O lúpus eritematoso sistêmico (LES) é uma doença auto-imune caracterizada pela produção de múltiplos auto-anticorpos, com componentes celulares nucleares como principal alvo. De etiologia desconhecida, envolve fatores genéticos, imunológicos, hormonais e ambientais. A deficiência na lectina ligadora da manose (MBL), um dos componentes do sistema de complemento, pode produzir uma apresentação anormal de antígenos para o sistema imunológico. Os polimorfismos genéticos na região promotora e codificante do gene MBL2 estão fortemente correlacionados com os níveis séricos da proteína MBL, tendo um possível impacto no mecanismo de tolerância imunológica. A influência do tabagismo ainda não foi avaliada em pacientes que apresentam estas variações alélicas. Nosso objetivo foi investigar o papel dos haplótipos associados à produção de MBL e tabagista sobre os índices de atividade, cronicidade e dano em pacientes com LES. Investigamos a frequência haplótipica da MBL em 327 pacientes com LES, classificados em Euro e Afro-descendentes. O hábito tabagista, dados clínicos e laboratoriais foram retirados dos prontuários e protocolos de pesquisa. A genotipagem do promotor e das variantes do exon 1 da MBL2 foram feitas por PCR-SSP e PCR-RFLP, respectivamente. Os índices SLICC e SLEDAI foram analisados comparando tabagismo, maços/ano (MA) e haplótipos através do teste Kruskal-Wallis e quiquadrado com Bonferroni para as outras análises. O estudo foi aprovado pelo comitê de ética do HCPA. Quando comparados fumantes e não-fumantes, não encontramos associação entre SLEDAI e SLICC com tabagismo, MA e os haplótipos da MBL. Em uma subanálise, manifestações como serosite (p = 0.025), pericardite (p = 0.015), convulsões (p = 0.011) e presença de anticorpos anti-Sm (p = 0.016) apresentaram uma maior frequência em não-fumantes. Entre fumantes, foi observado uma associação significativa entre alterações imunológicas (p = 0.032) e anti-RNP (p = 0,013) em pacientes que fumam de 4-24.7 MA, em comparação com quem fuma menos de 4 ou mais de 24.7 MA. Quando estratificados por etnia e os haplótipos da MBL, Euro-descendentes com haplótipos para deficiência de MBL apresentaram uma maior frequência de anticoagulante lúpico em fumantes (p = 0.016) e pleurite (p = 0.001) entre os que nunca fumaram. Nos haplótipos associados à baixa MBL, encontramos uma associação positiva entre pericardite em não-fumantes (p= 0.027). Entre os haplótipos para alta MBL, vimos uma menor frequência de distúrbios neurológicos (p = 0.05) e imunológicos (p = 0.027) e presença de anticorpos anti-Sm (p = 0.035) em não-fumantes. Em relação aos Afro-descendentes com haplótipos para baixa MBL, observou-se uma associação significativa entre o anti-RNP (p = 0.017) e não-fumantes. Aqueles indivíduos com haplótipo para alta MBL tiveram uma pequena associação entre o VDRL em não-fumantes (p = 0.048). Contudo, quando ajustado o p-valor para a correção de Bonferroni, todas essas associações perderam significância. Os resultados não apresentaram evidências de que o tabagismo possa atuar como um modulador dos índices de atividade, cronicidade e dano em pacientes com LES relacionado aos haplótipos da MBL. / Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibody production, with cellular nuclear components as the most notable targets. With an unknown etiology, it involves genetic, immunological, hormonal and environmental factors. Deficiencies in the mannose-binding lectin (MBL), a component of the complement system, can produce an abnormal presentation of antigens to the immune system. Genetic polymorphisms in the promoter and coding regions of the MBL2 gene are strongly correlated to serum levels of the MBL protein, with possible impact in the immunological tolerance mechanism. The influence of smoking has not been evaluated in patients who present these allelic variants. Our aim was to investigate the role of MBL haplotypes (divided as deficient, low and high serum level-associated haplotypes) and smoking habit on disease activity and damage indexes in SLE patients. We investigated the frequencies of haplotype variants in 327 European and African-descendants SLE patients. Smoking habits, clinical and laboratory data were revised from clinical charts and genotyping of the promoter and exon 1 variants of MBL2 were performed by PCR-SSP and PCR-RFLP, respectively. SLICC and SLEDAI score were analyzed comparing the haplotype, smoking habits and pack-years (PY) of smoking using Kruskal-Wallis test for quantitative variables and chi-square test with Bonferroni for other analysis. The study was approved by the local ethical committee. When comparing ever smokers vs. never smokers, we found a lack of association between SLICC and SLEDAI among smoking habit, PY and MBL haplotypes. Further subanalysis on SLE manifestations showed a higher frequency of serositis (p=0.025), pericarditis (p=0.015), convulsion (p=0,011) and presence of anti-Sm (p=0.016) on never smokers. Among ever smokers, a significant association was observed between immunologic disorders (p=0.032) and anti-RNP (p=0.013) in patients who smoke 4 – 24.7 PY, compared with less than 4 or more than 24.7 PY. When stratified by ethnicity and MBL haplotypes, European-descendants with deficient MBL haplotype showed a higher frequency of lupus anticoagulant in smokers (p=0.001) and pleuritis (p= 0.016) among never smokers. On low MBL haplotype, we found a positive association between pericarditis and never smokers (p= 0.027). Among high MBL haplotype we identified a smaller frequency of neurologic (p=0.05) and immunologic disorders (p= 0.027) and presence of anti-Sm (p= 0.035) in never smokers. In relation to African-descendants with low MBL haplotype, a significant association between anti-RNP (p=0.017) and never smokers was observed. Those with high MBL haplotype had small association between false positive VDRL and never smokers (p=0.048). However, by adjusting the p-value for Bonferroni correction, all these associations lost significance. Our findings presented no evidence that smoking may act as a modulator of disease activity and damage indexes on SLE patients associated to serum MBL haplotypes.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of high morbidity and mortality associated mainly with the activity of disease, infections and cardiovascular disease. In this condition, both premature atherosclerosis (AT) as well as left ventricular hypertrophy (LVH) are related to traditional risk factors for cardiovascular disease (CVD) and probably the peculiar characteristics of the pathophysiology of inflammatory disease. Some evidence shows the association of AT and LVH, which is considered a strong predictor for the presence of atherosclerotic plaques in carotid arteries. This study aimed to determine the frequency of AT and LVH in patients with SLE and to evaluate its relationship with traditional risk factors and factors specific to the disease. We conducted a prospective study of 70 SLE patients attending the outpatient clinic of Rheumatology, Federal University of Sergipe (UFS) and Private Practice of Rheumatology. We evaluated clinical, laboratory and research intima-media thickness of carotid arteries (CIMT) in atherosclerotic plaques and the index of left ventricular mass (LVMI), through questionnaires, the completion of the carotid duplex scan and echocardiogram, respectively. Statistical analysis was determined by multiple logistic regression, after performing descriptive statistics and odds ratios adjusted and simple. We observed the presence of AT in 34.3% of cases, LVH in 45.7% and concomitant LVH with AT in 23% of cases. AT was significantly associated with age > 50 years, systolic blood pressure (SBP), dyslipidemia, non-white race, renal disease, absence of antimalarial, late age of diagnosis, time course of disease and LVH, (p<0.05). In multivariate analysis, the relationship was demonstrated age > 50 years (OR:7.3), p = 0.01, absence of antimalarial (OR:4.7), p=0.006 and SBP (OR:1.5), p=0.05. LVH was associated with age > 50 years, not white race, hypertension (HBP), c-reactive protein > 1 mg/dL (CRP), time course of disease and AT (p <0.05). In the multivariate analysis, we found that hypertension (OR:11.4), p=0.001, CRP > 1 mg/dL (OR:8.2), p=0.004, AT (OR:6.04); p=0.02, remained linked to LVH and body mass index (BMI) > 25 kg/m² (OR:4.61), p=0.04, was added as a strong predictor of LVH. The data suggest that in SLE, the presence of AT and LVH are associated not only to some traditional risk factors for CVD such as hypertension and obesity, but also to the chronicity of the disease, its treatment; and serological markers of inflammation. / O lúpus eritematoso sistêmico (LES) é uma doença inflamatória crônica de elevada morbidade e mortalidade associada, sobretudo, à atividade de doença, infecções e doença cardiovascular. Nessa afecção, tanto a aterosclerose prematura (AT) como a hipertrofia ventricular esquerda (HVE) encontram-se relacionadas a fatores de risco tradicionais para doença cardiovascular (DCV) e provavelmente, a características peculiares na fisiopatogênese dessa doença. Algumas evidências demonstram a associação da AT e HVE, sendo esta considerada um forte preditor para a presença de placas ateroscleróticas nas carótidas. O presente estudo teve como objetivo determinar a frequência de AT e HVE em pacientes com LES e avaliar sua relação com fatores de risco tradicionais e fatores próprios da doença. Foi realizado um estudo prospectivo em 70 pacientes portadores de LES, atendidos no ambulatório de Reumatologia da Universidade Federal de Sergipe (UFS) e consultório particular de Reumatologia. Foram avaliados dados clínicos, laboratoriais e pesquisa da espessura médio-intimal das carótidas (EIMC), de placas ateroscleróticas e do índice de massa do ventrículo esquerdo (IMVE), por intermédio de questionário, da realização do duplex scan de carótidas e do ecocardiograma, respectivamente. A análise estatística foi determinada pela regressão logística múltipla, após realização de estatística descritiva e cálculo de odds ratio (OR) simples e ajustado. Observou-se a presença de AT em 34,3% dos casos, a HVE, em 45,7% e concomitância de AT com HVE em 23% dos casos. Na análise univariada, a AT associou-se significativamente à idade > 50 anos, pressão arterial sistólica (PAS), dislipidemia, raça branca, doença renal, ausência de antimalárico, idade tardia de diagnóstico, tempo longo de doença e HVE; (p<0,05). Em análise multivariada, a relação demonstrada foi idade > 50 anos, (OR:7,3); p=0,01, ausência do antimalárico, (OR:4,7); p=0,006 e pressão arterial sistólica (PAS) (OR:1,5); p=0,05. A HVE esteve associada à idade > 50 anos, cor não branca, hipertensão arterial sistêmica (HAS), proteína c reativa (PCR) > 1mg/dL, tempo longo de doença e AT, (p<0,05). Já na análise multivariada, observou-se que HAS (OR:11,4); p=0,001, PCR > 1 mg/dL, (OR:8,2); p=0,004 e AT (OR:6,04) ; p=0,02, permaneceram relacionadas à HVE e o índice de massa corpórea (IMC) > 25 kg/m² (OR:4,61); p=0,04, foi acrescentado como forte preditor de HVE. Os dados sugerem que, no LES, as presenças de AT e HVE estão associadas não somente a alguns fatores de risco tradicionais para DCV, como a HAS e obesidade, mas também à cronicidade da doença, tratamento instituído e marcadores inflamatórios da doença.

O desencadeamento do Lúpus Eritematoso Sistêmico (LES) está relacionado às situações estressantes e traumáticas da vida dos pacientes, o que sugere o fator psicológico como deflagrador da doença. A Nefrite Lúpica (NL) pode ser a primeira manifestação do LES e constitui fator de maior morbidade e mortalidade, por levar à insuficiência renal, com necessidade de hemodiálise, e colocar o sujeito diante de mudanças da rotina de vida, da autoimagem, o que faz da própria doença um evento traumático para o paciente. Dentro desse contexto, os objetivos desta pesquisa foram: (i) verificar a existência de eventos de vida associados ao deflagramento do LES nos relatos dos pacientes com NL e a forma como esses pacientes compreendem o seu adoecimento; e (ii) analisar correlações entre eventos de vida, estado de atividade do LES e perfil socioeconômico. Para a pesquisa empírica, adotou-se uma abordagem quali-quantitativa, por meio da aplicação dos seguintes instrumentos: entrevista semiestruturada (psicológica), entrevista para eventos de vida recentes (psiquiátrica) e instrumental de classificação socioeconômica. A amostra foi composta por 43 sujeitos internados no Serviço de Nefrologia do Hospital das Clínicas de São Paulo, sendo 22 pacientes do grupo caso, com NL e 21 pacientes do grupo controle, com doença glomerular primária. Os dados clínicos e laboratoriais foram coletados por meio do SLEDAI e por consulta ao prontuário. Os principais resultados obtidos demonstram que a ocorrência de eventos de vida não apresentou correlação à atividade do LES. Evidencia-se uma associação entre eventos de vida negativos e o deflagramento da doença nos dois grupos estudados, o que demonstra que eventos negativos também antecedem e podem estar associados ao início de outras patologias. Quanto à maneira como os pacientes com NL compreendem o seu adoecimento, observou-se que eles compreendem parcialmente sua doença, atribuindo um significado negativo e associam uma situação emocional ao início do adoecimento. São pacientes que percebem os problemas de suas vidas e possuem necessidade de lidar com o adoecimento implicando-se ao tratamento. Há sofrimento quanto ao adoecimento pelas mudanças e limitações que a doença impõe, principalmente em relação à autoestima, por isto, sofrem emocionalmente e possuem necessidade de serem escutados e amparados. Portanto, conclui-se que os eventos de vida negativos e/ou traumáticos estão relacionados ao deflagramento do LES tanto de forma objetiva como um acontecimento que envolve mudanças no ambiente social externo, sem considerar a subjetividade do sujeito quanto de forma subjetiva como um evento de vida singular, relatado pelos próprios pacientes como um evento traumático. Essas evidências sugerem que os pacientes com NL possuem fatores psicológicos particulares que atuam tanto no curso da doença, quanto em seu deflagramento / The onset of Systemic Lupus Erythematosus (SLE) is related to stressful and traumatic situations in patient lives, which suggests the psychological factor to trigger the disease. The Lupus Nephritis (LN) may be the first manifestation of SLE and is a major factor of morbidity and mortality, because it leads to kidney failure, requiring hemodialysis. Furthermore, the LN changes the routine of life and selfimage of patients, which makes the disease itself a traumatic event. Within this context, this study aims to: (i) verify the existence of life events associated with the outbreak of SLE, and how these patients understand their illness, and (ii) evaluate correlations between life events, status of SLE activity and socioeconomic profile. For the empirical research, we used a qualitative and quantitative approach, applying the following instruments: a semi-structured psychological interview; a psychiatric interview for recent life events and an instrumental for socioeconomic status. The sample was consisted of 43 subjects admitted to the Nephrology Department, at Hospital das Clinicas in Sao Paulo: 22 patients formed the case group, with LN and 21 formed the control group, with primary glomerular disease. The clinical and laboratory data were collected using the SLEDAI. The main results show that the occurrence of life events had no correlation with SLE activity. There was an association between negative life events and the outbreak of the disease in both groups, showing that negative events also precede and may be associated with the onset of other pathologies. Regarding the manner LN patients understand their illness, we see that they partially understand their disease, giving a negative meaning and associating an emotional situation at the beginning of illness. These are patients who perceive problems in their lives and need to deal with the disease giving importance to the treatment. The illness process causes suffering due to the changes and limitations the disease imposes, especially related to self-esteem, therefore, patients suffer emotionally and demand to be heard and supported. Thus, we conclude that the negative life events and/or trauma are related to the triggering of SLE both in an objective way as an event that involves changes in the external social environment, without taking into account the subjectivity of the subject as in a subjective singular life event, reported by the patient as a traumatic event. Based on this analysis, we suggest that patients with LN have particular psychological factors that operate both in the course of the disease, and in its triggering

Orientador: Simone Appenzeller / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T13:41:07Z (GMT). No. of bitstreams: 1 Barbosa_Renata_M.pdf: 1172344 bytes, checksum: 3fc9e9d779a4b94077d1d56223dc0d79 (MD5) Previous issue date: 2014 / Resumo: O nosso objetivo foi determinar a prevalência de atrofia hipocampal no lúpus eritematoso sistêmico juvenil (LESj) determinando a volumetria hipocampal por ressonância magnética e avaliar a possível relação entre atrofia hipocampal e fatores associados. Todos os pacientes com quatro ou mais critérios classificatórios de LES seguidos no ambulatório de reumatologia pediátrica com início da doença até aos 18 anos foram incluídos. Uma análise clínica e neurológica foi realizada de acordo com os critérios classificatórios do Colégio Americano de Reumatologia. Dados laboratoriais e de tratamento foram obtidos através da revisão criteriosa dos prontuários clínicos. Observamos que os volumes hipocampais dos nossos pacientes foram significativamente menores quando comparados aos volumes hipocampais dos nossos controles (p<0,001). A atrofia hipocampal foi identificada em 25 pacientes (34,72%) e no grupo controle 1 indivíduo (1,38%) apresentou atrofia hipocampal direita. A esclerose hipocampal esteve presente em 1(4%) paciente e o hipersinal em 13 (52%) pacientes. Em relação ao tratamento medicamentoso a atrofia hipocampal no LESj esteve associada ao uso de corticosteroides (p= 0,008), micofenolato mofetil (p=0,012), ciclosporina (p=0,018) e ciclosfosfamida (p=0,037). A idade de início da doença (p= 0,038) e dano cumulativo (p= 0,040) também se mostraram associados. Quanto à análise de dados laboratoriais, apenas o anticoagulante lúpico (p= 0,017) e a diminuição do complemento (p= 0,018) se mostraram associados. A esclerose hipocampal apresentou relação com pulso metilprednisolona no início da doença (p=0,023), ciclofosfamida (p=0,023) e com a função cognitiva organização perceptual, planejamento e praxia (p< 0,001). O hipersinal demonstrou associação com atrofia hipocampal (p=0,024), volume hipocampal direito (p=0,024), volume hipocampal esquerdo (p=0,007), no entanto a presença de hipersinal no hipocampo esquerdo apresentou associação apenas com a dose total de corticosteróides (p=0,034). Em relação aos domínios cognitivos, o raciocínio espacial apresentou uma correlação inversa com o volume hipocampal esquerdo (p=0,041; r= -0,281). A memória visográfica apresentou uma correlação direta com o volume hipocampal direito (p=0,042; r= 0,281). A velocidade de processamento associou-se com atrofia hipocampal (p=0,026). O raciocínio temporal demonstrou uma associação com atrofia hipocampal direita (p=0,015), atrofia hipocampal bilateral (p=0,012), e uma correlação inversa com o volume hipocampal direito (p=0,008; r= - 0,359) e volume hipocampal esquerdo (p=0,003; r= -0,400). A atrofia hipocampal é frequente no LESj. A idade de início da doença, tratamento medicamentoso e anticorpos antifosfolípides estão associados à sua ocorrência / Abstract: Our aimed was to determine the prevalence of hippocampal atrophy in childhood-onset SLE (cSLE) using manual magnetic resonance imaging (MRI) volumetric measurements and to evaluate the possible relationship between hippocampal atrophy and associated factors. All patients with four or more classification criteria for SLE, followed at the Pediatric Rheumatology Unit with diagnosis up to 18 years old was included. A clinical analysis and neurological evaluation was analyzed according to the American College of Rheumatology (ACR) classification criteria. Laboratory and treatment features were obtained through a review of clinical records. We observed that the hippocampal volumes of our patients were significantly smaller when compared hippocampal volumes to our controls (p <0.001). Hippocampal atrophy was identified in 25 patients (34.72%) and 1 (1.38%) control at the right hippocampus atrophy. Hippocampal sclerosis was present in 1 (4%) and increased signal in 13 (52%) patients. In relation to drug treatment in cSLE hippocampal atrophy was associated with the use of corticosteroids (p=0.008), mycophenolate mofetil (p=0.012), cyclosporine (p=0.018) e cyclophosphamide (p=0.037).The age of onset (p= 0.038) and cumulative damage (p= 0.040) were also associated. However the analysis of laboratory features, only lupus anticoagulant (p=0.017) and decreased complement (p=0.018) were associated. Hippocampal sclerosis showed relation with pulse methylprednisolone at disease onset (p=0.023), cyclophosphamide (p = 0.023) and cognitive function perceptual organization, planning and praxis (p <0.001). Increased signal showed association with hippocampal atrophy (p=0.024), right hippocampal volume (p=0.024), left hippocampal volume (p = 0.007). However presence of increased signal in the left hippocampus was associated with total corticosteroid dose (p=0.034). Considering cognitive domains, spatial reasoning showed inverse correlation with left hippocampal volume (p = 0.041, r = -0.281). Visografica memory showed a direct correlation with the right hippocampal volume (p= 0.042, r = 0.281). Processing speed is associated with hippocampal atrophy (p = 0.026). Temporal reasoning demonstrated an association with right hippocampal atrophy (p = 0.015), bilateral atrophy (p = 0.012) and inverse correlation with right hippocampal volume (p=0.008, r= -0.359) and left hippocampal volume (p = 0.003, r = -0.400). Hippocampal atrophy is prevalent in cSLE. The age of onset of disease, drug treatment and antiphospholipid antibodies are associated / Mestrado / Saude da Criança e do Adolescente / Mestra em Ciências

Les cellules dendritiques plasmacytoïdes (pDCs) sont caractérisées par leur capacité unique de sécrétion massive d’interféron de type I (IFN-I) suite à la stimulation des Tolllike récepteurs (TLR) 7 et 9. Un rôle fondamental des pDCs a été démontré dans le lupus érythémateux systémique via la production d’IFN-I. Les pDC expriment le récepteur de forte affinité aux immunoglobulines de type E (IgE), FcεRI, impliqué dans la régulation négative de la sécrétion d’IFN-I. L’objectif de notre étude est d’explorer, dans le contexte lupique, les effets du traitement par les IgE sur les fonctions des pDC, particulièrement sur la production d’IFN-I. In vitro, le traitement des pDC par des IgE monoclonales permet la surexpression du FcεRI à leur surface et diminue le taux de transcrits des TLR7/9 et de l’IRF7. De plus, les pDC traitées par des IgE diminuent leur production d’IFN-I et l’expression de marqueurs de maturation, induites par leur stimulation par des ligands des TLR7/9 et des complexes immuns lupiques. En outre, ces pDC pré-traitées par des IgE induisent la différenciation de LT4 naïfs allogéniques en LT4 produisant de l’IL-10. In vivo, les patients lupiques en phase quiescente de la maladie présentent des taux plus élevés d’IgE totales comparés aux patients en phase active (indépendamment d’allergies et d’infestations parasitaires). Chez les patientslupiques, le taux d’IgE totales est inversement corrélé au taux d’anti-ADN et à l’activité de la maladie (SLEDAI). L’ensemble de nos résultats suggère un rôle protecteur des IgE dans le lupus à travers la modulation de la réponse inflammatoire des pDC. / Plasmacytoid dendritic cells (pDCs) are characterized by their unique ability to produce large amounts of type I interferon (IFN-I) upon Toll-like receptors (TLR) 7 and 9 triggering. A fundamental role for pDCs has been shown in systemic lupus erythematosus (SLE) through IFN-I production. pDCs express the high affinity Fc receptor for immunoglobulin E (IgE), FcεRI, involved in the negative regulation of IFN-I secretion. The objective of our study is to investigate, in the context of SLE, the effects of IgE treatment on pDCs functions, especially on IFN-I production. In vitro, monoclonal IgE treatment of pDCs upregulate their surface expression of FcεRI and decrease transcripts levels of TLR7/9 and IRF7. IgE-treated pDCs decrease IFN-α secretion and downregulate maturation markers expression induced by TLR7/9 and immune complexes triggering. Moreover, the coculture of IgE pretreated pDCs with allogeneic naive LT4 promotes their differentiation into IL-10-secreting cells. In vivo, patients with quiescent SLE have higher IgE levels than patients with active disease (independently of allergy or parasitic infection). In SLE patients, IgE levels are inversely correlated to anti-DNA antibodies and disease activity (SLEDAI). All together, our data suggest a protective role for IgE in SLE through the modulation of the inflammatory response by pDC.

Orientador: Leandro Gustavo de Oliveira / Resumo: Introdução: O Lúpus Eritematoso Sistêmico (LES) é uma doença sistêmica de caráter autoimune, que acomete mulheres em idade reprodutiva, sendo que a inter-relação entre a doença e a gestação determina importantes desfechos maternos e perinatais. Objetivos: Descrever os desfechos maternos e perinatais em gestações de pacientes portadoras de LES e avaliar o impacto da nefrite lúpica sobre os resultados encontrados. Métodos: Este é um estudo observacional descritivo desenvolvido para avaliar as inter-relações entre gestação e lúpus eritematoso sistêmico em pacientes atendidas na Maternidade do Hospital das Clínicas da Faculdade de Medicina de Botucatu – HCFMB. O período de estudo foi de janeiro de 2010 a agosto de 2019. Resultados: Foram avaliadas 38 gestações em 31 pacientes com LES. A média das idades foi de 27,4 + 6 anos. A média das idades gestacionais ao nascimento foi de 36 + 3 semanas. As principais intercorrências observadas foram: anemia (39,4%), nefrite lúpica (29%) e hipertensão arterial crônica (10,5%). Hidroxicloroquina foi utilizada em 47,4% das gestações. Em 51,4% das pacientes houve necessidade de antecipação do parto e em 13,1% houve piora da função renal. A incidência de pré-eclâmpsia foi de 19,4%. Prematuridade ocorreu em 20% dos casos e restrição de crescimento fetal, em 19,4%. Nefrite lúpica determinou maior ocorrência de flare (p<0,05) e maior necessidade de antecipação do parto (p< 0,05). Conclusão: O presente estudo permitiu avaliar a inter-relação entre L... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Systemic Lupus Erythematosus is an autoimmune systemic disease that affects women of reproductive age, and the interrelation between disease and pregnancy determines important maternal and perinatal outcomes. Objectives: To describe maternal and perinatal outcomes in pregnancies of patients with SLE and to evaluate the impact of lupus nephritis on the results found. Methods: Descriptive observational study developed to assess the interrelation between pregnancy and systemic lupus erythematosus in patients attended at the Maternity of the Clinics Hospital from Botucatu Medical School – HCFMB. The study period corresponded to January 2010 until August 2019. Results: Thirty-eight pregnancies were evaluated in 31 patients with SLE. Their average age was 27.4 + 6.0 years. The average gestational age at birth was 36 + 3 weeks. The main clinical complications observed were anemia (39.4%), lupus nephritis (29%) and chronic hypertension (10.5%). In 51,4% of the patients, it was necessary to anticipate delivery and in 13.1%, there was worsening of the renal function. Prematurity occurred in 20% of cases and FGR in 19,4%. Hydroxicloroquine was used in 47,4% of the pregnancies. Lupus nephritis determined a higher occurrence of flare (p<0.05) and a greater need to anticipate delivery (p<0.05). Conclusion: The present study made it possible to relate the main clinical characteristics and the maternal and perinatal outcomes from the pregnant women with SLE treated at the prena... (Complete abstract click electronic access below) / Mestre

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B cells play crucial roles in the development of the two human autoimmune diseases, type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). In the past decade, numerous studies showed positive responses of B cell depletion therapies in these two diseases. However, the beneficial effects are temporary and accompanied with adverse events. In this dissertation, we aimed to identify novel targets for a better modulation of disease development using mouse models. These diseases have circulating autoantibodies that are mostly mutated with an IgG isotype, indicating B cells that are producing them have been through the process of affinity maturation. Activation-induced cytidine deaminase (AID) is a core enzyme that regulates somatic hypermutation (SHM) and class switch recombination (CSR), the two key mechanisms in affinity maturation. We showed that genetic ablation of AID significantly inhibited the development of TID in NOD mice. Homologous recombination (HR) pathway is important for the repair of AID-induced DNA double strand breaks during CSR. 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, also known as DIDS, is a small molecule that inhibits HR pathway and subsequently leads to apoptosis of class switching cells. DIDS treatment remarkably retarded the progression of TID, even when started at a relatively late stage, indicating the potential of this treatment for disease reversal. In both approaches, we observed a notable expansion of CD73+ B cells, which exerted an immunosuppressive role and could be responsible for T1D resistance. Next we examined the effect of targeting affinity maturation through these two approaches in lupus-prone mice. The genetic abrogation of AID in BXSB mice significantly ameliorated lupus nephritis and prolonged their lifespan. AID-deficient mice also exhibited improvement on disease hallmarks with increased marginal zone B cells and more normal splenic architecture. DIDS treatment notably reduced class switching when B cells were stimulated in vitro. However, the administration of DIDS did not strikingly alter the course of SLE in either BXSB mice or MRL/lpr mice. These findings demonstrated that affinity maturation could be a potential target for T1D and SLE, while further explorations into targeting other components in the repair pathway are warranted for SLE. Lastly, we assessed the effect of maternal AID modulation on the SLE development in the offspring using BXSB mouse model. Interestingly, the absence of maternal AID resulted in offspring that developed significantly more severe lupus nephritis compared to control. The offspring born to AID-deficient dams also exhibited elevated levels of pathogenic autoantibodies and exacerbated disease features. Therefore, the modulation of maternal AID could influence the SLE development in the offspring, and future investigations are needed to determine the underlying mechanisms responsible for the disease acceleration. / Doctor of Philosophy / The failure of the immune system to differentiate self from non-self leads to the development of autoimmune diseases. Type 1 diabetes (T1D) and systemic lupus erythematosus (SLE) are complex autoimmune diseases affecting millions of people in the world. Despite intensive research regarding these two diseases, no known cure is available indicating an imperative need for the development of novel therapies. With the importance of B cells in the pathogenesis of these two diseases, intensive research focused on whole B cell depletion therapies. However, these therapies exhibited high risks of infections as a result of depleting all the B cells. In this dissertation, we sought to selectively target specific B lymphocyte subsets that are crucial contributing factors in the development of T1D and SLE. While the effect of therapeutic treatment varied among different mouse models, the genetic manipulation of specific B cells successfully retarded the progression of both T1D and SLE and extended the lifespan of the mice. Further studies shed light on the possible mechanisms that are responsible for the disease inhibition. These data proved that targeting specific B cell compartment could be a potential disease management in T1D and SLE patients. In addition, using the established mouse model, we demonstrated the modulation of maternal factors significantly impact the SLE development in the offspring. Future experiments to identify the underlying mechanisms could provide more targets for the therapeutic development.

Le récepteur DcR3 (Decoy receptor 3) est un membre de la famille des récepteurs aux facteurs de nécrose tumorale (TNF). Il est fortement exprimé dans les tissus humains normaux ainsi que les tumeurs malignes. DcR3 est un récepteur pour trois ligands de la famille du TNF tels que FasL, LIGHT et TL1A. Étant une protéine soluble donc dépourvue de la portion transmembranaire et intracytoplasmique, le récepteur DcR3 est incapable d’effectuer une transduction de signal intracellulaire à la suite de son interaction avec ses ligands. De ce fait, DcR3 joue un rôle de compétiteur pour ces derniers, afin d’inhiber la signalisation via leurs récepteurs fonctionnels tels que Fas, HVEM/LTbetaR et DR3. Lors de nos précédentes études, nous avons pu démontrer, que DcR3 pouvaist moduler la fonction des cellules immunitaires, et aussi protéger la viabilité des îlots de Langerhans. À la suite de ces résultats, nous avons généré des souris DcR3 transgéniques (Tg) en utilisant le promoteur du gène β-actine humaine afin d’étudier plus amplement la fonction de ce récepteur. Les souris Tg DcR3 ont finalement développé le syndrome lupus-like (SLE) seulement après l’âge de 6 mois. Ces souris présentent une variété d'auto-anticorps comprenant des anticorps anti-noyaux et anti-ADN. Elles ont également manifesté des lésions rénales, cutanées, hépatiques et hématopoïétiques. Contrairement aux modèles de lupus murin lpr et gld, les souris DcR3 sont plus proche du SLE humain en terme de réponse immunitaire de type Th2 et de production d'anticorps d'anti-Sm. En péus, nous avons constaté que les cellules hématopoïétiques produisant DcR3 sont suffisantes pour causer ces pathologies. DcR3 peut agir en perturbant l’homéostasie des cellules T pour interférer avec la tolérance périphérique, et ainsi induire l'autoimmunité. Chez l'humain, nous avons détecté dans le sérum de patients SLE des niveaux élevés de la protéine DcR3. Chez certains patients, comme chez la souris, ces niveaux sont liés directement aux titres élevés d’IgE. Par conséquent, DcR3 peut représenter un facteur pathogénique important du SLE humain. L’étude des souris Tg DcR3, nous a permis aussi d’élucider le mécanisme de protection des îlots de Langerhans. Le blocage de la signalisation des ligands LIGHT et TL1A par DcR3 est impliqué dans une telle protection. D'ailleurs, nous avons identifié par ARN microarray quelques molécules en aval de cette interaction, qui peuvent jouer un rôle dans le mécanisme d’action. Nous avons par la suite confirmé que Adcyap1 et Bank1 joue un rôle critique dans la protection des îlots de Langerhans médiée par DcR3. Notre étude a ainsi élucidé le lien qui existe entre la signalisation apoptotique médiée par Fas/FasL et la pathogénèse du SLE humain. Donc, malgré l’absence de mutations génétiques sur Fas et FasL dans le cas de cette pathologie, DcR3 est capable de beoquer cette signalisation et provoquer le SLE chez l’humain. Ainsi, DcR3 peut simultanément interférer avec la signalisation des ligands LIGHT et TL1A et causer un phénotype plus complexe que les phénotypes résultant de la mutation de Fas ou de FasL chez certains patients. DcR3 peut également être utilisé comme paramètre diagnostique potentiel pour le SLE. Les découvertes du mécanisme de protection des îlots de Langerhans par DcR3 ouvrent la porte vers de nouveaux horizons afin d'explorer de nouvelles cibles thérapeutiques pour protéger la greffe d'îlots. / Decoy receptor 3 (DcR3) is a member of the tumor necrosis factor (TNF) receptor family, and is widely expressed in human normal tissues and malignant tumors. It is a decoy receptor of three TNF family members, i.e., FasL, LIGHT and TL1A. The interaction of DcR3 and its ligands will not transmit signal into cells via DcR3 because DcR3 is a soluble protein without a transmembrane and intracellular segment. Thereby, DcR3 competitively inhibits signaling through three functional receptors, i.e., Fas, HVEM/LTbetaR and DR3. In previous studies, we found that DcR3 could modulate immune cell function, and protect islet viability. Herein, we generated DcR3 transgenic (Tg) mice driven by the human β-actin promoter to further investigate the function of DcR3. Interestingly, the DcR3 Tg mice developed a lupus-like syndrome at 6 months of age. They presented a variety of autoantibodies including anti-nucleus and anti-dsDNA antibodies. They also manifested renal, dermal, hepatic and hematopoietic lesions. Compared to lpr and gld mouse lupus models, DcR3 Tg mice more closely resembled human SLE in terms of Th2-biased immune response and anti-Sm antibody production. Furthermore, we found that DcR3-producing hematopoietic cell were sufficient to cause these pathological changes. Mechanistically, DcR3 may break T-cell homeostasis to interfere with peripheral tolerance, and then induce autoimmunity. In humans, we detected high DcR3 levels in SLE patient sera. The high DcR3 levels were related to elevated IgE titer in some SLE patients, as was the case in the mouse model. Therefore, DcR3 may represent an important pathogenetic factor of human SLE. Utilizing the DcR3 Tg mouse, we further elucidated the mechanism by which DcR3 protected islets from primary nonfunction (PNF). Blocking of LIGHT and TL1A signaling by DcR3 are involved in such protection. Moreover, by mRNA microarray we identified possible downstream molecules, which may mediate such protection. We confirmed that Adcyap1 and Bank1 played critical roles in mediating DcR3’s effect in islet protection. Our studies resolved a puzzle about the relationship between the Fas/FasL apoptosis signaling pathway and the pathogenesis of human SLE. DcR3 can block Fas/FasL pathway even if there is no genetic mutation in Fas and FasL. DcR3 can simultaneously interfere with LIGHT and TL1A signaling to cause a more complex phenotype than the simple Fas or FasL mutation in patients. DcR3 can also be employed as a potential diagnostic parameter for SLE. The discovery of the mechanism of DcR3 in protecting islets allows us to explore novel therapeutic targets to protect islet graft.