Introdução: A idade ao diagnóstico do lúpus eritematoso sistêmico juvenil (LESJ) pode influenciar a expressão da doença em termos de apresentação clínica inicial, padrão de envolvimento de órgãos e achados sorológicos. Objetivo: Avaliar dados demográficos, características clínicas e alterações laboratoriais no momento do diagnóstico da doença em três grupos etários diferentes de pacientes com LESJ: grupo A com início precoce (< 6 anos), grupo B com início em idade escolar ( >= 6 e < 12 anos) e grupo C com início em adolescentes ( >= 12 e < 18 anos). Métodos: Estudo multicêntrico brasileiro de coorte retrospectiva em 10 centros de reumatologia, incluindo 847 pacientes com o diagnóstico de LESJ. Resultados: Os pacientes foram divididos em três grupos: A com 39 (4%), B com 395 (47%) e C com 413 (49%). Dos 39 pacientes com LESJ do grupo A, 3 (8%) tinham < 2 anos, 4 (10%) >= 2 e < 3 anos e 32 (82%) >= 3 e < 6 anos. Setenta e quatro pacientes com LESJ foram analisados para os níveis séricos de C1q e a deficiência completa de C1q foi observada em 3/74 (4%), todos estes pertencentes ao grupo A. Os grupos foram semelhantes quanto às altas frequências de sexo feminino, nefrite, envolvimento neuropsiquiátrico, SLEDAI-2K ( >= 8), perfil de autoanticorpos, proteínas de fase aguda elevada e baixos níveis de complemento (p > 0,05). No entanto, as frequências de febre (78% vs. 61% vs. 47%, p < 0,0001), hepatomegalia (42% vs. 29% vs. 14%, p < 0,0001), esplenomegalia (28% vs. 12% vs. 4%, p < 0,0001) e lúpus discoide (13% vs. 4% vs. 4%, p=0,020) foram significantemente maiores no grupo A em comparação com os grupos B e C. As frequências de perda de peso > 2kg (19% vs. 28% vs. 36%, p < 0,017), fotossensibilidade (34% vs. 41% vs. 51% p < 0,006), leucopenia < 4.000/mm3 (14% vs. 25% vs. 30%, p=0,048) e linfopenia < 1.500/mm3 (22% vs. 41% vs. 47%, p=0,011) foram significantemente menores no grupo A. Conclusão: O presente estudo multicêntrico identificou que a apresentação inicial de LESJ foi caracterizada por alta frequência de envolvimento de órgãos internos nos três grupos estudados e algumas características clínicas e laboratoriais distintas nos grupos de início precoce e adolescentes / Introduction: Age at diagnosis of childhood-onset systemic lupus erythematosus (cSLE) may influence disease expression in terms of initial clinical presentation, pattern of organ involvement and serological findings. Objective: To evaluate demographic data, clinical and laboratory features at disease diagnosis in three different age groups of childhood systemic lupus erythematosus (cSLE): group A early-onset ( < 6 years), group B school age ( >= 6 and < 12 years) and group C adolescent ( >= 12 and < 18 years). Methods: Brazilian multicenter cohort retrospective study in 10 Pediatric Rheumatology centers, including 847 cSLE patients. Results: Patients were divided in three groups: A with 39 (4%), B 395 (47%) and C 413 (49%). Of 39 cSLE patients of group A, 3 (8%) were < 2 years, 4 (10%) >= 2 to < 3 years and 32 (82%) >= 3 and < 6 years. Seventy-four cSLE patients were analyzed for C1q levels and complete C1q deficiency was observed in 3/74 (4%), all of them of group A. Groups were similar regarding high frequencies of female gender, nephritis, neuropsychiatric involvement, SLEDAI-2K ( >= 8), autoantibody profile, elevated acute phase proteins and low complement levels (p > 0.05). However, the frequency of fever (78% vs. 61% vs. 47%, p < 0.0001), hepatomegaly (42% vs. 29% vs. 14%, p < 0.0001), splenomegaly (28% vs. 12% vs. 4%, p < 0.0001) and discoid lupus (13% vs. 4% vs. 4%, p=0.020) was significantly higher in the group A compared to groups B and C. The frequency of weight loss > 2kg (19% vs. 28% vs. 36%, p=0.017), photosensitivity (34% vs. 41% vs. 51%, p=0.006), leukopenia < 4,000/mm3 (14% vs. 25% vs. 30%, p=0.048) and lymphopenia < 1,500/mm3 (22% vs. 41% vs. 47%, p=0.011) was significantly lower in the group A. Conclusions: Our large multicenter study identified that the initial presentation of cSLE is characterized by comparable high frequency of internal organ involvement and some distinct clinical and laboratory features in early-onset and adolescent groups

A população de cães errantes tem sido um problema na sociedade moderna e levanta discussão sobre o bem estar dos animais, a responsabilidade ambiental e assuntos relacionados saúde pública, como agressão, zoonoses e acidentes de trânsito. São Paulo é uma cidade com mais de dez milhões de habitantes e uma população de cães domiciliados em torno de 2,5 milhões de animais. Não há pesquisas a respeito da distribuição da população de cães errantes e isso dificulta o planejamento de ações de intervenção neste campo. O problema foi abordado do ponto de vista da probabilidade de abandono e capacidade de suporte ambiental. Foi criado um escore composto por treze variáveis de risco de abandono. Os dados foram agrupados por distrito administrativo e estes classificados em três categorias (tercis). Foi definida uma amostra de conveniência de seis áreas a serem visitadas, duas em cada categoria, que fossem pequenas e isoladas, passiveis de percorrer a pé. O número de animais foi estimado pelo método de pseudo-captura, utilizando fotos e anotações para identificar os animais. Simultaneamente, foi aplicado um questionário em uma amostra aleatória sistemática dos domicílios de cada área. Das seis áreas visitadas, em duas foi observada presença de cães errantes e em apenas uma delas, uma população fixa. Dos fatores associados a presença de cães errantes, destacam-se os relacionados a proximidade homem-cão e ao ambiente. Intervenções nestes fatores e incentivo à guarda responsável podem ser soluções desejáveis para redução gradativa da população de cães errantes / The stray dog\'s population of has been a problem in modern society and raises discussion on different issues like animal welfare, environmental responsibility and public health matters such as dogs bites, zoonosis and traffic accidents. Sao Paulo is a city with over ten million inhabitants and a population of owned dogs around 2.5 million animals. There are no surveys on the distribution of the population of stray dogs and this hampers any plan of intervention. The problem was accessed from the standpoint of relinquishment probability and environmental carrying capacity. A score was created with thirteen variables, of known risk factors of relinquishment. The data was grouped by district and classified in to three categories (terciles). a convenience sample of six areas was defined, two in each category, which were small and isolated, liable to go through on foot. The number of animals was estimated by the pseudo capture method, using photos and notes to identify the animals. Simultaneously, a questionnaire was administered in a systematic random sample of households in each area. Of the six areas visited, in only two it the presence of stray dogs was observed and only one showing a fixed stray population. Of the factors associated to the presence of stray dogs, one can distinguish: degree of human-dog proximity and those related to environment. Intervention on these factors and encouraging responsible ownership could be a solution to gradually reduce the population of stray dogs.

Made available in DSpace on 2016-04-28T20:40:12Z (GMT). No. of bitstreams: 1 Angela de Leao Bley.pdf: 2495072 bytes, checksum: 2b7e47197a1fceb8afd65e25f430f637 (MD5) Previous issue date: 2009-10-16 / This research intends to analyze the Sandplay psychotherapy technical effects of Systemic Lupus Erythematosus (SLE) on 5 patients carrying such pathology. In fact, chronicle diseases like SLE affect not only the patient s health but also his/her social and psychological life as such diseases require endure attention concerning patient s quality of life. SLE is a chronicle and self immune pathology which shows different marks. Its development reflects moments of its activity and moments of its remission and these social and psychological effects of Lupus on adolescents and theirs families is easily seen in their daily lives, in their new responsibilities they all must face up. It is widely known that during such a period of life, adolescents have to face up brand new issues in their lives, they have to leave things they had praised behind, and they have to grab new issues with which they will have to learn how to deal. This is a major part of their healthy process of living and yet they have to deal with Lupus, a pathology that transforms even more their bodies. Thus, it is of great importance a psychological therapy. One could wonder about the effectiveness of Sandplay as a non-verbal therapy which can be used to touch the inner part of one self. In order to do so, it is analyzed the frequency of categories that pursuit a qualifying profile. Such a therapeutic process consists of 12 sessions inside a sand case and divided in different phases in which this therapeutic evolution can be studied. The pathology is dealt by a rheumatologist and in the end the 5 girls clinical data are compared to the control group for a conclusion. Sandplay is shown as a very important psychotherapy, for it helps to enhance these patients quality of lives / Este estudo tem por objetivo analisar o efeito da técnica psicoterápica do Sandplay em 5 pacientes portadoras de Lúpus Eritematoso Sistêmico (LES). As doenças crônicas, entre elas o (LES), afetam além da saúde física do paciente, a vida social e psicológica dele e exige atenção permanente em virtude das implicações no desenvolvimento do paciente e na sua Qualidade de Vida. O LES é uma doença autoimune, crônica, que pode se apresentar de várias maneiras. A sua evolução é marcada por períodos de atividade e de remissão. As questões psicossociais no Lúpus em jovens são evidentes na quebra da rotina diária e nas novas responsabilidades que tanto o paciente quanto a sua família se veem obrigados a enfrentar. A adolescência, fase de vida em que as jovens dessa pesquisa se encontram, é uma época em que vários lutos precisam ser elaborados para um desenvolvimento saudável. As jovens portadoras de doença crônica, além dessas perdas, têm que enfrentar uma doença que modifica o seu corpo, a sua fisionomia, o que acaba por dificultar ainda mais esse processo. Entende-se então a importância de acompanhamento psicológico nessa fase. O Sandplay, por ser uma técnica não verbal que atinge níveis profundos da psique, poderia ajudar também no controle da doença? O método utilizado é qualitativo-quantitativo; a análise dos cenários e a categorização das expressões verbais e imagéticas foram realizadas qualitativamente enquanto a análise da frequência das categorias encontradas segue um perfil qualitativo. O processo terapêutico, que consta de pelo menos 12 sessões na caixa de areia, está dividido em fases para que seja possível o estudo da evolução da terapia. A parte relativa à patologia é acompanhada por uma médica reumatologista e ao final os dados clínicos das 5 meninas são comparados aos dados do grupo controle para a análise final. Vai-se observar que a técnica psicoterápica do Sandplay pode ter ajudado porque propicia a melhora da qualidade de vida nas pacientes estudadas

Results of the above studies thus suggested that immune dysregulation in SLE result in derangement of a spectrum of inflammatory mediators leading to possible multiple organs auto-inflammatory damages. However, the exact etio-pathogenic mechanism could not simply be explained by these phenomena. Infection has been invoked as an underlying etiology or trigger for the induction of autoimmune disease. Epstein-Barr virus (EBV) possesses multiple features that characterise its involvement in initiating or perpetuating SLE disease. Several research groups demonstrated that the peripheral blood EBV DNA load is significantly higher in SLE patients, yet cell-free viral DNA was also reported in other EBV-associated diseases such as nasopharyngeal carcinoma (NPC) and certain lymphomas, suggesting that relatively little is known about its biology and dynamic distribution in the blood circulation. In the second part of our study, we examined the cell-free and cell-associated distribution profile of EBV DNA load in SLE. Our data showed that the distribution of EBV DNA in the cell-free and cell-associated compartments exhibited a heterogeneous pattern in SLE patients. Contrary to the exclusive presence of circulating cell-free EBV DNA in NPC patients, both cell-free and cell-associated EBV DNA were detected in some SLE patients, while in others, no EBV DNA was measurable in either blood compartments. The level of cell-associated EBV viral load was significantly higher in SLE patients with active disease than those who presented with milder disease activity. This phenomenon indicated a possible association of EBV viral infection with the level of immune competence in SLE patients. It has been reported that EBV encodes proteins which shares significantly homology sequence with human IL-6, IL-8, IL-10, IL-12 and colony-stimulating factor (CSF)-1. This proposition brought our attention to the immune perturbation by EBV on the cytokine balance, possibly constitute in part, to the immune dysregulation and Th1 and Th2 dichotomy in SLE exacerbation. (Abstract shortened by UMI.) / The first section of this research study aimed to explore the messengers that influence Th1/Th2 cells differentiation, development, effector functions and hence their plausible contribution in SLE immunopathogenesis. We focused on studying the expression of cytokine and chemokine milieu that directs the traffic of T lymphocytes; co-stimulatory molecules in the activation of T lymphocytes; transcription factors T-bet and GATA-3 in regulating the differentiation of Th1 and Th2 cell lineage. We also investigated the involvement of the lymphocyte subpopulation, Th17 in the auto-inflammatory axis of SLE exacerbation. / Lit, Choi Wan. / Advisers: Christopher W.K. Lam; Y.M. Dennis Lo. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3358. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 203-235). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Le lupus érythémateux disséminé est une maladie autoimmune systémique déclenchée par une combinaison de facteurs génétiques, hormonaux et environnementaux. Il se caractérise notamment par la présence d’autoanticorps dirigés principalement contre des éléments nucléaires. Les traitements proposés aux patients sont essentiellement palliatifs et non curatifs et engendrent de nombreux effets secondaires indésirables. Des nouvelles stratégies thérapeutiques plus spécifiques sont basées sur l’utilisation de peptides dérivés d’autoantigènes. Le peptide P140, découvert au laboratoire, est un candidat prometteur dans ce domaine. Il correspond à la séquence 131-151 de la protéine splicéosomale U1-70K et est chimiquement phosphorylé sur le résidu sérine 140. Son administration à des souris lupiques MRL/lpr diminue la sévérité des symptômes sans effet immunosuppresseur. Il est actuellement évalué chez l’homme dans un essai clinique de phase III. Le mécanisme d’action du peptide P140 commence à être bien connu chez la souris lupique. Récemment, mon équipe à montré que le peptide P140 affecte directement ou indirectement deux formes d’autophagie, la macroautophagie et l’autophagie médiée par les chaperonnes (CMA). De plus, il réduit l’expression des molécules du CMH-II ce qui conduirait à une baisse de la présentation antigénique et à une diminution de l’activation des LT autoréactifs. Finalement, une baisse de la production des autoanticorps, notamment des anticorps reconnaissant l’ADN double brin est observée suite à l’injection du peptide aux souris. L’objectif de mon projet de thèse a été de consolider ces résultats et également d’étudier le mode d’action du peptide chez l’homme puisque ceci n’avait pas encore été fait. Nous avons démontré que comme chez la souris, le peptide P140 réduit l’expression des molécules du CMH-II à la surface des LB de patients lupiques. De plus, nous avons montré que plus le score d’activité de la maladie est élevé, plus l’effet du peptide sur l’expression du CMH-II est important. En revanche, bien que nous ayons confirmé la dérégulation de la macroautophagie dans les LT CD8+ de patients, le peptide P140 ne semble pas affecter ce processus cellulaire. Nous étudions actuellement l’effet du peptide sur la CMA. Enfin, nous avons montré que chez la souris MRL/lpr et chez l’homme, le peptide P140 réduit le nombre de plasmablastes. Cette altération de la différenciation des LB conduit à une baisse de la production des IgM et des IgG, ce qui explique son effet bénéfique sur la maladie lupique. / Systemic lupus erythematosus (SLE) is a systemic autoimmune disease triggered by genetic, hormonal and environmental factors. It is mainly characterized by the presence of autoantibodies directed against nuclear elements. Most of current treatments proposed to patients are palliative and not curative and lead to numerous side effects. New therapeutical strategies are based on the use of peptides derivated from autoantigens. The P140 peptide discovered in our laboratory is a promising candidate. It corresponds to the 131-151 sequence of the U1-70K spliceosomal protein and is phosphorylated on ser140 residue. Its administration to MRL/lpr lupus-prone mice reduces symptom severity without immunosuppressive effect. It is currently evaluated in phase III of clinical trial. The mechanism of action of P140 peptide has been mostly elucidated in lupus mice. Recently, my team has shown that P140 peptide affects direclty or indireclty macroautophagy and chaperone-mediated autophagy (CMA), two major forms of autophagy. Furthermore, it reduces the expression of MHC class II molecules, which leads to the decrease of antigenic peptide presentation and activation of autoreactive T cells. Finally, a reduction of autoantibodies levels against double stranded DNA is shown after P140 injection in mice. The aim of my thesis project was to consolidate these data and to study the mode of action of P140 in humans since this was not done until now. We have shown that like in lupus-prone mice, P140 peptide reduces expression of MHC-II molecules on the surface of B cells from SLE patients. Furthermore, we have demonstrated that higher the disease activity score was, higher the effect of P140 peptide was. Unfortunately, although we confirmed the dysregulation of macroautophagy in CD8+ T cells from SLE patients, P140 peptide does not seem to affect this cellular process. We are currently studying the effect of the peptide on CMA. Finally, we have shown that in both MRL/lpr mice and humans, P140 peptide reduces the number of plasmabasts. This alteration of B cell differentiation lead to the decrease of IgM and IgG production, thus explaining the P140’ benefical effect on the course of lupus disease.

O Lúpus Eritematoso Sistêmico (LES) é uma doença inflamatória crônica autoimune que apresenta uma ampla variedade de manifestações clínicas e anormalidades imunológicas, afetando principalmente mulheres. É caracterizado pela perturbação da homeostase imunológica, que envolve a indução e produção de autoanticorpos, bem como pela formação e deposição de complexos imunes, que conduzem a uma intensa resposta inflamatória e dano tecidual. Há evidências de que fatores imunológicos, ambientais, hormonais e genéticos estão implicados na patogênese da doença. Genes e proteínas envolvidas na metabolização/detoxificação de xenobióticos são frequentemente utilizados como marcadores de susceptibilidade para o desenvolvimento de doenças, cuja etiologia está relacionada à exposição a fatores de risco ambientais. Enzimas do Citocromo P450 (CYP) são as principais responsáveis pela fase I de detoxificação, na qual ativam o xenobiótico, tornando-o mais eletrofílico e, desta forma, mais reativo. As Glutationa S-transferases (GST) são enzimas detoxificantes de fase II e normalmente conjugam a glutationa reduzida com uma variedade de compostos eletrofílicos, como espécies reativas de oxigênio, facilitando a excreção de produtos tóxicos. Polimorfismos nos genes CYP e GST são capazes de alterar a expressão e a atividade catalítica das enzimas, sendo responsáveis por diferenças interindividuais quanto à capacidade de biotransformação de xenobióticos. O objetivo do nosso trabalho foi avaliar a influência de três polimorfismos GST (GSTM1 nulo, GSTT1 nulo, e GSTP1*Val) e dois polimorfismos CYP (CYP1A1*2C e CYP2E1*5B) na predisposição ao LES em uma amostra de 370 pacientes com LES e 329 doadores de sangue saudáveis provenientes da região sul do Brasil. Os polimorfismos CYP foram genotipados por PCR-RFLP, enquanto que os polimorfismos GST foram genotipados por PCR multiplex (GSTM1 nulo, GSTT1 nulo) e PCR-RFLP para GSTP1. As freqüências alélicas e genotípicas foram comparadas entre pacientes e controles usando o teste de Qui-Quadrado ou o teste Exato de Fisher. As análises foram realizadas subdividindo os indivíduos de acordo com sua origem étnica. Entre os indivíduos Euro-descendentes, observou-se uma menor freqüência de genótipos heterozigotos GSTP1*Val em pacientes com LES em comparação aos controles (p=0,0047; OR 0,63 CI 95% 0,43 – 0,93 em relação a GSTP1*Ile/Ile e OR 0,49 CI 95% 0,26 – 0,92 em relação a GSTP1*Val/Val). No grupo Afro-descendente, houve tendência a uma maior freqüência do alelo GSTP1*Val em pacientes quando comparados aos controles (p=0,061). O alelo CYP2E1*5B foi significativamente mais freqüente nos pacientes do que em controles (p=0,038; OR 2,69 CI 95% 1,00 – 8,42). Não foi observada qualquer implicação clínica dos polimorfismos CYP e GST nos pacientes com LES. Nossos dados sugerem um papel protetor do genótipo heterozigoto GSTP1*105Ile/Val em Euro-descendentes e uma possível influência do alelo CYP2E1*5B na susceptibilidade ao LES entre Afro-descendentes. / Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that presents a variety of clinical manifestations and immunological abnormalities, particularly affecting women. It is characterized by disruption of immunologic homeostasis, which results in the induction and production of autoantibodies, as well as the formation and deposition of immune complexes, leading to an intense inflammatory response and tissue damage. There is evidence that immunological, environmental, hormonal and genetic factors are involved in the pathogenesis of the disease. Genes and proteins involved in metabolism/detoxification of xenobiotics are often used as markers of susceptibility to the development of diseases whose etiology is related to exposure to environmental risk factors. Cytochrome P450 (CYP) enzymes are primarily responsible for phase I detoxification, in which activate the xenobiotic, making it more electrophilic and thus more reactive. The Glutathione S-transferases (GST) are phase II detoxifying enzymes and usually conjugate reduced glutathione with a variety of electrophilic compounds, such as reactive oxygen species, facilitating the excretion of toxic products. Polymorphisms in the CYP and GST genes can alter the expression and catalytic activity of enzymes, being responsible for interindividual differences regarding the capacity of xenobiotics biotransformation. The aim of our study was to evaluate the influence of three GST polymorphisms (GSTM1 null, GSTT1 null and GSTP1*Val) and two CYP polymorphisms (CYP1A1*2C and CYP2E1*5B) in SLE predisposition in a sample of 370 SLE patients and 329 healthy blood donors, both from southern Brazil. The CYP polymorphisms were genotyped by PCR-RFLP, while the GST polymorphisms were genotyped by multiplex PCR and PCR-RFLP for GSTP1. Allelic and genotypic frequencies were compared between patients and controls using the Chi-square test or Fisher´s exact test. Analyses were performed subdividing the individuals according to their ethnic origin. Among European-derived individuals, it was observed a lower frequency of GSTP1*Val heterozygous genotypes in SLE patients compared to controls (p = 0.0047; OR 0.63 CI 95% 0.43 - 0.93 in relation to GSTP1*Ile/Ile) and (OR 0.49 95% CI 0.26 - 0.92 in relation to GSTP1*Val/Val). In African-derived group, there was a trend to a higher frequency of GSTP1*Val allele in patients when compared to controls (p=0.061). The CYP2E1*5B allele was significantly more frequent in patients than controls (p=0.038, OR 2.69 95% CI 1.00 - 8.42). We did not observe any clinical implication of the CYP and GST polymorphisms in patients with SLE. Our data suggest a protective role of the GSTP1*105Ile/Val heterozygous genotype in European-derived and a possible influence of the CYP2E1*5B allele in SLE susceptibility among African-derived.

Le lupus érythémateux disséminé est une maladie autoimmune systémique provoquant des lésions tissulaires graves. Notre laboratoire a découvert un peptide phosphorylé, appelé P140, présentant des propriétés thérapeutiques pour le traitement du lupus. Le mode d’action du peptide P140 dans le traitement du lupus repose sur son interaction avec la protéine de choc thermique HSPA8/HSC70 et l’objectif de mon projet de thèse a été de consolider et compléter ce mécanisme. Nous avons démontré qu’après internalisation par endocytose dépendante des clathrines, le peptide P140 se localise rapidement au sein du lysosome des lymphocytes B. Dans cet organelle, il réduit l’import de substrat cytosolique par autophagie dépendante des chaperonnes en ciblant et réduisant l’activité de HSPA8 intralysosomale. Nous avons également entrepris une analyse comparative du répertoire des lymphocytes T et B des souris lupiques par rapport aux souris saines. Nos résultats révèlent un changement dans la fréquence de certains réarrangements du TCR entre les souris lupiques et les souris saines et un effet bénéfique du peptide P140 sur certains réarrangements associés au lupus. / Systemic lupus erythematosus is a multi-organ autoimmune disease provoking tissue damages. Our laboratory has discovered a phosphorylated peptide, named P140, with therapeutic activities in lupus. The mode of action used by P140 peptide relies on its interaction with the heat shock protein HSPA8/HSC70. The aim of my thesis project was to consolidate and complete this HSPA8-dependent mechanism. We have demonstrated that, upon internalization by clathrin-mediated endocytosis, P140 peptide homes rapidly into B cell lysosome. In this organelle, the peptide reduces chaperone-mediated autophagy by interacting and inhibiting intralysosomal HSPA8 activity. We also performed a comparative analysis of T cell and B cell repertoire on lupic mice compared to healthy mice Our results show a modification in the frequency of certain TCR rearrangements between lupus-prone mice and healthy mice and a beneficial effect of P140 peptide on certain lupus-associated rearrangements.

Introdução: A idade ao diagnóstico do lúpus eritematoso sistêmico juvenil (LESJ) pode influenciar a expressão da doença em termos de apresentação clínica inicial, padrão de envolvimento de órgãos e achados sorológicos. Objetivo: Avaliar dados demográficos, características clínicas e alterações laboratoriais no momento do diagnóstico da doença em três grupos etários diferentes de pacientes com LESJ: grupo A com início precoce (< 6 anos), grupo B com início em idade escolar ( >= 6 e < 12 anos) e grupo C com início em adolescentes ( >= 12 e < 18 anos). Métodos: Estudo multicêntrico brasileiro de coorte retrospectiva em 10 centros de reumatologia, incluindo 847 pacientes com o diagnóstico de LESJ. Resultados: Os pacientes foram divididos em três grupos: A com 39 (4%), B com 395 (47%) e C com 413 (49%). Dos 39 pacientes com LESJ do grupo A, 3 (8%) tinham < 2 anos, 4 (10%) >= 2 e < 3 anos e 32 (82%) >= 3 e < 6 anos. Setenta e quatro pacientes com LESJ foram analisados para os níveis séricos de C1q e a deficiência completa de C1q foi observada em 3/74 (4%), todos estes pertencentes ao grupo A. Os grupos foram semelhantes quanto às altas frequências de sexo feminino, nefrite, envolvimento neuropsiquiátrico, SLEDAI-2K ( >= 8), perfil de autoanticorpos, proteínas de fase aguda elevada e baixos níveis de complemento (p > 0,05). No entanto, as frequências de febre (78% vs. 61% vs. 47%, p < 0,0001), hepatomegalia (42% vs. 29% vs. 14%, p < 0,0001), esplenomegalia (28% vs. 12% vs. 4%, p < 0,0001) e lúpus discoide (13% vs. 4% vs. 4%, p=0,020) foram significantemente maiores no grupo A em comparação com os grupos B e C. As frequências de perda de peso > 2kg (19% vs. 28% vs. 36%, p < 0,017), fotossensibilidade (34% vs. 41% vs. 51% p < 0,006), leucopenia < 4.000/mm3 (14% vs. 25% vs. 30%, p=0,048) e linfopenia < 1.500/mm3 (22% vs. 41% vs. 47%, p=0,011) foram significantemente menores no grupo A. Conclusão: O presente estudo multicêntrico identificou que a apresentação inicial de LESJ foi caracterizada por alta frequência de envolvimento de órgãos internos nos três grupos estudados e algumas características clínicas e laboratoriais distintas nos grupos de início precoce e adolescentes / Introduction: Age at diagnosis of childhood-onset systemic lupus erythematosus (cSLE) may influence disease expression in terms of initial clinical presentation, pattern of organ involvement and serological findings. Objective: To evaluate demographic data, clinical and laboratory features at disease diagnosis in three different age groups of childhood systemic lupus erythematosus (cSLE): group A early-onset ( < 6 years), group B school age ( >= 6 and < 12 years) and group C adolescent ( >= 12 and < 18 years). Methods: Brazilian multicenter cohort retrospective study in 10 Pediatric Rheumatology centers, including 847 cSLE patients. Results: Patients were divided in three groups: A with 39 (4%), B 395 (47%) and C 413 (49%). Of 39 cSLE patients of group A, 3 (8%) were < 2 years, 4 (10%) >= 2 to < 3 years and 32 (82%) >= 3 and < 6 years. Seventy-four cSLE patients were analyzed for C1q levels and complete C1q deficiency was observed in 3/74 (4%), all of them of group A. Groups were similar regarding high frequencies of female gender, nephritis, neuropsychiatric involvement, SLEDAI-2K ( >= 8), autoantibody profile, elevated acute phase proteins and low complement levels (p > 0.05). However, the frequency of fever (78% vs. 61% vs. 47%, p < 0.0001), hepatomegaly (42% vs. 29% vs. 14%, p < 0.0001), splenomegaly (28% vs. 12% vs. 4%, p < 0.0001) and discoid lupus (13% vs. 4% vs. 4%, p=0.020) was significantly higher in the group A compared to groups B and C. The frequency of weight loss > 2kg (19% vs. 28% vs. 36%, p=0.017), photosensitivity (34% vs. 41% vs. 51%, p=0.006), leukopenia < 4,000/mm3 (14% vs. 25% vs. 30%, p=0.048) and lymphopenia < 1,500/mm3 (22% vs. 41% vs. 47%, p=0.011) was significantly lower in the group A. Conclusions: Our large multicenter study identified that the initial presentation of cSLE is characterized by comparable high frequency of internal organ involvement and some distinct clinical and laboratory features in early-onset and adolescent groups

Le lupus érythémateux disséminé est une maladie auto-immune systémique chronique dont les atteintes sont multiples, l’atteinte rénale constituant la plus sévère. Une conjonction de facteurs génétiques et environnementaux conduit au développement de la maladie qui se traduit par une rupture de tolérance au soi. L’un des signes biologiques majeurs est la production d’auto-anticorps dirigés contre des composants nucléaires qui, en se déposant dans divers tissus dont les reins, génèrent une inflammation chronique conduisant au dysfonctionnement de l’organe. Le dépôt d’autoanticorps s’accompagne d’infiltrats de cellules immunitaires, qui, dans ce type d’inflammation, peuvent se transformer en structures lymphoïdes ectopiques fonctionnelles appelées Organes Lymphoïdes Tertiaires (OLT). Des OLT sont retrouvés dans diverses pathologies et participent à la génération locale de réponses immunitaires bénéfiques (infections/cancers) ou délétères (maladies auto-immunes). Mon projet de thèse a porté sur la mise en évidence d’OLT dans les reins au cours du lupus et sur l’étude des mécanismes permettant leur formation. Nous avons tout d’abord caractérisé les infiltrats inflammatoires présents dans les reins de souris NZB/W, modèle murin spontané de lupus. Ces infiltrats sont hautement organisés et constituent des OLT fonctionnels, potentiellement impliqués dans la néphrite lupique. Nous nous sommes ensuite intéressés aux mécanismes de mise en place de ces OLT et avons identifié les lymphocytes T et le récepteur aux chimiokines CXCR3 comme des éléments clés de ce processus et de la pathologie lupique. Les données obtenues apportent une meilleure compréhension fondamentale de la néogenèse lymphoïde au cours du lupus et ouvrent la voie vers de nouvelles stratégies thérapeutiques permettant de traiter la néphrite lupique. / Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with multiple outcomes, with renal damage being the most severe. A combination of genetic and environmental factors leads to the development of the disease, which results in a break of immune tolerance. One of the major biological signs is the production of autoantibodies to nuclear components that, by depositing in various tissues including the kidneys, generate chronic inflammation leading to organ dysfunction. Deposition of autoantibodies is accompanied by immune cell infiltrates, which in this type of inflammation can be transformed into functional ectopic lymphoid structures called Tertiary Lymphoid Organs (TLO). TLO are found in various diseases and participate in the local generation of beneficial (infections / cancers) or deleterious (autoimmune diseases) immune responses. My thesis project focused on the demonstration of TLO in the kidneys during lupus and on the study of the mechanisms allowing their formation. We first characterized the inflammatory infiltrates present in the kidneys of NZB/W mice, a spontaneous murine model of lupus. These infiltrates are highly organized and constitute functional TLO that are potentially implicated in lupus nephritis. We then investigated the mechanisms of development of these TLO and identified T lymphocytes and the CXCR3 chemokine receptor as key components of this process and lupus pathology. The data obtained provide a better understanding of lymphoid neogenesis during lupus and pave the way for new therapeutic strategies to treat lupus nephritis.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.