The capricious roman goddess Fortune is known for her strong power to influence or even decide the destiny of humans. In ancient Rome she was considered to be a good goddess, who brought the gifts of destiny and who also was seen as a possible ally. During the Middle Ages this position changed. Fortune was given two sides, a good and friendly one and a cruel impenetrable side. She was seen as one of God´s ministers and became an expression of divine providence. My purpose with this essay is to analyse three artworks of Fortune by Giovanni Bellini, Albrecht Dürer and Master MZ, but also some texts by the renaissance humanist Niccolò Machiavelli. When examining this representation I will try to determine the iconography of Fortune and see how or if the interpretations of her differs. The study has shown that the different representations of Fortune differ from one another of the artworks. However, there is one major resemblance that presents itself in each and every one of the artworks as well as in Machiavelli’s texts, the fact that Fortune is considered to be capricious. This attribute is frequent. In the works of art Fortune is depicted along with some kind of circular object like a ball or a sphere, a clear indication of instability. In Machiavelli’s texts Fortune is often, metaphorically or directly expressed, as capricious and unpredictable. According to Machiavelli, humans therefore have to be prepared, hold capability or virtù, to be able to resist her rapid changes. Like the humanist Machiavelli was it is likely that he represents the ancient view of Fortuna, although some medieval element cannot be omitted. Furthermore, in all of the selected works of art together, one can see elements of both an antique view of Fortuna as well as a medieval. Although the Renaissance was strongly influenced by ancient ideas and ways of life, it becomes clear that also some medieval features survived into the mindset of the Renaissance.

Systemic lupus erythematosus (SLE) and Sj?gren?s syndrome (SS) are both heterogeneous autoimmune diseases with strong B cell aspects. A proportion of SLE and SS patients exhibit elevated serum BAFF (B cell activating factor of the TNF family); BAFF plays a key role in B cell homeostasis, survival and tolerance. BAFF transgenic (Tg) mice develop nephritis and salivary gland destruction that resemble aspects of SLE and SS respectively. Autoimmune disease development in BAFF Tg mice correlates with marginal zone (MZ) B cell expansion and the abnormal presence of MZ-like B cells outside of the spleen. The role of MZ B cells in BAFF induced autoimmune disease was analysed by crossing BAFF Tg mice with Lymphotoxin-β knockout mice (creating LTβ-BTg mice) which lack most peripheral lymph nodes, and also lack MZ B cells as a result of disrupted splenic architecture. LTβ-BTg mice were not protected against nephritis but exhibited reduced salivary gland infiltration and destruction. Indicating that the development of sialadenitis but not nephritis in BAFF Tg mice is MZ B cell dependent. Nephritis development in LTβ-BTg mice was associated with the detection of B-1 B cells in the inflamed kidneys. As B-1a B cell survival is dependent on the spleen, the contribution of B-1a B cells to nephritis development in BAFF Tg mice was assessed by crossing BAFF Tg mice to congenitally asplenic Hox11-/- mice (creating Hox11 -BTg mice). The absence of a spleen and B-1a B cells in Hox11-BTg mice delayed the nephritis development. In contrast, splenectomy of BAFF Tg mice at 12 weeks of age did not alter nephritis onset. In these mice B-1a B cells persisted in the peritoneal cavity and MZ-like B cells were detected in the periphery 8 months after surgery. In summary, nephritis development in BAFF Tg mice is unaltered by the absence of MZ B cells, but delayed in the absence of a spleen, MZ and B-1a B cells. Thus, B-1a and B-1b B cells may be potential targets for the treatment of nephritis in SLE patients with elevated BAFF.

Systemic lupus erythematosus (SLE) and Sj?gren?s syndrome (SS) are both heterogeneous autoimmune diseases with strong B cell aspects. A proportion of SLE and SS patients exhibit elevated serum BAFF (B cell activating factor of the TNF family); BAFF plays a key role in B cell homeostasis, survival and tolerance. BAFF transgenic (Tg) mice develop nephritis and salivary gland destruction that resemble aspects of SLE and SS respectively. Autoimmune disease development in BAFF Tg mice correlates with marginal zone (MZ) B cell expansion and the abnormal presence of MZ-like B cells outside of the spleen. The role of MZ B cells in BAFF induced autoimmune disease was analysed by crossing BAFF Tg mice with Lymphotoxin-β knockout mice (creating LTβ-BTg mice) which lack most peripheral lymph nodes, and also lack MZ B cells as a result of disrupted splenic architecture. LTβ-BTg mice were not protected against nephritis but exhibited reduced salivary gland infiltration and destruction. Indicating that the development of sialadenitis but not nephritis in BAFF Tg mice is MZ B cell dependent. Nephritis development in LTβ-BTg mice was associated with the detection of B-1 B cells in the inflamed kidneys. As B-1a B cell survival is dependent on the spleen, the contribution of B-1a B cells to nephritis development in BAFF Tg mice was assessed by crossing BAFF Tg mice to congenitally asplenic Hox11-/- mice (creating Hox11 -BTg mice). The absence of a spleen and B-1a B cells in Hox11-BTg mice delayed the nephritis development. In contrast, splenectomy of BAFF Tg mice at 12 weeks of age did not alter nephritis onset. In these mice B-1a B cells persisted in the peritoneal cavity and MZ-like B cells were detected in the periphery 8 months after surgery. In summary, nephritis development in BAFF Tg mice is unaltered by the absence of MZ B cells, but delayed in the absence of a spleen, MZ and B-1a B cells. Thus, B-1a and B-1b B cells may be potential targets for the treatment of nephritis in SLE patients with elevated BAFF.

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No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) TESE-CARLITOS-CORRIGIDA-FINAL.pdf: 24327580 bytes, checksum: d6527e9bfddbf4dfa439fd0ec2ae2db7 (MD5) Previous issue date: 2018-02-05 / FAPEAM - Fundação de Amparo à Pesquisa do Estado do Amazonas / Different societies always tried to read and interpret the apparent solar movement and mobility of the shadows, to organize structures of daily life. Among the various functions of the shadows, it is worth noting the utilization for the thermal comfort, use to improve the quality of the meat in the animal production. In agriculture are used in the production of cultivars of low photojournalism. In architecture, medicine, philosophy, geography, mathematics, physics, drawing, art, among other areas of scholastic knowledge, they occupy the prominent place, constituting subjects in the syllabus contents of school teaching. Knowledge about the spherical shape of the earth has had its presuppositions in the perception of shadows, and, still today, many people, as is the case of the inhabitants of the town of Here and of the city of Macapá, use these phenomena for orientation in the construction of houses for thermal comfort, tracing of paths and azimuths in the hiking trails, determination of distances from shading numbering along the route, production of annual calendars based on natural cycles based on shadows, among others. The thesis analyzed how the inhabitants of the city of Macapá in Brazil and of the settlement of Here in Mozambique, perceive and use their experiences of life to take advantage of the shadows. Looking for similarities and differences, which reflect socioenvironmental particularities of the places chosen for study. The striking moment of the shadows' trajectory corresponds to the instant when objects and things shadow the projected shadows, in the phase called the equinox, occurring in the city of Macapá twice a year (March and September) and at the December solstice in the town of Macapá. Here, occurring once a year. The research methodology was based on the bibliographical review and field work, in a theoretical approach conjugated between the ecological paradigm of anthropological thought of Ingold. In Macapá, the protagonists were made during the equinoxes involving the inhabitants participating in the ritual of passing of the sun by the obelisk of the monument Marco Zero and tourists. In Here, prioritized meetings in the headquarters of the town, with the madoda. The results of the study show that, of the 465,495 inhabitants of Macapá, more than half live in urban areas, traveling on foot, motorcycle, bicycle, in high temperature environments. The temperature values are aggravated by the location of the city on the line of the Ecuador, with intense verticalization of residences, in a place suffocated by the humidity of the Amazon river, mainly in the equinox of the waters. For the inhabitants of Macapá, the identity of the city is impregnated in its location on the imaginary line of Ecuador that names streets, public and private institutions, organizing various daily activities according to the influence of the factors of the geographical situation on the line. The socio-environmental organization in the city obeys the water and drought equinoxes. The perception about shadows of the residents of Here is steeped in concepts about flowering, foliage abscision, position astronomy, solar clock, photo journalism and establishment of seasons from their life experiences allowing to draw calendar based on natural cycles for varied activities. / Distintas sociedades procuraram fazer leitura, interpretação do movimento aparente solar e mobilidade das sombras, para organizar estruturas do quotidiano. Dentre as várias funções das sombras, destaca-se o aproveitamento do conforto térmico, utilização para melhoria da qualidade da carne na produção animal. Na agricultura são aproveitadas na produção de cultivares de baixo fotoperiodismo. Na arquitetura, medicina, filosofia, geografia, matemática, física, desenho, arte, dentre outras áreas de saber escolar, ocupam o lugar de destaque, constituindo matérias nos conteúdos programáticos de ensino escolar. Conhecimentos sobre a forma esférica da Terra tiveram seus pressupostos na percepção de sombras, sendo que, ainda na atualidade, muitos povos como é o caso dos moradores do povoado de Aqui e da cidade de Macapá, utilizam esses fenômenos para orientação na construção de moradias para conforto térmico, traçado de rumos e azimutes nas trilhas de caminhadas, na determinação de distâncias a partir de numeração de sombras ao longo do percurso, produção de calendários anuais baseados em ciclos naturais das sombras, entre outras. A Tese analisou como os moradores da cidade de Macapá Estado de Amapá no Brasil e do povoado de Aqui na província de Inhambane em Moçambique, percebem e utilizam suas experiências de vida para aproveitamento das sombras. Procurando semelhanças e diferenças, que refletem particularidades socioambientais dos lugares escolhidos para estudo. O momento marcante da trajetória das sombras corresponde ao instante em que os objetos e coisas se sobrepõem a elas, na fase denominada equinócio, acontecendo na cidade de Macapá duas vezes por ano (março e setembro) e no solstício de dezembro no povoado de Aqui, ocorrendo uma vez por ano. A metodologia de pesquisa baseou-se na revisão bibliográfica e trabalho de campo, numa abordagem teórica conjugada entre o paradigma ecológico do pensamento antropológico de Ingold com as observações e entrevistas aos sujeitos sociais. Em Macapá, as entrevistas foram feitas durante os equinócios envolvendo os moradores participantes no ritual de passagem do sol pelo obelisco do monumento Marco Zero. Em Aqui, priorizaram-se reuniões na sede do povoado, com os madoda. O estudo aponta que, dos 465.495 habitantes de Macapá, mais da metade vive na área urbana trafegando a pé, de moto, de bicicleta, em ambientes de temperaturas altas. Os valores da temperatura são agravados pela localização da cidade sobre a linha do Equador, com intensa verticalização de residências, em um local sufocado pela umidade da floresta amazônica e do rio Amazonas, principalmente no equinócio das águas. Para os moradores de Macapá, a identidade da cidade está impregnada na sua localização sobre a linha imaginária do Equador, nomeando ruas, instituições públicas e privadas, organizando diversas atividades do cotidiano de acordo com a influência dos fatores da situação geográfica sobre a linha. A organização socioambiental na cidade obedece, aos equinócios das águas e das secas. A percepção sobre sombras dos moradores de Aqui está explicada de conceitos sobre floração, abscisão foliar, astronomia de posição, relógio solar, foto periodismo e estabelecimento de estações do ano partir de suas experiências de vida permitindo elaborar calendário baseado em ciclos naturais para variadas atividades.

L’infection au VIH a plusieurs effets délétères, dont la dérégulation du compartiment des lymphocytes B. Cette dérégulation s’installe rapidement après l’infection et perdure au-delà de la thérapie antirétrovirale, pouvant mener à diverses maladies auto-immunes ainsi qu’à des lymphomes. Chez les individus atteints du VIH, cette dérégulation mène à l’augmentation de la fréquence des cellules B précurseurs de la zone marginale (MZ) dans le sang ainsi qu’à leur production d’IL-10, à l’augmentation du B-cell activating factor (BAFF), et à l’hyperglobulinémie. De plus, Nef a été détecté dans le sérum et dans les cellules dendritiques des patients infectés, les niveaux de Nef des patients corrélant avec leurs niveaux de BAFF. L’analyse d’un RNAseq effectué sur des cellules B MZ précurseurs démontre la diminution hautement significative d’expression des NR4As et de CD83 chez les patients VIH+ progresseurs comparativement aux contrôles VIH- et aux élites contrôleurs. Notre équipe a d’ailleurs démontré le potentiel et la fonction Breg associés à l’expression des NR4As et CD83 chez les cellules B MZ précurseurs du sang et d’amygdales. Aussi, la majorité de cette population co-exprime CD73 et CD39, molécules impliquées dans la synthèse de l’adénosine, cette dernière ayant un contrôle sur l’expression des NR4As. Nous voulions donc étudier l’effet de niveaux élevés de BAFF et de Nef sur la modulation de l’expression des NR4As, de CD83, CD73 et CD39 chez les cellules B MZ d'amygdales et l’effet de la déhydroergotamine (DHE) sur ce modèle, des études ayant déjà illustré sa modulation positive des NR4As. Nous étions aussi intéressés par la production d’IL-10 par ces cellules B MZ ainsi que l’effet de Nef sur son expression. Nous avons trouvé qu’après incubation avec BAFF et Nef, l’expression de NR4A1 et de CD83 était souvent plus basse qu’après une incubation avec BAFF seul qui semblait augmenter l’expression de ces dernières, ce qui concorde avec les résultats du RNAseq mentionné plus haut. Après une incubation avec Nef seul, l’expression des NR4As et de CD83 est similaire à l’expression mesurée après une incubation sans traitement, mais certains patients ont démontré une diminution légère de l’expression de ces molécules, chose normale puisque les échantillons contenaient tous des niveaux basaux de BAFF. De plus, nos résultats démontrent que le DHE augmente l’expression de NR4A1 et 3 après que leur expression ait été diminuée par Nef et son effet semble être plus important au niveau des cellules B MZ et MZ précurseurs. Ces résultats suggèrent l’utilité du DHE pour la diminution des niveaux inflammatoires chez les individus atteints du VIH, les NR4As ayant un rôle anti-inflammatoire par la diminution des fréquences de NFkB, molécule modulée positivement par Nef. Nous avons remarqué que les populations exprimant IL-10 co-expriment principalement CD10. L’effet de Nef n’a malheureusement pas été remarqué sur l’expression d’IL-10, d’autres études étant nécessaires avec nos populations d’amygdales. Bref, nos résultats suggèrent l’utilité d’agents thérapeutiques ciblant les NR4As en addition à la thérapie antirétrovirale, leur modulation chez les lymphocytes B MZ et MZ précurseurs pouvant être un aspect clé du contrôle des niveaux inflammatoires chez les individus atteints du VIH. / HIV infection is accompanied by many deleterious effects, including B cell dysfunction. This dysfunction begins rapidly after infection and persists throughout the course of infection, without being fully restored by antiretroviral therapy. These alterations can lead to lymphomas and a multitude of auto-immune diseases. In people living with HIV, B-cell deregulation leads to an increase in “precursor-like” marginal zone (MZ) B cell frequency and their secretion of IL-10, to an increase in B-cell activating factor (BAFF), and to hyperglobulinemia. In addition, Nef has been detected in the serum and dendritic cells of infected individuals, its levels correlating with BAFF levels in affected patients. The analysis of an RNA-seq performed on precursor-like MZ B cells indicated a highly significant drop in NR4A1-3 and CD83 levels in HIV+ progressors compared to HIV- controls and HIV+ elite controllers. In fact, our team has previously demonstrated regulatory “Breg” potential associated to NR4A and CD83 expression in blood and tonsil precursor-like MZ B cells. The majority of this population also co-expresses CD73 and CD39, molecules involved in adenosine synthesis, adenosine being a regulator of NR4A expression. Therefore, we wanted to study the effects of BAFF and Nef on the modulation of NR4A, CD83, CD73 and CD39 expression in tonsil MZ B cells as well as the effect of dihydroergotamine (DHE) on this model, studies having already shown its positive modulation on the NR4As. We were also interested in the effects of Nef on IL-10 production by MZ B cells. We found that after incubation with BAFF and Nef, NR4A1 and CD83 expression was often lower than after an incubation with BAFF only, which seemed to increase their expression. This corresponds with the results of the RNA-seq mentioned above. After incubation with Nef alone, NR4A and CD83 expression is similar to the expression levels found after incubation without treatment. Some patients did demonstrate a slight decrease in the expression of these molecules, a normal observation considering all samples contain a basal level of BAFF. In addition, our results demonstrate that DHE increases NR4A1 and NR4A3 levels after their expression is initially decreased iv by Nef, and its effect seems more significant in MZ and precursor-like MZ B cells. These results suggest the usefulness of DHE for the reduction of inflammatory levels in individuals living with HIV, the NR4As having an anti-inflammatory role by decreasing the frequency of NFkB, a molecule positively modulated by Nef. Furthermore, we noted the populations expressing IL-10 mainly co-express CD10. Unfortunately, Nef’s previously reported effect on IL-10 expression was not noticed, indicating the need for further studies using our tonsil samples. In conclusion, our results suggest the value of therapeutic agents targeting NR4As in addition to antiretroviral therapy, their modulation of MZ and precursor-like MZ B cells possibly being the key to controlling inflammatory levels in individuals living with HIV.

<p>Koordinatne merne mašine (KMM) su dominantni merni instrumenti u<br />dimenzionalnoj metrologiji. NJihovom upotrebom se može izmeriti<br />bilo koja makro tolerancija označena na tehničkoj dokumentaciji.<br />Tolerancija ravnosti je često prisutna u cilju izvršenja zahtevanih<br />funkcionalnih zahteva radnog predmeta. Istraživanja sprovedena u<br />ovom radu se bave problemom procene greške ravnosti merene na KMM<br />zasnovane na metodi minimalne zone i procene merne nesigurnosti za<br />ovaj merni zadakat. Aksenat je stavljen na primeni Monte Karlo<br />metode kao simulacionog alata za procenu merne nesigurnosti.<br />Razvijena je nova metodologija za procenu greške ravnosti kao i<br />simulacioni model za procenu merne nesigurnosti za ovaj merni<br />zadatak.</p> / <p>Coordinate measuring machines (CMMs) are dominant measuring<br />instruments in dimensional metrology. These machines can measure any<br />macro-tolerance indicated in the technical documentation. Flatness tolerance<br />is often present with the aim of completing the needed functional<br />requirements of a workpiece. The investigation conducted in this paper<br />considers the problem of assessing the flatness error measured on a CMM<br />based on the minimum zone method and on the method of evaluating<br />measurement uncertainty for this measuring task. The emphasis is on the<br />use of Monte Carlo method as a simulation tool for evaluating measurement<br />uncertainty. A new methodology for assessing the flatness error has been<br />developed, as well as a simulation model for evaluating measurement<br />uncertainty for this measuring task.</p>

No description available.

<p>Functional impairment is increasingly prevalent among middle-aged and older adults, with 2 in 5 adults over the age of 65 having some form of disability, the majority being limitations on mobility. Many older adults are able to maintain functional capacity well into later life, but the factors that contribute to high levels of function and the mechanisms by which they operate are unclear, although prior work has demonstrated the importance of social relationships for health. Guided by principles from the life course perspective and perspectives on social connectedness, this dissertation examined the role of social connectedness across the life course as a predictor of functional capacity in adulthood. I used existing longitudinal data from the national Midlife in the United States (MIDUS) study to pursue three central aims.</p> <p><br></p> <p>First, Paper 1 compared theoretical and data-driven approaches to classifying life course relationships, including multiple dimensions of social connectedness at different time points across the life course. Results showed that the data-driven approach (i.e., latent profile analysis) was a stronger predictor of functional limitations than the theoretical approach and revealed relationship trajectories consistent with life course cumulative processes. Second, using the profiles obtained from Paper 1, Paper 2 probed the association between life-course social connectedness and functional limitations by examining the potential mediating role of candidate biological and behavioral mechanisms, and moderation by socioeconomic status (SES). Paper 2 findings suggested that observed differences in later-life functional limitations based on life-course social connectedness can be at least partially explained by physical activity, but do not vary by SES. Contrary to hypotheses, inflammation was not a significant mediator. Third, Paper 3 used monozygotic twin data and within-family analyses to sharpen the focus on potential causal associations between life-course social connectedness and adult functional status. Results suggested that the association is likely driven by genetic and/or shared environmental influences. </p> <p><br></p> <p>Taken together, these results add to our understanding of social connectedness and health and address important gaps in the literature. These findings are used to generate theory- and intervention-relevant insights into the successful maintenance of health, independence, and function across the lifespan.</p>

:Einleitung S. 85 Internationale Industriekooperation als Marktoffensive S. 86 Montageproduktion auf Manufakturniveau S. 88 Technologietransfer und Finanzjonglage S. 92 Industriekooperation als Fehlinvestition S. 97 Zusammenfassung S. 99

La plupart des infections par le VIH-1 sont acquises lors de rapports hétérosexuels. En Afrique subsaharienne on observe 71 % des infections mondiales et 60 % des nouvelles infections par le VIH-1 touchent les femmes. Le tractus génital féminin (TGF) constitue la principale porte d’entrée pour le VIH-1 et joue un rôle important dans la défense de l’organisme contre les microorganismes pathogènes tout en maintenant une tolérance de la flore commensale. On y trouve les cellules épithéliales qui participent à l’élaboration des réponses immunes en collaboration avec les cellules dendritiques (DCs), mais également d’autres types de cellules immunitaires qui confèrent une protection à la muqueuse vaginale, notamment à travers la production de cytokines et de chimiokines. Nous avons établi une cohorte de travailleuses du sexe (CSWs) au Bénin et nous avons identifié des femmes hautement exposées et séronégatives au VIH-1 (HESN), qui demeurent séronégatives après plus de sept années actives dans le travail du sexe. Les personnes HESN étant un excellent modèle d’immunité naturelle contre le VIH-1, le but de notre projet consiste donc à étudier les cellules immunitaires impliquées dans la protection de l’hôte face au VIH-1, au niveau du tractus génital féminin. Nous émettons l’hypothèse que le maintien de faibles conditions inflammatoires dans le TGF des femmes HESN préviendrait une activation immunitaire excessive en préservant l’intégrité de la barrière de la muqueuse vaginale et contribuerait ainsi à maintenir une protection contre l’infection par le VIH-1. Des études antérieures sur les HESN béninoises et kenyanes ont démontré que ces femmes présentent de faibles niveaux d’inflammation dans leur TGF inférieur. En accord avec cela, nous avons observé de faibles niveaux de BLyS/BAFF dans la muqueuse vaginale des HESN comparativement aux travailleuses du sexe séropositives (CSWs+ HIV+). BLyS/BAFF est une molécule importante pour la différenciation des cellules B et pour la sélection de cellules B de première ligne de la zone marginale (MZ). De ce fait, nous rapportons pour la première fois la présence de cellules B CD1c+ de type MZ qui sont capables de se lier naturellement à la gp120 glycosylée, au niveau de la muqueuse vaginale. Or, des cellules B CD1c+ exprimant IgG sont augmentées chez les CSWs+ HIV+ comparativement aux HESN, ce qui pourrait contribuer à l’hyperglobulinémie observée dans le TGF inférieur des CSWs+ HIV+. Les faibles niveaux de BLyS/BAFF retrouvés dans la muqueuse vaginale des HESN semblent donc préserver une homéostasie au sein du compartiment B et des cellules B CD1c+ du TGF. De plus, nous y détectons une réactivité des IgG1 avec la gp-41 de l’enveloppe virale, qui pourrait contribuer à leur immunité naturelle. Avec les cellules épithéliales, les DCs sont l’une des premières à être en contact avec le virus dans le TGF. Elles jouent un rôle essentiel dans l’orchestration des réponses immunitaires. Nous pensons que les DCs contribuent au maintien de faibles conditions inflammatoires dans le TGF des HESN, prévenant ainsi l’activation immunitaire excessive et préservant l’intégrité de la barrière muqueuse de façon à maintenir une protection/contrôle contre le virus. Nous avons caractérisé une population myéloïde endocervicale « tolérogénique » HLA-DR+CD14+CD11c+ exprimant HLA-G, ILT4, CD103 et de forts taux d’IFN-α et d’IL-10 dont la fréquence relative était augmentée au niveau du col de l’utérus des HESN comparativement aux CSWs+ HIV+. De plus, des populations Tregs/Tr1 étaient aussi augmentées chez les HESN. Ces données reflètent à la fois une réponse antivirale et une contribution au contrôle des conditions inflammatoires dans le TGF des HESN. Afin de mieux comprendre la nature des cellules myéloïdes tolérogéniques, nous avons voulu dériver des monocytes en cellules dendritiques (MoDCs). Toutefois, nous avons remarqué que la différenciation des MoDCs des HESN était altérée. Suite à cela, nous avons caractérisé le profil transcriptomique des monocytes. Les résultats préliminaires mettent en lumière l’éventuel rôle des récepteurs nucléaires NR4A dans la modulation des MoDCs et, possiblement, sur le plan des cellules myéloïdes tolérogéniques chez les HESN. Dans l’ensemble, ces résultats nous ont permis d’acquérir de nouvelles connaissances sur les mécanismes mis en place chez les HESN dans l’immunité naturelle contre le VIH-1. / Most HIV-1 infections are acquired through heterosexual intercourse. In sub-Saharan Africa, 71% of global infections are observed and 60% of new HIV-1 infections affect women. The female genital tract (FGT) constitutes a main portal of entry for HIV-1 and plays an important role in protecting the host against pathogens while maintaining a tolerance to a commensal flora. FGT immunity involves genital epithelial cells as well as dendritic cells (DCs) and many other types of immune cells which confer protection, through the production of chemokines and cytokines. We established a cohort of commercial sex workers (CSWs) in Benin and identified HIV-1 highly exposed seronegative (HESN) individuals, who remain uninfected after more than seven years of active prostitution. These HESN individuals being an exceptional model of natural immunity against HIV-1, the aim of our project is to characterize immune cells involved in protection from HIV-1 infection, in the female genital tract. We hypothesize that maintenance of low inflammatory conditions in the FGT of HESN women helps to prevent excessive immune activation likely preserving the mucosal barrier integrity and would help to maintain a protection against HIV infection. Previous studies of Beninese and Kenyan HESN have shown that these women have a low inflammatory profile in their lower FGT. Accordingly, we found that vaginal mucosa of HESN had lower soluble BLyS/BAFF levels when compared to HIV-infected CSWs (CSWs+ HIV+). BLyS/BAFF is highly recognized for its role in B-cell ontogenesis, as well as cell fate decision towards the innate marginal zone (MZ) B-cell pool. For the first time, we report the presence of genital MZ-like CD1c+ B-cells that naturally bind to fully glycosylated gp120 in the vaginal mucosa. However, CD1c+ B-cells expressing IgG are increased in the lower FGT of CSWs+ HIV+ when compared to HESN, suggesting that these cells could contribute to the hyperglobulinemia observed in the lower FGT of CSWs+ HIV+. The low levels of BLyS/BAFF found in the vaginal mucosa of HESN thus appear to preserve homeostasis of the FGT B cell compartment and CD1c+ B-cells. In addition, we detect a reactivity of IgG1 to HIV-gp41 in cervico-vaginal lavages (CVL) supernatants of HESN, which could contribute to their natural immunity. Epithelial cells and DCs are one of the earliest cell types to sense the virus in the FGT. They play a key role in the orchestration of immune responses. We characterized a "tolerogenic" endocervical myeloid HLA-DR+CD14+CD11c+ population expressing HLA-G, ILT4, CD103 and high levels of IFN-α and IL-10, that was increased in the cervix of HESN when compared to CSWs+ HIV+. In addition, frequencies of Tregs/Tr1 cells were also increased in HESN. We believe that DCs contribute to maintaining low inflammatory conditions in the FGT of HESN, preventing excessive immune activation and preserving the integrity of the mucosal barrier to maintain a protection/control against the virus. These data reflect both an antiviral response and a contribution to the control of inflammatory conditions in the FGT of HESN. To better understand the nature of tolerogenic myeloid cells, we wanted to derive monocyte-derived dendritic cells (MoDCs). However, derivation of blood MoDCs was impaired in HESN. As a result, we decided to characterize the transcriptomic profile of total blood monocytes. Preliminary results appear to demonstrate the possible role of NR4A nuclear receptors in MoDCs modulation, and possibly in tolerogenic myeloid cells in HESN. Overall, our results contribute to a better understanding of the mechanisms established by HESN in natural immunity to HIV-1.