The presence of autoantibodies in systemic lupus erythematosus (SLE) suggests a breach of tolerance. Recently, the IgM-IgD+ naïve B cell population has been shown to be enriched for self-reactive cells that are anergic in healthy subjects. Therefore, to determine whether there is altered selection of self-reactive cells in SLE, this population was examined using multiparameter flow cytometry. SLE patients had increased proportions of IgM-IgD+ cells in mature and transitional B cell compartments that were activated as compared to controls. Comparison of mature and transitional IgM-IgD+ B cell proportions suggested altered selection between the transitional to mature stages in SLE. There was no correlation between altered B cell function or genetic polymorphisms in B cell signalling molecules and the expansion or activation of IgM-IgD+ cells. Thus, selection of self-reactive B cells appears to be abnormal in SLE, but this does not appear to result from altered responses to Ig crosslinking.

The presence of autoantibodies in systemic lupus erythematosus (SLE) suggests a breach of tolerance. Recently, the IgM-IgD+ naïve B cell population has been shown to be enriched for self-reactive cells that are anergic in healthy subjects. Therefore, to determine whether there is altered selection of self-reactive cells in SLE, this population was examined using multiparameter flow cytometry. SLE patients had increased proportions of IgM-IgD+ cells in mature and transitional B cell compartments that were activated as compared to controls. Comparison of mature and transitional IgM-IgD+ B cell proportions suggested altered selection between the transitional to mature stages in SLE. There was no correlation between altered B cell function or genetic polymorphisms in B cell signalling molecules and the expansion or activation of IgM-IgD+ cells. Thus, selection of self-reactive B cells appears to be abnormal in SLE, but this does not appear to result from altered responses to Ig crosslinking.

No description available.

No description available.

A paracoccidioidomicose (PCM), doença sistêmica de caráter granulomatoso, causada pelo fungo termodimórfico Paracoccidioides brasiliensis. A PCM é endêmica na América Latina e atinge principalmente indivíduos do sexo masculino com atividades econômica ligada a agricultura. Os pacientes com PCM exigem tratamento a base de sulfametoxazol/trimetoprim, anfotericina B, e derivados azólicos por longos períodos. A gp43, possui 416 aminoácidos, onde um trecho específico de 15 aminoácidos (QTLIAIHTLAIRYAN) designado como (P10), é reconhecido pelos linfócitos T de camundongos e humanos. No presente estudo avaliamos o efeito aditivo da imunização do P10 com às drogas antifúngicas utilizadas no tratamento da PCM. Nossos resultados indicam um efeito aditivo entre a imunização com P10 e o tratamento medicamentoso em camundongos Balb/c infectados. Associado a redução significativa da carga fúngica no pulmão, baço e fígado desses animais, detectamos aumento dos níveis de IL-12 e IFN-? e diminuição de IL-4 e IL-10. / Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis, a thermal dimorphic fungus. PCM is endemic in Latin America affecting mainly rural workers. The patients with PCM demand treatment the base of sulfametoxazole/trimethoprim, amphotericin B and derivatives azolic. The gp43 has 416-mer and mice and human T lymphocytes are stimulated by a 15-mer peptide designated as P10 (QTLIAIHTLAIRYAN). In the present work we evaluated the additive effect of P10 immunization and antifungal drugs utilizing in PCM treatment. Ours results showed an additive protective effect between immunization with P10 and drugs treatment with infected Balb/c mice. Associated to the reduction of fungal burden in the lung, spleen and liver we observed increase of levels of IL-12 and IFN-? and reduction of IL-4 and IL-10.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 112-132).

A side effect of generating an immune system for defense against invading pathogens is the potential to develop destructive cells that recognize self-tissues. Typically, through the "education" of developing immune cells, the organism inactivates potentially self-destructive cells, resulting in what is called self-tolerance. I proposed to explore the molecular mechanisms responsible for the induction and maintenance of tolerance. Our lab has developed a model of induced immune tolerance to skin and islet allografts utilizing a donor-specific transfusion of spleen cells and a brief course of anti-CD40L antibody. Because the difficulty in isolation of tolerant T cells from this system is prohibitive to performing large screens on these cells directly, I have chosen to study an in vitro CD4+Th1 cell line, A.E7, which can be made anergic via stimulation through the T cell receptor in the absence of costimulation. I hypothesized that anergized T cells upregulate genes that are responsible for the induction and maintenance of anergy and therefore exhibit a unique RNA expression profile. I have screened anergic cells using Affymetrix GeneChips and identified a small number of genes that are differentially expressed long-term in the anergic population compared to mock-stimulated and productively activated controls. The results have been confirmed by quantitative RT-PCR for each of the candidates. One of the most promising, the zinc-finger transcription factor Egr-2, was verified to be expressed long-term by western blotting, demonstrating perfect correlation between Egr-2 protein expression and the anergic phenotype. Silencing Egr-2 gene expression by siRNA in A.E7 T cells prior to anergy induction rescues the cells from the inability to phosphorylate ERK-1 and ERK-2 and also results in increased proliferation in response to antigen rechallenge. In this study I report that Egr-2 is specifically expressed long-term in anergic cells, protein expression correlates inversely with responsiveness to antigen rechallenge, and that Egr-2 is required for the full induction of anergy in T cell clones.

This study investigated the role of tolerance induction in an inflammatory setting in regard to the early growth response genes Egr2 and Egr3. T cells robustly respond to pathogenic antigens during infection, but are tolerant to stimulation by self-antigens. The intrinsic mechanisms for self-tolerance in the periphery are still not clear. Egr2 and 3 are induced in tolerant T cells in response to antigen stimulation by NFAT-medicated tolerant signalling; however, their function in tolerant T cells is still unknown. The study demonstrated that Egr2 and 3, induced in tolerant T cells, are not directly involved in defective proliferation and IL-2 production, the hallmarks of T cell tolerance. However, they are essential for preventing inflammatory response of tolerant T cells. In the absence of Egr2 and 3, tolerant T cells show impaired proliferation and production of IL-2, but produce high levels of IFN-γ, a key inflammatory cytokine. This phenotype resembles CD4 T cells from autoimmune diseases such as lupus which show poor proliferative response, but hyper-inflammation. Our study demonstrated, for the first time, a distinctive mechanism to control inflammation from proliferative tolerance regulated by Egr2 and 3, which may be an important mechanism for the control of autoimmune diseases.

À l’heure de la prise de conscience de la finitude des ressources et du besoin grandissant d'énergie, la notion de développement durable doit prendre une place centrale dans l'évolution de la société. Pour atteindre ce but, il est maintenant reconnu, qu'un changement de consommation profond est nécessaire ; et ce, qu'il s'agisse de consommation énergétique, alimentaire ou de produits finis. Nous croyons que ce changement de paradigme n’est possible que si tous les acteurs avancent de concerts sur les différentes problématiques auxquelles nous sommes confrontées. Chacun à son échelle doit ainsi pouvoir prendre les décisions qui s'imposent à tous. C'est la logique qui a motivé l'outil d'exergo-graphie présenté dans le chapitre 3. Inscrit dans la lignée des diagrammes de Sankey, il permet de représenter les bilans exergétiques sous forme graphique afin d’en communiquer plus facilement les enseignements. Nous l’appliquons à deux cas d'analyses faites sur les installations de chauffage et de production d’ECS du bâtiment A de l’UPN. Pour chacune, nous étudions la possibilité d’une solution de production durable de la chaleur (PAC géothermique et solaire thermique). Après en avoir présenté les analyses, nous en dressons les représentations graphiques que nous comparons à celles du système actuel. Au préalable, le chapitre 1 introduit les concepts de base de l’analyse exergétique, approfondis dans le chapitre 2, au travers d’une modélisation des systèmes fluides statiques et dynamiques. Finalement, dans le chapitre 4, nous introduisons un modèle-jouet qui, proposant une représentation fractale de la chaleur, tente d’établir un lien conceptuel entre le comportement microscopique, statistique, du support de la chaleur, et les observables macroscopiques qui la caractérisent. / At this time of awareness of the finiteness of resources, and of increasing needs for energy, the concept of sustainable development must play a central role in the forthcoming developments of our society. To do so, it is now an accepted fact that a deep change of our consumption habits is necessary; whether it is energy, food or final goods consumption. We believe this paradigm shift is only possible if all actors face together the various issues we are dealing with. Everyone, at one own scale, must be able to make informed decision. This is the idea that leads to the exergo-graphy tool presented in chapter 3. In line with the so called Sankey diagrams, it allows to graphically represent exergy balances in order to communicate more easily on their lessons. We apply it to two analysis done on the heating and DHW installations of the building A of the UPN. For each, we investigate the possibility of a sustainable heat production solution (geothermal heat pump and solar thermal energy). After presenting the analyses, we draw their graphical representations which we then compare to those of the current system. Beforehand, the first chapter introduces the basic notions of exergetic analysis, discussed further in chapter 2, through a model for static and dynamic fluid systems. Finally, in chapter 4, we introduce a toy-model which, proposing a fractal representation of exergy, tries to establish a conceptual link between microscopic, statistical, behaviour of heat background support, and the macroscopic observables that characterize it.

A paracoccidioidomicose (PCM), doença sistêmica de caráter granulomatoso, causada pelo fungo termodimórfico Paracoccidioides brasiliensis. A PCM é endêmica na América Latina e atinge principalmente indivíduos do sexo masculino com atividades econômica ligada a agricultura. Os pacientes com PCM exigem tratamento a base de sulfametoxazol/trimetoprim, anfotericina B, e derivados azólicos por longos períodos. A gp43, possui 416 aminoácidos, onde um trecho específico de 15 aminoácidos (QTLIAIHTLAIRYAN) designado como (P10), é reconhecido pelos linfócitos T de camundongos e humanos. No presente estudo avaliamos o efeito aditivo da imunização do P10 com às drogas antifúngicas utilizadas no tratamento da PCM. Nossos resultados indicam um efeito aditivo entre a imunização com P10 e o tratamento medicamentoso em camundongos Balb/c infectados. Associado a redução significativa da carga fúngica no pulmão, baço e fígado desses animais, detectamos aumento dos níveis de IL-12 e IFN-? e diminuição de IL-4 e IL-10. / Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis, a thermal dimorphic fungus. PCM is endemic in Latin America affecting mainly rural workers. The patients with PCM demand treatment the base of sulfametoxazole/trimethoprim, amphotericin B and derivatives azolic. The gp43 has 416-mer and mice and human T lymphocytes are stimulated by a 15-mer peptide designated as P10 (QTLIAIHTLAIRYAN). In the present work we evaluated the additive effect of P10 immunization and antifungal drugs utilizing in PCM treatment. Ours results showed an additive protective effect between immunization with P10 and drugs treatment with infected Balb/c mice. Associated to the reduction of fungal burden in the lung, spleen and liver we observed increase of levels of IL-12 and IFN-? and reduction of IL-4 and IL-10.