O transplante autólogo de células-tronco hematopoéticas é indicado no tratamento de doenças autoimunes graves e refratárias ou que comprometem a qualidade de vida do paciente. Tal tratamento possui sólidas bases experimentais e clínicas e para alguns já apresenta superioridade ao tratamento convencional. No entanto, é um procedimento considerado agressivo, de alto custo financeiro, que pode acarretar eventos adversos, complicações, fatores de tensão física e psíquica para o paciente e sua família. Essa complexidade exige uma assistência de enfermagem especializada, capaz de assistir o paciente em cada uma das fases do tratamento, a fim de identificar os riscos, as intercorrências e propondo intervenções adequadas. Além disso, é fundamental que o paciente adquira conhecimentos e habilidades para se adaptar às condições impostas pela terapêutica, assim reunirá recursos de autonomia para realizar seu autocuidado. Frente ao exposto, as tecnologias podem ajudar e facilitar a aprendizagem, pois abordam o conteúdo por meio de várias formas e formatos. Nesse contexto, a enfermagem depara-se com o desafio de integrar o uso da Internet® no cuidado prestado ao paciente. A utilização dessa rede enfoca, principalmente, a disponibilização de informação de saúde ou estabelecimento de contato virtual para providenciar informação acessada de forma rápida e adequada à demanda da pessoa. Desta forma, o objetivo deste estudo foi desenvolver um ambiente virtual de aprendizagem com orientações sobre transplante autólogo de células-tronco hematopoéticas para doenças autoimunes. Trata-se de um estudo metodológico, com o objetivo de desenvolver o ambiente virtual de aprendizagem, website, com orientações sobre transplante autólogo de células-tronco hematopoéticas para doenças autoimunes. O website foi construído conforme o modelo de design instrucional, o qual percorreu as seguintes etapas: análise, design, desenvolvimento e implementação. Este foi desenvolvido em plataforma web, na linguagem de marcação Hypertext Markup Language, utilizando-se o programa WebAcappella, Responsive Website Creator 5 e disponibilizado no endereço eletrônico: http://www.transplantardai.com.br. O conteúdo do website foi estruturado nos seguintes tópicos: História, Transplante, Doenças Autoimunes, Links Interessantes, Orientações, Fala Equipe e Dúvidas Frequentes. Os ícones e menus foram criados de modo que o conteúdo atraia o usuário, sem cansar ou distraí-lo, a fim de otimizar os recursos disponíveis no ambiente e facilitar o acesso à busca dessas informações. Assim sendo, o presente estudo desenvolveu um ambiente virtual de aprendizagem que pode ser uma ferramenta utilizada para orientar, cuidar e interagir / Autologous hematopoietic stem cell transplantation is indicated for the treatment of severe or refractory autoimmune diseases, or those which compromise patients\' quality of life. This treatment has solid experimental and clinical foundations, and in some cases, it outranks conventional treatments. However, it is considered an aggressive and high-cost procedure that may lead to adverse events, complications, and factors of physical and psychic tension to patients and their families. This complexity requires specialized nursing care, capable of assisting patients in each phase of the treatment, so as to identify risks and propose appropriate interventions. In addition, patients must acquire knowledge and skills to adapt to the conditions imposed by the treatment, thus gathering autonomy resources to perform self-care. In the light of this, technologies can help and facilitate learning, as they approach content in several ways and formats. In this context, nursing faces the challenge of integrating the use of the Internet® in the care provided to patients. The use of this network focuses, mainly, on making health information available or establishing virtual contact to provide information that can be accessed fast and that is suitable to the person\'s demand. This was a methodological study, with the aim of developing a virtual learning environment and a website, with instructions on autologous hematopoietic stem cell transplantation for autoimmune diseases. The website was built according to an instructional design model, through the following steps: analysis, design, development, and implementation. It was developed on a web platform, using the Hypertext Markup Language and the programs WebAcappella and Responsive Website Creator 5, being available at http://www.transplantardai.com.br. The website content was structured in the following topics: History, Transplantation, Autoimmune diseases, Interesting links, Instructions, Talk to the team and Frequently asked questions. The icons and menus were created so that the content would be attractive to users, without making them tired or distracting them, in order to optimize the resources available in the environment and facilitate access to the search for information. Therefore, the present study developed a virtual learning environment that can be used for guidance, caring, and interaction

This research study explored the experiences of 19 women who had been diagnosed with, or were still seeking the diagnosis of SLE (lupus) and their decisions regarding support group participation. The aim of this study was to evaluate the variety of factors influencing their choices in types and sources of support, their coping strategies and the reasons behind their decisions to either choose or not choose lupus support groups as a viable support resource. Those women identified as support groups attendees recalled a more emotion-focused response to their diagnosis and showed stronger reliance on seeking emotional forms of support. Conversely, those women who chose not to participate in groups (non-attendees) utilized more problem-focused strategies when they received their news of the illness and indicated more reliance on instrumental forms of support. Additionally, the women who do not attend support groups did not seem to have more social support from outside sources, but did show a tendency to utilize relationship-focused coping more than other forms of coping strategies overall. Both groups showed a heavy reliance on their medical providers for both emotional and instrumental forms of support suggesting this source as an important factor in individual choices in coping strategies and support sources. The decisions to attend or not attend differed only in the strategies they relied on and specific group structure, timing and locations. The results of this study supports earlier research in the types and sources of social support used in adapting to a chronic illness. This study also encourages incorporating individual support services through medical providers and the development of programs that acknowledge individual coping and support needs.

No description available.

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

Introdução: a síndrome antifosfolípide (SAF) primária é uma vasculopatia autoimune mediada por autoanticorpos com trombose como sua principal manifestação clínica. A presença de anticorpos antifosfolípides (aPL), embora relevante para confirmar o diagnóstico, não parece ser suficiente para explicar completamente a fisiopatologia da doença e um segundo gatilho é usualmente necessário. Além das hipóteses de infecções virais e insulto inflamatório como possíveis desencadeantes, parece que os receptores toll like (TLR) e o Interferon (IFN) tipo I são possíveis protagonistas nesse processo, contribuindo para o início da trombose. Recentemente, dois pequenos estudos demonstraram que uma porcentagem relevante de pacientes com SAF primária tem uma regulação positiva de genes IFN em células mononucleares do sangue periférico (CMSP). Entretanto, 20% e 28% dos pacientes nessas duas coortes tiveram anticorpos anti-dsDNA positivos, um autoanticorpo altamente específico do lúpus eritematoso sistêmico (LES). Objetivo: avaliar se os pacientes com SAF bem caracterizados apresentam assinatura para interferon nas células mononucleares periféricas. Secundariamente foram avaliadas possíveis associações clínico laboratoriais com a assinatura de IFN. Métodos: foram selecionados 53 pacientes do sexo feminino com diagnóstico de SAF primária de acordo com os critérios de Sidney, com idade igual ou maior a 18 anos, selecionados no Ambulatório de SAF da Disciplina de Reumatologia do HCFMUSP, pareados por sexo e idade com 50 controles saudáveis. Um terceiro grupo com 29 paciente com antecedente de trombofilias não imunomediadas também foi incluido. Após a coleta de sangue as CMSPs foram purificadas por metodologia de Ficoll. A expressão gênica das CMSPs foi realizada através do TaqMan® RNA Assay em placas TLDA. Foram pesquisados 41 genes induzidos por IFN (GIIs). Uma análise de componente principal (ACP) foi realizada para determinar quais genes deveriam compor a assinatura de IFN. O teste de z-score foi utilizado para normalizar e calcular a assinatura de IFN para cada paciente. O cutoff da assinatura de IFN foi definido por uma curva ROC, e foi escolhido o ponto que maximizava a sensibilidade e especificidade. Características demográficas, clínicas e laboratoriais foram analisadas buscando por associações com a assinatura de IFN. Resultados: 11 genes estavam superexpressos nos pacientes com SAF em comparação aos controles. Após a análise de ACP foram escolhidos 6 genes que representavam mais de 95% do comportamento da amostra para compor a assinatura de IFN: DNAJA1, IFI27, IFI6, IFIT5, MX1 e TYK2. O cutoff encontrado pela curva ROC foi de 3,9 folds (AUC = 0,706, S = 0,49, E = 0,86, VPP = 0,79, VPN = 0,61). A assinatura de IFN estava presente em 49% dos pacientes com SAF primário vs. 14% dos controles saudáveis e 17% dos controles positivos (p < 0,001). Foi encontrada associação entre a assinatura de IFN e uma ocorrência mais precoce do primeiro evento clínico (p = 0,023), e com ocorrência de eventos obstétricos (em especial pré-eclâmpsia, p = 0,032). Não foi econtrada nenhuma associação entre a assinatura de IFN e número de eventos trombóticos, exames laboratoriais, comorbidades, antecedentes familiares de doenças autoimunes, e escores de risco de retrombose. De todos os tratamentos em uso a única associação encontrada foi entre uma menor assinatura de IFN e o uso de estatinas (p = 0,026). Conclusão: esse estudo indica que pacientes com SAF primária bem caracterizados apresentam uma assinatura de IFN tipo I, não observada em outras trombofilias não imunidade-mediadas ou em controles saudáveis. Também demonstrou-se que essa superexpressão de genes regulados por IFN tipo I está associada a um início mais precoce dos eventos e pré-eclâmpsia. Mais estudos são necessários para determinar se este subgrupo de pacientes se beneficiará de intervenções terapêuticas direcionadas à via de sinalização IFN tipo I / Introduction: primary antiphospholipid syndrome (PAPS) is an autoimmune vasculopathy mediated by autoantibodies with thrombosis as its main clinical manifestation. The presence of antiphospholipid antibodies, while relevant to confirm the diagnosis, does not seem to be sufficient to fully explain the pathophysiology and a second trigger is usually needed. Besides the hypotheses of viral infections and inflammatory insult as possible triggers, type I Interferon (IFN) has been pointed as a possible protagonist. Recently, two studies have demonstrated that a relevant percentage of PAPS patients have an up-regulation of IFN genes in peripheral blood mononuclear cells (PBMC). However, 20% and 28% of patients in these 2 cohorts, had antidsDNA positive antibodies, a highly specific Systemic Lupus Erythematosus (SLE) autoantibody. Objective: The aim of this study is to determine the prevalence of type I IFN signature in PBMC of patients with PAPS without specific SLE autoantibodies and search for it with clinical and laboratorial associations. Methods: 53 PAPS patients (according to Sydney´s criteria) were consecutively selected and age-matched with 50 healthy controls. A third group, with non-immune-mediated thrombophilia patients, was also included. The expression of 41 IFN induced genes was analysed using real time quantitative PCR (TaqMan Low Density Array). A principal component analysis (PCA) was used to determine which genes should compose the IFN signature and z-score was calculated. The IFN signature score cut-off was defined with a ROC curve, as the point that maximized both the specificity and sensitivity. Clinical and laboratorial features were analysed searching for associations with IFN signature. Results: 11 IFN genes were highly expressed in primary APS patients. After PCA, 6 genes remained in the IFN signature: DNAJA1, IFIT5, IFI27, MX1, IFI6, TYK2. The ROC cutoff was 3,9 folds (AUC = 0.706, S = 0.49, E = 0.86, VPP = 0.79, VPN = 0.61). The type I IFN signature was present in 49% of patients with primary APS compared to 14.0% of healthy controls and 17% of non-immune-mediated thrombophilia patients (p < 0.0001). The mean IFN score was significantly higher in PAPS patients (4.0 fold higher, p < 0.0001) than in controls. A higher IFN signature was associated with a younger age at the first APS event (p = 0.023) and with the presence of obstetric events, especially with preeclampsia (p = 0.032). There was no association between IFN signature and number of thrombotic events, laboratory exams, comorbidities, family history of autoimmune diseases, and thrombosis risk scores. Treatment with statins was associated with lower levels of IFN scores (p = 0.026). Conclusion: our result indicates that PAPS patients, without lupus specific antibodies, have an enhanced type I IFN gene signature, not observed in non-immune mediated thrombophilia. We also provide novel data demonstrating that this overexpression of type I IFN-regulated genes is associated with an earlier onset of APS events and preeclampsia. Further studies are necessary to determine if this subgroup of patients will benefit of interventions targeting the type I IFN signalling pathway

Orientadores: Gil Guerra Junior, Gabriel Hessel / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T04:12:05Z (GMT). No. of bitstreams: 1 Whitacker_FatimaCristinadeFreitas_M.pdf: 1719204 bytes, checksum: 7c00e2334204e8bd5e787cd47276ce2f (MD5) Previous issue date: 2008 / Resumo: Justificativa: Há quatro décadas é conhecida a associação entre Diabetes mellitus tipo 1 (DM1) e doença celíaca. Entretanto, a manifestação predominantemente atípica desta doença em diabéticos, dificulta seu diagnóstico e o reconhecimento de possíveis efeitos desta associação no controle do diabetes. Objetivos: Estimar a prevalência da associação entre DM1 e doença celíaca e verificar a presença de sintomas da doença celíaca, a ocorrência de outras doenças auto-imunes entre os pacientes e seus parentes de primeiro grau e as possíveis influências da doença celíaca no controle do diabetes. Casuística e métodos: Estudo transversal com 195 pacientes com DM1, que responderam um questionário sobre a presença de sintomas gastrintestinais e a ocorrência de doenças auto-imunes em familiares. Foi dosada a IgA e pesquisado o anticorpo anti-endomísio (EMA). Os pacientes com EMA positivo foram submetidos à biópsia intestinal. Aqueles com doença celíaca confirmada por biópsia (grupo casos) foram pareados com pacientes apenas diabéticos (grupo controle) segundo idade no momento da triagem, tempo de duração do diabetes e gênero. Resultados: O EMA foi positivo em nove pacientes. Em sete a biópsia confirmou DC (prevalência de 4%). No pareamento de casos (DM1 e doença celíaca) e controles (somente DM1), os sintomas gastrintestinais foram significativamente mais freqüentes no grupo casos, porém não houve diferença entre os grupos quanto ao controle do diabetes. Conclusões: A prevalência de doença celíaca neste grupo de pacientes com DM1 foi de 4%. A amostra de pacientes celíacos apresentou predomínio de sintomas gastrintestinais e a presença de doença celíaca não interferiu no controle do diabetes / Abstract: Justify: There were four decades that the association between Diabetes Mellitus type 1 (DM1) and celiac disease is known. However, the manifestation of celiac disease in diabetic patients is predominantly atypical, what difficult its diagnosis and the recognition of possible effect of this association in the control of diabetes. Objectives: To estimate the prevalence of DM1 and celiac disease association and to verify the existence of celiac disease symptoms, the occurrence of other autoimmune diseases among the patients and their first-degree relatives and the possible influences of celiac disease in diabetes control. Patients and methods: It was done a cross-sectional study with 195 patients that ansewered a questionnaire about gastrintestinal symptoms and the occurrence of autoimmune diseases in theirs first-degree relatives. IgA was measured and antiendomysial antibody (EMA) screened. The patients with positive EMA were submitted to intestinal biopsy. Those with celiac disease confirmed by biopsy (case group) were paired with DM1 patients without celiac disease (control group) according to age at the screening, time of diabetes duration and gender. Results: EMA was positive in nine patients. In seven of them the biopsy confirmed celiac disease (4.0%). Comparing the cases with controls, the gastrointestinal symptoms were significantly more frequent in the first group and there was no difference between the groups regarding to the control of diabetes. Conclusions: The prevalence found was 4.0%. This sample of celiac patients showed a predominance of gastrointestinal symptoms and the celiac disease did not influence the diabetes control / Mestrado / Pediatria / Mestre em Saude da Criança e do Adolescente

O presente estudo teve como objetivo avaliar a eficácia do imunossupressor tópico tacrolimus a 0,1%, aplicado de forma oclusiva com o auxílio de moldeiras individualizadas de silicone em pacientes com gengivite descamativa decorrentes do líquen plano oral (LPO) e do penfigóide das membranas mucosas (PMM). Foram selecionados consecutivamente 18 pacientes que preencheram os critérios de inclusão adotados, sendo 17 mulheres (8 LPO / 9 PMM) e 1 homem com LPO. Após o estabelecimento do diagnóstico os pacientes foram avaliados por um mesmo avaliador quanto aos sinais e sintomas, utilizando-se para isso duas escalas visuais analógicas, uma para dor e outra para ardência, além de um periograma especialmente desenhado para avaliação clínica, demarcando as áreas onde haviam a presença de lesões gengivais no dia zero e no dia 90. Após adequação periodontal os pacientes eram moldados para confecção de uma moldeira individual de silicone para servir de suporte oclusivo para a medicação estudada. A terapêutica adotada foi dividida em duas fases de 45 dias totalizando 90 dias. Na primeira fase os pacientes foram orientados a usar de 1 a 2 gramas da medicação em cada moldeira, duas vezes ao dia por 20 minutos e na segunda fase somente uma vez ao dia. Os possíveis efeitos colaterais eram monitorados durante as consultas de retorno a cada 15 dias. Ao final dos 90 dias avaliamos o percentual de remissão dos sinais, classificada como completa (100%), excelente (75% a 99%), boa (50% a 74%), regular (1 a 44%), inalterada ou com piora do quadro. Nos pacientes estudados obtivemos remissão completa em 4 (30,76%), 4 com remissão excelente (30,76%), 4 com remissão boa (30,76%) e um com remissão regular (7,69%). Em relação aos sintomas da dor obtivemos uma redução média de 60% e em relação a ardência uma redução média de 65,5%. Os pacientes com LPO obtiveram uma redução média da dor de 42,5% e da ardência de 58%, nos pacientes com PMM a redução da dor foi de 92,8% e da ardência de 80,7%. A comparação dos escores de dor antes e após o tratamento apresentou valor de p<0,01 quando realizado o teste de Wilcoxon para amostras pareadas. O mesmo resultado (p<0,01) foi encontrado quando comparados os escores de ardência. Os valores obtidos demonstraram que a diminuição dos escores de dor e ardência foi estatisticamente significante. Como efeitos colaterais observamos que todos relataram alteração transitória de paladar e um paciente com LPO desenvolveu candidose. Concluímos que o tacrolimus a 0,1% aplicado topicamente com moldeiras individuais de silicone foi eficaz no tratamento das gengivites descamativas quanto a dor, ardência e remissão clínica das lesões gengivais em pacientes com LPO e PMM. / The objective of this study was to evaluate the efficacy of application of the topical immunosuppressor 0.1 % tacrolimus in patients with desquamative gingivitis (DG) associated with oral lichen planus (OLP) and mucous membrane pemphigoid (MMP). We selected 18 patients that fulfilled the inclusion criteria: 17 females (8 OLP/ 9MMP) and one male (OLP). After diagnosis, all subjects were evaluated by the same researcher, who assessed pain and burning using two visual analogical scales, one for pain and the other for burning, in conjunction with a diagram of the gingival mucosa. Measurements were made on day zero and day 90. After the periodontal assessment, individualized silicone rubber trays were prepared in order to deliver the drug. The therapeutic strategy was divided in two phases of 45 days for a total of 90 days. In the first treatment phase it was recommended that all patients use one or two grams of 0.1 % tacrolimus in his/her tray for twenty minutes, twice daily; in the second phase, the treatment was to be used only once daily. All side effects were monitored during biweekly return visits. At the end of 90 days, the response to therapy was assessed according to the following scale, as a percentage of remission: complete (100 %), excellent (75 % to 99 %), good (50 % to 74 %), poor (1 % to 49 %), no response (0 %) and worsened. We observed complete remission in 4 patients (30.76 % of the experimental group), excellent in 4 patients (30.76 %), good in 4 patients (30.76 %), and poor in one (7.69%). Pain was reported to be reduced by 60 % while burning was reduced by 65.5 %. OLP patients showed an average reduction by 42.5% of pain and 58% of burning. MMP patients showed an average reduction by 92.8% of pain and 80.7% of burning. After treatment, the data were analyzed by Wilcoxons test; significant differences (p < 0.01) were found for both pain and burning. Side effects included transitory alteration of taste, and one patient was diagnosed with candidiasis. From this study, we conclude that topical application of 0.1% tacrolimus using silicone rubber trays is an effective treatment for desquamative gingivitis, decreasing pain, burning and clinical lesions in OLP and MMP patients.

Le syndrome de Sjögren (SS) est l'une des maladies autoimmunes (MAI) systémiques les plus fréquentes chez l’Homme. Cette maladie est caractérisée par une infiltration lymphocytaire dans les glandes exocrines conduisant à des symptômes dits de « yeux secs » et à la bouche sèche. Il n’existe actuellement aucun traitement curatif pour cette maladie. Le peptide P140 a été démontrée comme un outil thérapeutique efficace chez les patients atteints d'un lupus érythémateux disséminé (LED) et des souris modèles développant un lupus.L'autophagie est une voie intracellulaire conservée qui joue un rôle central dans le maintien de l'homéostasie cellulaire. En outre, l'autophagie a été démontrée comme un mécanisme de régulation de l'autoimmunité. Les effets bénéfiques du peptide P140 dans le lupus semblent étroitement liés à son effet d'inhibition de l’autophagie qui est hyper-activée dans le lupus. A ce jour, très peu de données sont connues concernant l'autophagie dans le SS. Le sujet de ma thèse porte i. sur l’étude et la compréhension des phénomènes de l’autophagie dans le SS et ii. sur l’effet éventuel du peptide P140 dans cette maladie.Dans cette étude, nous avons d’abord montré des effets protecteurs du P140 contre le SS dans les souris modèle MRL/lpr, comme en témoignent l’amélioration de l'inflammation, une diminution de l'infiltration lymphocytaire dans les SG de souris et une baisse des niveaux d'autoanticorps circulants. Nous avons également constaté que l'autophagie et les lysosomes étaient défectueux dans les SG des souris MRL/lpr et que le P140 rétabli le flux autophagique et l'acidité lysosomale. Ces résultats suggèrent que l'autophagie défectueuse et des défauts des lysosomes pourraient contribuer à la pathologie du SS et que les effets thérapeutiques de P140 pourraient être liés à son effet sur l'autophagie et les lysosomes.Les résultats obtenus dans le cadre de cette thèse nous offrent des informations décisives sur la pathogenèse de SS et suggèrent que l'autophagie pourrait être une cible thérapeutique de choix dans le SS. Au-delà, les effets protecteurs de P140 dans le modèle de souris SS nous éclairent sur l'application thérapeutique du P140 dans d'autres MAIs. / Sjögren's syndrome (SS) is one of the most common systemic autoimmune diseases (AIDs) in human. This disease is characterized by lymphocytic infiltration in the exocrine glands which leads to symptoms named dry eyes and dry mouth. There is no cure for SS currently. P140 peptide has been demonstrated to be an effective therapeutic tool in patients with systemic lupus erythematosus (SLE) and lupus mouse model. Autophagy is a conserved intracellular pathway that plays a central role in maintaining cellular homeostasis. In addition, autophagy has been demonstrated to be a mechanism of autoimmune regulation. The beneficial effects of P140 peptide in lupus seem to be closely related to its inhibitory effect on autophagy which is overactivated in lupus. However, the role of autophagy in SS is largely unknown. The aim of my thesis is: 1, to study the role of autophagy in SS and 2, to examine the possible effect of the P140 peptide in this disease. In this study, we first demonstrated the protective effects of P140 against SS in MRL/lpr mouse model, as evidenced by ameliorated inflammation, decreased lymphocyte infiltration in mouse salivary glands (SGs), as well as decreased levels of circulating autoantibodies. We also found that autophagy and lysosomes were defective in SGs of MRL/lpr mice and that P140 restored the autophagic flux and lysosomal acidity. These results suggest that defective autophagy and lysosome dysfunction may contribute to the pathology of SS and that the therapeutic effects of P140 may be related to its effect on autophagy and lysosomes. The results obtained in this study provide us valuable information about the pathogenesis of SS, and suggest that autophagy could be a potential therapeutic target in SS. Moreover, the protective effects of P140 in SS mouse model shed light on the therapeutic application of P140 in other AIDs.

Orientador: Simone Appenzeller / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T09:49:15Z (GMT). No. of bitstreams: 1 Martin_NailuAngelicaSinicato_M.pdf: 860113 bytes, checksum: c0bfa5d101d3506d0fc6439346e326ff (MD5) Previous issue date: 2013 / Resumo: Lupus Eritematoso Sistêmico (LES) e uma doença autoimune, crônica e mutissistemica, caracterizada por períodos de atividade e remissão. Anormalidades como leucopenia, anemia hemolítica, presença de auto-anticorpos como anti-DNA de fita dupla (anti-dsDNA), anti-Smith (anti-Sm) e fator antinuclear (FAN) podem ser encontradas. Quando diagnosticado ate os 16 anos de idade e denominado LESj. Devido ao elevado acometimeto cardíaco nesses pacientes e muito importante avaliar os fatores de risco para o desenvolvimento de doenças coronarianas. O presente estudo, de característica transversal, teve como objetivo avaliar a presença de SM nos pacientes com LESj e comparar com controles sem histórico de doença autoimune e cardiovasculares e avaliar a composição corporal e observar a associação com a atividade e dano da doença, uso de corticosteróides e TNF-?. Foram selecionados pacientes consecutivos com LESj acompanhados na Unidade de Reumatologia Pediátrica da UNICAMP entre 2010/2012. Manifestações clinicas, laboratoriais e medicação em uso foram avaliadas. A atividade da doença [SLE Disease Activity Index (SLEDAI)], dano cumulativo [Lupus International Collaborating Clinics (SLICC)] foi determinado para cada paciente no dia da coleta de sangue. A SM foi avaliada através do critério da IDF - International diabetes federation. A dosagem da citocina foi realizada por ELISA (Enzyme Linked Immuno Sorbent Assay). Observamos uma prevalência de SM de aproximadamente 20% dos pacientes incluídos. Observamos um numero similar de pacientes com LES <18 anos com síndrome metabólica quando comparada com ? 18 anos de idade (p = 0,202). Observamos que pacientes com LES <18 anos apresentaram mais hipertrigliceridemia e pacientes ? 18 anos apresentaram mais frequentemente hipercolesterolemia, altos níveis de LDL-C e hipertrigliceridemia, Observamos correlação do SLEDAI ajustado ao longo do tempo com a definição do IDF nos pacientes com LES ? 18 anos (r = 0,229, p = 0,033). Observamos também uma maior razão CA/CQ em pacientes com LESj quando comparado ao grupo controle (p <0,001). Observou-se correlação com o IMC e CA (r = 0,58, p <0,001) e CQ (r = 0,53, p <0,001) nos pacientes com LESj e entre IMC e peso (r = 0,86, p <0,001), altura (r = 0,26, p = 0,030), CA (r = 0,59, p <0,001) e CQ (r = 0,55, p <0,001) nos controles. Observamos uma correlação entre CA e IMC (r = 0,53, p <0,001) e o IAC (r = 0,39, p <0,001) nos pacientes com LESj. Observamos uma correlação entre o IAC e o IMC (r = 0,48, p <0,001). A analise da DXA mostrou que em pacientes com SLEj 36,8% de massa de corpo inteiro corresponde a gordura, e 42,3% esta localizada na região do tronco. Em nosso estudo observamos um aumento dos níveis séricos de TNF-? em pacientes com LESj, houve o aumento dos níveis de TNF-? em pacientes com doença ativa, alem de uma correlação positiva entre a pontuação de SLEDAI, níveis de TNF-? também se correlacionaram com a porcentagem de gordura e a massa gorda na região do tronco. De acordo com nossos resultados, os pacientes com LESj, possuem maior prevalência de SM e uma distribuição central de gordura corporal maior do que indivíduos controlem. Devido ao grande aumento do risco cardiovascular nesses pacientes e necessario a avaliacao rotineira da SM e da composição corporal / Abstract: Systemic lupus erythematosus (SLE) is a chronic, multisystemic, relapsing and remitting autoimmune disease. Abnormalities such as leukopenia, hemolytic anemia, presence of autoantibodies such as anti-double-stranded DNA (anti-dsDNA), anti-Smith (anti-Sm) and antinuclear antibodies (ANA) can be found. When the diagnosis was made until 16 years old the patients was called childhood-onset SLE. Because of the greatest rate of cardiac involvement of these patients is very important to evaluate the risk factors to coronary diseases development The present cross-sectional study aimed to evaluate the presence of MetS in SLE patients and to compare with controls without autoimmune disease history and to evaluate the body composition and observe its association with the activity disease, laboratory data and corticosteroid treatment and TNF-?. We selected consecutive pediatric SLE patients followed at the Pediatric Rheumatology Unit of UNICAMP between 2010/2012. Clinical, laboratory, disease activity [SLE Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index (SDI)] and current drug exposure were evaluated. The MetS was evaluated by IDF - International diabetes federation criteria. The measurement of cytokines was performed by ELISA (Enzyme Linked Immuno Sorbent Assay). The prevalence of MetS in approximately 20% of patients included. We observed a similar number of SLE patients <18 years with MetS compared with ? 18 years of age (p = 0.202). We found that SLE patients <18 years presented with hypertriglyceridemia and patients ? 18 years were more frequently hypercholesterolemia, high LDL-C and hypertriglyceridemia observed correlation of SLEDAI adjusted over time with the definition of the IDF in SLE patients ? 18 years (r = 0.229, p = 0.033). We also observed a higher ratio HC / WC procedures in patients with SLE compared to the control group (p <0.001). Correlation with BMI and WC (r = 0.58, p <0.001) and HC (r = 0.53, p <0.001) in patients with SLE and between BMI and weight (r = 0.86, p <0.001), height (r = 0.26, p = 0.030), WC (r = 0.59, p <0.001) and HC (r = 0.55, p <0.001) in controls. We observed a correlation between WC and BMI (r = 0.53, p <0.001) and BAI (r = 0.39, p <0.001) in patients with SLE. We observed a correlation between the BAI and BMI (r = 0.48, p <0.001). The DXA analysis showed that in patients with cSLE 36.8% by weight of the whole body matches the fat, and 42.3% is located in the trunk. In our study we observed an increase in serum levels of TNF-? in patients with cSLE, there were increased levels of TNF-? in patients with active disease, and a positive correlation between the SLEDAI score, levels of TNF-? also correlated with the percentage of fat and fat mass in the trunk region. According to our results, patients with cSLE, have a higher prevalence of MetS and a central distribution of body fat greater than control subjects. Due to the large involvement of CVD in these patients is necessary routine assessment of MetS and body composition / Mestrado / Pediatria / Mestra em Ciências

Il existe un sur-risque de lymphome dans trois des principales maladies auto immunes (MAI) systémiques : la polyarthrite rhumatoïde (PR), le lupus érythémateux systémique (LES) et le syndrome de Sjögren (SSp) avec un risque relatif évalué respectivement à 2, 3 et 15 à 20. L’objectif de ce travail a été l’étude des mécanismes physiopathologiques impliqués dans la survenue de cette complication. Nous avons évalué le rôle de l’activité de la MAI. Nous avons pu montrer que l’ESSDAI, score d’activité du SSp, et la positivité du facteur rhumatoïde (FR) étaient 2 facteurs prédictifs de lymphome chez les patients atteints de SSp soulignant ainsi le rôle de l’activité de la maladie et de la stimulation chronique du lymphocyte B auto-réactif. L’étude de CXCL13 et CCL11 a mis en évidence l’association entre leur taux sérique et le risque de lymphomes dans le SSp. CXCL13 était aussi associé de manière indépendante avec l’activité de la maladie. Ce travail souligne l’existence d’un continuum entre activité de la maladie, activation chronique des LB et émergence d’un clone lymphomateux. Nous nous sommes intéressés aux susceptibilités génétiques favorisant les lymphomes des MAI. Nous avons étudié les anomalies de TNFAIP3 qui code pour la protéine A20, impliquée dans le contrôle de la voie NF-kB. Notre travail a démontré que plus des ¾ des patients SSp ayant développé un lymphome du MALT présentaient une anomalie de TNFAIP3 d’origine somatique ou germinale. Le concept novateur résultant de ce travail est qu’une mutation germinale entrainant un défaut de fonction minime dans toutes les cellules peut ne s’exprimer que dans un type cellulaire, le LB auto-immun soumis à une stimulation permanente dans le cadre d’une MAI. Dans un autre exemple de lymphome associé à la stimulation antigénique chronique, les lymphomes du VHC, nous avons démontré que le même polymorphisme exonique de TNFAIP3, le rs230926, était aussi associé au sous-groupe des lymphomes survenant chez les patients avec positivité du FR. Nous avons étudié l’impact des traitements anti-TNF sur la survenue de lymphome dans un contexte d’auto-immunité B. Dans une 1ere étude in vitro, nous avons démontré que les anti-TNF impactaient négativement l’activité anti-lymphomateuse des lymphocytes NK. Nous avons mené une étude sur un modèle de souris BAFF-Tg. Les résultats préliminaires sont en faveur d’une survie diminuée des souris traitées par anti-TNF. La cause (atteinte rénale ou lymphome) reste à déterminer. Ce travail démontre le rôle majeur de l’activité de la maladie et notamment de la stimulation antigénique chronique des lymphocytes B auto-immuns dans la lymphomagenèse des MAI. Dans ce contexte, un défaut de contrôle de l’activation du LB d’origine génétique ou une diminution de l’immunosurveillance par exemple par le biais de certains traitements immunosuppresseurs, est susceptible de précipiter la transformation lymphomateuse du LB auto-réactif et l’émergence de lymphome. / Three major systemic autoimmune diseases (AID), rheumatoid arthritis, lupus and primary Sjögren’s syndrome (pSS), have consistently been associated with the development of B‑cell non-Hodgkin lymphoma. The objective of this thesis was to study the mechanisms leading to lymphoma development in patients with AID. First, we have demonstrated that disease activity assessed by ESSDAI and positivity of rheumatoid factor (RF) were 2 independent predictors of lymphoma in pSS patients. Then, we have shown that CXCL13 and CCL11 serum levels were associated with lymphoma complicating pSS. CXCL13 was independently associated with disease activity. Second, we have assessed the role of genetic abnormalities of TNFAIP3 which encoded A20, a central gatekeeper of NF-kB. We have found that ¾ of pSS patients with MALT lymphomas had functional abnormalities of TNFAIP3 of somatic or germline origin. It demonstrates the major consequences of subtle germline abnormalities in gene involved in the control of NF-kB pathway in the context of chronic antigenic stimulation. Again, in lymphoma complicating hepatitis C, another situation of chronic antigenic stimulation, we found that a missense variant of TNFAIP3 was associated with the presence of RF in patients with lymphoma. Last, we have studied the impact of anti-TNF on development of AID associated lymphomas. In vitro, we found that chronic exposure to anti-TNF negatively impact anti-lymphoma activity of NK cells. In vivo, in mice transgenic for BAFF, we have found that mice treated with anti-TNF had a decreased survival. Studies are ongoing to determine the cause of this increased mortality. To sum up, this work demonstrates the key role of diseases activity and notably of chronic antigenic stimulation of auto-reactive B cell in lymphomas complicating AID. In this context, genetic impairment of check-point controlling B cell activation or decreased immunosurveillance induced by some immunosuppressive drugs may promote lymphomatous escape of auto-reactive B cell.