yet. However, an imbalance between subpopulations of monocytes may be involved in the immunopathogenesis of TB, since macrophages are important cells in the initial immune responses of the disease. In this study we evaluated the monocyte subsets in patients with active and latent TB (ILTB). Volunteers with active TB, ILTB and healthy subjects were recruited to evaluate the frequency, levels of activation and cytokine production of blood monocytes subsets circulating and after the antigenic stimulation by flow cytometry. Our results did not show significant differences in the frequency, activation levels and cytokine production of monocytes subsets between studies groups. However, patients with active TB have an increased of frequency and activated levels of classical monocytes after antigenic stimulation compared to healthy controls. An expansion of CD16+ in monocytes subsets of TB patient was not observed. Moreover, it was observed an expansion and increased activation of CD16- monocytes after antigenic stimulation in individuals TB and LTB. Thus, the classical monocytes seems to play a role in TB infection, since this subpopulation expands and appears more active primarily after antigenic stimulation in response to Mce1A. However, this expansion of classical monocytes in TB still needs to be evaluated.

As relações socioespaciais interurbanas transformaram-se com o passar do tempo, mas é no século XX com a industrialização e a aceleração da urbanização que esse processo alcança um novo patamar. Especificamente no caso brasileiro, essas transformações se tornam mais significativas a partir dos anos 1950, quando expressivos crescimentos demográficos e expansões territoriais são vistos nos núcleos urbanos do país. Nesse processo, ocorre a aproximação entre cidades vizinhas, que ao estreitarem seus vínculos passam a ter fortes relações de interdependência e complementariedade entre si, formando um minissistema urbano único, com características próprias que ultrapassa a divisão político-administrativa municipal, conhecido como: aglomerações urbanas. Hoje, mais da metade da população brasileira vive em áreas aglomeradas que, por sua vez, vêm se tornando cada vez mais dinâmica e complexa. Frente a esse cenário, esse trabalho busca contribuir no estudo das aglomerações urbanas, analisando como elas afetam configuracionalmente as cidades que a compõem através de diferentes recortes espaciais. O trabalho é desenvolvido a partir de uma abordagem configuracional, entendendo que o espaço urbano é formado por células conectadas ente si, permitindo que o tema seja explorado de forma quantitativa através da modelagem. A pesquisa analisa características de proximidade e atratividade nas cidades de Bento Gonçalves, Garibaldi e Carlos Barbosa (Serra Gaúcha/RS), através do cálculo de indicadores espaciais destes locais. Como método de análise é feita a comparação dos resultados obtidos nos diferentes recortes espaciais (cenários) da área de estudo, que representam as diferentes escalas em que o fenômeno atua, agregando aos dados espaciais, informações socioeconômicas das localidades. Os resultados obtidos sugerem a redistribuição dos valores das medidas calculadas nas diferentes escalas consideradas, indicando a variação da hierarquia das porções de espaços que compõe as cidades aglomeradas nos diferentes cenários estudados. Já a metodologia aplicada se demonstrou como uma eficiente ferramenta de exploração do tema, contribuindo no entendimento e planejamento urbano de cidades aglomeradas. / Interurban socio-spatial relationships have changed over time, but in the twentieth century, with industrialization and the acceleration of urbanization, this process reaches a new level. Specifically in the Brazilian case, these transformations have become more significant since the 1950s, when expressive demographic growth and territorial expansion are seen in the urban centers of the country. In this process, neighboring cities approached each other and, by doing so, by doing so, tighten bonds, develop strong relations of interdependence and complementarity between them, forming a unique urban mini-system with its own characteristics that goes beyond the municipal political-administrative division, known as urban agglomerations. Today, more than half of the Brazilian population lives in agglomerated areas that are becoming increasingly dynamic and complex. In this scenario, this work seeks to contribute to the study of the urban agglomerations' theme, analyzing them through different spatial subsets. The work is developed from a configurational approach, understanding that the urban space is formed by cells connected to each other, allowing the theme to be explored quantitatively through modeling. The research analyzes characteristics of proximity and attractiveness in the cities of Bento Gonçalves, Garibaldi and Carlos Barbosa (Serra Gaúcha / RS), through the calculation of spatial indicators of these sites. As a method of analysis, the results obtained in the different spatial subsets (scenarios) of the study area are compared, representing the different spaces in which the phenomenon acts, adding to the spatial data, socio-economic information of the localities. The conclusion suggests the redistribution of the measures' values calculated in the different scales considered, indicating the variation of the spaces' hierarchy that compose the cities agglomerated in the different scenarios. The applied Methodology proved to be an efficient tool for exploring the theme, contributing to the understanding and urban planning of agglomerated cities.

The interaction between epithelial cells and macrophages is integral to mucosal immune fate: determining the decision between tolerance and immune activation/inflammation. Endotoxin tolerisation (ET) is a circumstance where cells go through a hypo-responsive state, unable to respond to further endotoxin-LPS challenge. Mucosal macrophages (MΦs) have a dual functionality that determines tolerance to commensal organisms or immune response to entropathogens such as E. coli. In the case of mucosal inflammatory pathologies, such as Crohn’s disease, this state of tolerance is broken, resulting in destruction of gut mucosal tissue where the macrophage phenotype has been altered from a regulatory M2-like subset phenotype to an inflammatory M1-like subset phenotype, responding to both pathogenic and commensal bacteria. Chronic inflammation by bacterial pathogen related molecular patterns (PAMPs), such as LPS, is well established to induce tolerisation. The aims of this project were firstly, to characterise the control of macrophage differentiation in a mucosal setting by investigating the immunomodulatory effects of PAMPs, such as LPS in presence or absence of TNFα and to investigate ET mechanisms associated with MΦ subsets responding to the entropathogen E. coli K12-LPS. Secondly, to investigate the effect of epithelial cells on macrophage subsets behaviour upon inflammation and ET. M1- and M2-like MΦs were generated in vitro from the THP-1 monocyte cell line by differentiation with PMA and vitamin D3, respectively, whereas differentiated epithelial cells (Caco-2) were obtained by long term culturing for 21 days. A transwell co-culture system of Caco2 cells and MΦ subsets was developed to mimic the cell-to-cell cross-talk between epithelial cells and immune cells. Mono- and co-culture models were pre-treated with either LPS, TNFα or IL-1β prior to stimulation by PAMPs. TNFα, IL-1β, IL-18, IL-6 and IL-10 were qualified by ELISA. Cytokines, PRRs and endogenous negative regulatory molecules were detected by RT-PCR and WB and epithelial barrier function was measured by trans epithelial electrical resistance (TEER). ET induced by K12-LPS failed to demonstrate a differential subset-specific response in MΦ mono-culture system whereas, LPS differentially suppress LPS induced cytokine expression in MΦ co-culture system. Tolerised M1- and M2-like MΦs exhibited a significant reduction in expression and secretion of pro-inflammatory cytokines and comparable levels of anti-inflammatory cytokine, IL-10. The suppression of pro-inflammatory cytokine in these MΦs appeared to be linked to the differential TLR4 expression and up-regulation of negative regulators, such as IRAK-M and Tollip. In addition, MΦ subsets differentially responded to inflammation induced by pro-inflammatory cytokines, TNFα and IL-1β in mono- and co-culture models. In conclusion, tolerisation induced in MΦs is presented by the suppression of pro-inflammatory cytokine, which is associated with corresponding up-regulation of IL-10, TLR4 receptor and the negative regulators, in a subset-independent manner. In the case of cross-talk between epithelial cells and macrophages however, a differential sensitivities to ET was displayed. These findings allow more understanding of MΦ subsets functions and ET mechanisms, which may be beneficial for the development of in-vitro models of MΦ subsets and therapeutics targeting Crohn’s diseases.

Made available in DSpace on 2015-10-06T13:03:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-08-23. Added 1 bitstream(s) on 2015-10-06T13:18:56Z : No. of bitstreams: 1 000819087.pdf: 1423284 bytes, checksum: a89857bcef9822e82a34c2b6424c6064 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A leishmaniose visceral é uma doença que causa manifestações clínicas variadas em cães, que podem apresentar desde alterações subclínicas a desordens generalizadas, incluindo alterações neurológicas. Há evidências do comprometimento das barreiras encefálicas, como a presença de infiltrado inflamatório com predomínio de linfócitos T CD3+ no sistema nervoso central. Deste modo, o objetivo deste trabalho foi determinar e comparar os imunofenótipos de linfócitos T no sangue periférico e no liquor e avaliar as lesões encefálicas em cães infectados. Verificou-se que os linfócitos T presentes em maior quantidade no liquor foram os duplos negativos (DN) e os duplos positivos (DP), com predomínio de TCRαβ. Também verificou-se que as células sanguíneas não diferiram das células do liquor em quantidade, o que indica que pode estar havendo um comprometimento da barreira hematoliquórica, permitindo que as células do sangue migrem para o liquor. Ocorreu também o predomínio de infiltrado linfohistioplasmocitário no encéfalo, principalmente em leptomeninges. Porém, não houve correlação entre a inflamação nessa área e as células T. Além disso, a correlação positiva entre a inflamação no subepêndima e as células T DN do liquor indica que essas células chegam no encéfalo também pelos vasos subependimários. Em conjunto, os resultados contribuem para explicar a inflamação observada no encéfalo de cães com leishmaniose, sendo que as células T DN podem ser responsáveis pela progressão neurológica da doença / Visceral leishmaniasis (VL) is a disease causing several clinical manifestations in dogs, that can present from subclinical to generalized disorders, including neurological disorders. There are evidences of cerebral barriers involvement, such as the presence of inflammatory infiltrate with predominance of CD3+ T cells in the brain of infected dogs. Therefore, the aim of this study was to determine and to compare the immunophenotypes of T lymphocytes in the peripheral blood and in the cerebrospinal fluid (CSF) of dogs with VL and evaluate the brain lesions. It was detected that the double negative (DN) and double positive (DP) T cells were present in higher percentage in the CSF, with predominance of TCRαβ. Besides, the amount of blood T cells did not differ from those observed in the CSF, indicating that the blood-CSF barrier may be damaged, allowing the migration of cells from the blood to the CSF. Moreover, inflammatory infiltrate with predominance of lymphohistioplasmacytic cells was observed, mainly in leptomeninges. However, there was no correlation between the intensity of the inflammation in this area and the T cells. Furthermore, the positive correlation between intensity of the inflammation in the subependimal area and DN T cells in the CSF indicates that these cells also may reach the brain through the subependymal vessels. Together, the results contribute to explain the inflammation observed in the brain of dogs with VL, where the DN T cells may contribute to the neurological progression of the disease

Seja (X; t) um espaço topológico e seja F a família de todos os subconjuntos de X que satisfazem uma propriedade topológica dada P (invariante por homeomorfismos). Se acrescentarmos abertos novos à topologia e se F\' é a família de todos os subconjuntos do novo espaço que satisfazem a propriedade P, podemos ter que F ≠ F\'. Se isto sempre acontece, dizemos que o espaço (X; t) é maximal com respeito à família F. Neste trabalho estudaremos os espaços topológicos maximais com respeito a algumas famílias de subconjuntos: discretos, compactos, densos, conexos e das sequências convergentes. / Let (X; t) be a topological space and let F be the family of all subsets of X that satisfy a given topological property P (invariant under homeomorphisms). If we add new open sets to the topology and if F\' is the family of all subsets of the new space which satisfy the property P, we can have F ≠ F\'. If this is always the case, we say that (X; t) is maximal with respect to the family F. We show here some characterizations of maximal spaces with respect to the family of some of its subsets: compacts, dense, discrete and convergent sequences.

Resumo: A leishmaniose visceral é uma doença que causa manifestações clínicas variadas em cães, que podem apresentar desde alterações subclínicas a desordens generalizadas, incluindo alterações neurológicas. Há evidências do comprometimento das barreiras encefálicas, como a presença de infiltrado inflamatório com predomínio de linfócitos T CD3+ no sistema nervoso central. Deste modo, o objetivo deste trabalho foi determinar e comparar os imunofenótipos de linfócitos T no sangue periférico e no liquor e avaliar as lesões encefálicas em cães infectados. Verificou-se que os linfócitos T presentes em maior quantidade no liquor foram os duplos negativos (DN) e os duplos positivos (DP), com predomínio de TCRαβ. Também verificou-se que as células sanguíneas não diferiram das células do liquor em quantidade, o que indica que pode estar havendo um comprometimento da barreira hematoliquórica, permitindo que as células do sangue migrem para o liquor. Ocorreu também o predomínio de infiltrado linfohistioplasmocitário no encéfalo, principalmente em leptomeninges. Porém, não houve correlação entre a inflamação nessa área e as células T. Além disso, a correlação positiva entre a inflamação no subepêndima e as células T DN do liquor indica que essas células chegam no encéfalo também pelos vasos subependimários. Em conjunto, os resultados contribuem para explicar a inflamação observada no encéfalo de cães com leishmaniose, sendo que as células T DN podem ser responsáveis pela progressão neurológica da doença / Abstract: Visceral leishmaniasis (VL) is a disease causing several clinical manifestations in dogs, that can present from subclinical to generalized disorders, including neurological disorders. There are evidences of cerebral barriers involvement, such as the presence of inflammatory infiltrate with predominance of CD3+ T cells in the brain of infected dogs. Therefore, the aim of this study was to determine and to compare the immunophenotypes of T lymphocytes in the peripheral blood and in the cerebrospinal fluid (CSF) of dogs with VL and evaluate the brain lesions. It was detected that the double negative (DN) and double positive (DP) T cells were present in higher percentage in the CSF, with predominance of TCRαβ. Besides, the amount of blood T cells did not differ from those observed in the CSF, indicating that the blood-CSF barrier may be damaged, allowing the migration of cells from the blood to the CSF. Moreover, inflammatory infiltrate with predominance of lymphohistioplasmacytic cells was observed, mainly in leptomeninges. However, there was no correlation between the intensity of the inflammation in this area and the T cells. Furthermore, the positive correlation between intensity of the inflammation in the subependimal area and DN T cells in the CSF indicates that these cells also may reach the brain through the subependymal vessels. Together, the results contribute to explain the inflammation observed in the brain of dogs with VL, where the DN T cells may contribute to the neurological progression of the disease / Orientador: Gisele Fabrino Machado / Banca: Valéria Marçal Felix de Lima / Banca: Antonio Carlos Alessi / Mestre

As relações socioespaciais interurbanas transformaram-se com o passar do tempo, mas é no século XX com a industrialização e a aceleração da urbanização que esse processo alcança um novo patamar. Especificamente no caso brasileiro, essas transformações se tornam mais significativas a partir dos anos 1950, quando expressivos crescimentos demográficos e expansões territoriais são vistos nos núcleos urbanos do país. Nesse processo, ocorre a aproximação entre cidades vizinhas, que ao estreitarem seus vínculos passam a ter fortes relações de interdependência e complementariedade entre si, formando um minissistema urbano único, com características próprias que ultrapassa a divisão político-administrativa municipal, conhecido como: aglomerações urbanas. Hoje, mais da metade da população brasileira vive em áreas aglomeradas que, por sua vez, vêm se tornando cada vez mais dinâmica e complexa. Frente a esse cenário, esse trabalho busca contribuir no estudo das aglomerações urbanas, analisando como elas afetam configuracionalmente as cidades que a compõem através de diferentes recortes espaciais. O trabalho é desenvolvido a partir de uma abordagem configuracional, entendendo que o espaço urbano é formado por células conectadas ente si, permitindo que o tema seja explorado de forma quantitativa através da modelagem. A pesquisa analisa características de proximidade e atratividade nas cidades de Bento Gonçalves, Garibaldi e Carlos Barbosa (Serra Gaúcha/RS), através do cálculo de indicadores espaciais destes locais. Como método de análise é feita a comparação dos resultados obtidos nos diferentes recortes espaciais (cenários) da área de estudo, que representam as diferentes escalas em que o fenômeno atua, agregando aos dados espaciais, informações socioeconômicas das localidades. Os resultados obtidos sugerem a redistribuição dos valores das medidas calculadas nas diferentes escalas consideradas, indicando a variação da hierarquia das porções de espaços que compõe as cidades aglomeradas nos diferentes cenários estudados. Já a metodologia aplicada se demonstrou como uma eficiente ferramenta de exploração do tema, contribuindo no entendimento e planejamento urbano de cidades aglomeradas. / Interurban socio-spatial relationships have changed over time, but in the twentieth century, with industrialization and the acceleration of urbanization, this process reaches a new level. Specifically in the Brazilian case, these transformations have become more significant since the 1950s, when expressive demographic growth and territorial expansion are seen in the urban centers of the country. In this process, neighboring cities approached each other and, by doing so, by doing so, tighten bonds, develop strong relations of interdependence and complementarity between them, forming a unique urban mini-system with its own characteristics that goes beyond the municipal political-administrative division, known as urban agglomerations. Today, more than half of the Brazilian population lives in agglomerated areas that are becoming increasingly dynamic and complex. In this scenario, this work seeks to contribute to the study of the urban agglomerations' theme, analyzing them through different spatial subsets. The work is developed from a configurational approach, understanding that the urban space is formed by cells connected to each other, allowing the theme to be explored quantitatively through modeling. The research analyzes characteristics of proximity and attractiveness in the cities of Bento Gonçalves, Garibaldi and Carlos Barbosa (Serra Gaúcha / RS), through the calculation of spatial indicators of these sites. As a method of analysis, the results obtained in the different spatial subsets (scenarios) of the study area are compared, representing the different spaces in which the phenomenon acts, adding to the spatial data, socio-economic information of the localities. The conclusion suggests the redistribution of the measures' values calculated in the different scales considered, indicating the variation of the spaces' hierarchy that compose the cities agglomerated in the different scenarios. The applied Methodology proved to be an efficient tool for exploring the theme, contributing to the understanding and urban planning of agglomerated cities.

In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confirming its prognostic impact in multivariate analysis, we could identify 30% of IGHV-mutated CLL (M-CLL) cases with high expression and poor outcome, which otherwise lacked any other poor-prognostic marker. In paper II, we investigated the prognostic impact of a previously reported 5 CpG signature that divides CLL patients into three clinico-biological subgroups, namely naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL) and intermediate CLL (i-CLL), in 135 CLL patients using pyrosequencing. We validated the signature as an independent marker in multivariate analysis and further reported that subset #2 cases were predominantly classified as i-CLL, although displaying a similar outcome as n-CLL. In paper III, we investigated the methylation status and expression level of miR26A1 in both CLL (n=70) and MCL (n=65) cohorts. High miR26A1 methylation was associated with IGHV-unmutated (U-CLL) and shorter overall survival (OS) in CLL, while it was uniformly hypermethylated in MCL. Furthermore, overexpression of miR26A1 resulted in significant downregulation of EZH2 that in turn led to increased apoptosis. In paper IV, we performed DNA methylation profiling in 176 CLL cases assigned to one of 8 major stereotyped subsets (#1-8) in relation to non-subset CLL (n=325) and different normal B-cell subpopulations. Principal component analysis of subset vs. non-subset CLL revealed that U-CLL and M-CLL subsets generally clustered with n-CLL and m-CLL, respectively, indicating common cellular origins. In contrast, subset #2 emerged as the first defined member of the i-CLL subgroup, which in turn alludes to a distinct cellular origin for subset #2 and i-CLL patients. Altogether, this thesis confirms the prognostic significance of RNA and epigenetic-based markers in CLL, provides insight into the mechanism of miRNA deregulation in lymphoid malignancies and further unravels the DNA methylation landscape in stereotyped subsets of CLL.

Les monocytes détectent des signaux métaboliques circulants qu’ils traduisent en signaux immunologiques. ils infiltrent les tissus inflamés et sont également les précurseurs des macrophages. Dans l’obésité, la fréquence, le nombre, le phénotype et la fonctionnalité des sous populations de monocytes (CD14++CD16- [CM], CD14++CD16+ [IM] et CD14+CD16++ [NCM]) sont spécifiquement modulés. Le phénotype des monocytes est pro-inflammatoire avec une plus forte réponse à la stimulation de TLR4 et de TLR8. Nos travaux suggèrent une capacité migratoire accrue des CM et des IM. La comparaison du transcriptome des sous populations chez des sujets obèses et des témoins, révèle une signature spécifique de chaque sous population montrant un plus fort impact de l’obésité sur les CM. Ils soutiendraient l’inflammation en modulant des gènes impliqués dans la signalisation cellulaire. Ils migreraient avec les IM vers les tissus inflamés. Les NCM resteraient plus longtemps dans la circulation où leur fonction de « patrouilleurs » serait accrue. Les gènes les plus modulés par les CM et les IM, respectivement Clusterine et CDGSH iron sulfur domain 1 sont des ponts entre la réponse immunitaire, le métabolisme et la réponse au stress. L’étude des « tops » gènes dont l’expression est la plus fortement modulée et des fonctions les plus probablement modulées révèle que le métabolisme des monocytes serait modifié dans l’obésité. Ce travail ouvre des perspectives concernant : 1) une éventuelle composante auto-immune de l’inflammation de bas grade et 2) des relations entre des modifications du métabolisme des monocytes et leur fonctionnalité. / Systemic inflammation is pivotal in establishing and sustaining the obesity low-grade inflammatory status. Studying monocytes is important because they can detect metabolic cues in the circulation that are then translated into immunological factors. Monocytes infiltrating inflamed tissues are also macrophage precursors. In obesity, frequency, number, phenotype and functionality of the three monocyte-subsets (CD14++CD16- [CM], CD14++CD16+ [IM] et CD14+CD16++ [NCM]) are specifically altered. We observed a pro-inflammatory phenotype of monocytes in obesity with an increased response to TLR4 and TLR8 stimulation. Our work suggests an increased migratory capacity of CM and IM. Comparison of the transcriptome of the three subsets in obese and control subjects shows an increased imprint of obesity on CM. CM could sustain inflammation by modulating genes involved in cell signaling. They most probably migrate with the IM toward inflamed tissues. Whereas, NCM should stay longer in the circulation where their patrolling function could be increased. The most modulated genes by CM and IM, respectively Clusterin and CDGSH iron sulfur domain 1 (CISD1) are bridges between immune response, metabolism and stress response. The analysis of the top modulated genes and of the most probably modulated functions indicates that monocyte metabolism is altered by obesity. We open new paths of research: 1) a possible auto-immune trait of the low grade inflammation and 2) a possible link between altered monocyte metabolism and their functionality.

Let G be a finite permutation group acting on a finite set Ω. Then we denote by σk(G,Ω) the number of G-orbits on the set Ωk, consisting of all k-subsets of Ω. In this thesis we develop methods for calculating the values for σk(G,Ω) and produce formulae for the cases that G is a doubly-transitive simple rank one Lie type group. That is G ∼ = PSL(2,q),Sz(q),PSU(3,q) or R(q). We also give reduced functions for the calculation of the number of orbits of these groups when k = 3 and go on to consider the numbers of orbits, when G is a finite abelian group in its regular representation. We then consider orbit lengths and examine groups with “large” G-orbits on subsetsof size 3.