A vacina contra hepatite B tem sido implicada como um desencadeador de doenças auto-imunes, mas ainda não existem estudos prospectivos no lúpus. Assim, avaliamos prospectivamente a segurança e eficácia da imunização com a vacina recombinante contra hepatite B (Euvax B® - LG) em pacientes com diagnóstico de lúpus. Foram selecionadas 28 pacientes com a doença inativa (SLEDAI<4), com idade entre 18 e 50 anos e sorologia negativa para o vírus da hepatite B (VHB). Os critérios de exclusão foram o uso de prednisona >=20 mg/dia e drogas imunossupressoras, anti-dsDNA e anticardiolipina negativos. Os dados clínicos e laboratoriais foram coletados na entrada do estudo e um mês após cada dose da vacina. Além disso, obtivemos dados do ano anterior usando o prontuário eletrônico padronizado. A média de idade foi de 34 ± 7,7 anos e a média da duração da doença foi de 10,4 ± 6,7 anos. Soroconversão adequada foi atingida no final do estudo (93%), embora tenhamos observado uma baixa freqüência após a primeira dose (4%) e após a segunda dose (54%). Nenhuma alteração significativa na média de SLEDAI foi detectada após cada dose durante o estudo (0,14 ± 0,52 vs. 0 vs. 0,61 ± 1,66 vs. 0,36 ± 1,34, p=0,11). Reforçando estes achados, os 11% de atividade de doença durante o período de vacinação foi semelhante aos 21% observados no ano anterior (p=0,46). Além disso, a média da dose de prednisona na entrada foi comparável à dose do final do estudo (2,86 ± 3,06 vs. 4,64 ± 8,25 mg/d, p=0,32). A freqüência do uso de terapia imunossupressora no período da vacinação (11%) foi semelhante aos 14% observados no ano anterior (p=0,66). A vacinação contra hepatite B apresentou uma resposta de anticorpos protetores adequada e foi segura nos pacientes com lúpus inativo. / Hepatitis B vaccination has been implicated as a potential trigger for autoimmune diseases but there are no prospective studies in lupus. We therefore assessed prospectively the safety and efficacy of immunization with recombinant DNA hepatitis B vaccine (Euvax B® - LG) in SLE patients. Twenty-eight consecutive inactive SLE patients (SLEDAI<4), age between 18-50 years and negative serology for hepatitis B virus (HBV) were selected. Exclusion criteria were prednisone > 20mg/day and immunosuppressive drugs. Clinical and laboratorial assessments were obtained at study entry and one month after the three doses. In addition, a previous one year evaluation was performed using a standard electronic protocol. The mean age was 34 ± 7.7 years and disease duration was 10.4 ± 6.7 years. An adequate seroconversion was achieved at the end of the study (93%), although a lower frequency after the first (4%) and second dose (54%) was observed. No significant change in mean SLEDAI score was detected after each dose throughout the study (0.14 ± 0.52 vs. 0 vs. 0.61 ± 1.66 vs. 0.36 ± 1.34, p=0.11). Reinforcing these findings, the 11% flares during vaccination was similar to the 21% observed in the previous year (p=0.46). Furthermore, the mean prednisone dose at study entry was comparable to the end of the study (2.86 ± 3.06 vs. 4.64 ± 8.25 mg/d, p=0.32). In addition, the frequency of immunosuppressive therapy during the vaccination period (11%) was alike to the 14% observed in the previous year before entry (p=0.66). Hepatitis B vaccination was safe in inactive SLE patients with an adequate vaccine response rate.

OBJETIVO. Identificar fatores preditivos para o desenvolvimento da osteonecrose (ONA) em pacientes com Lúpus Eritematoso Sistêmico (LES) de diagnóstico recente. METODOLOGIA. Quarenta e seis pacientes consecutivos, de uma coorte informatizada no ambulatório de LES do serviço de Reumatologia do Hospital das Clínicas de São Paulo, participaram deste protocolo que ocorreu entre julho de 2004 e julho de 2005. Os critérios de inclusão foram: pacientes do sexo feminino; menos de cinco anos de diagnóstico de LES; e idade maior que 18 anos. Todas as pacientes foram submetidas à ressonância nuclear magnética (RNM) dos quadris para o diagnóstico de ONA, independente da sintomatologia. Variáveis clínicas foram obtidas através de prontuários médicos, entrevista e exame clínico. Variáveis laboratoriais incluíram: lipoproteínas séricas, auto-anticorpos, fatores trombofílicos e de hipofibrinólise. Densidade mineral óssea foi medida através da densitometria de dupla emissão de raios-X. Fraturas vertebrais foram investigadas através da realização de radiografias da coluna. RESULTADOS. A ONA foi encontrada em 10 das 46 pacientes. Idade, duração de doença e raça não diferiram entre pacientes lúpicas com e sem ONA. Comparações envolvendo as várias manifestações clínicas do LES, perfil lipoprotéico e de auto-anticorpos, freqüência de trombofilia e hipofibrinólise também não foram estatisticamente diferentes entre os grupos. A freqüência de pacientes com SLEDAI ?8 no ano anterior ao diagnóstico clínico de ONA foi significativamente maior (60%) do que no grupo sem ONA considerando-se o ano anterior à entrada no estudo (19,4%), p=0,011. Corroborando com esse achado, a dose cumulativa de glicocorticóide (GC) utilizada no anterior ao diagnóstico de ONA foi maior quando comparada ao ano anterior à entrada no estudo(p=0,045). Não foram observadas diferenças com relação aos dados densitométricos e radiográficos da coluna. Na análise multivariada somente o SLEDAI permaneceu como fator de risco independente para ONA (OR=6,6, IC=1,07-41,29, p=0,042). CONCLUSÃO. Este estudo revela que a atividade de doença no ano anterior ao diagnóstico clínico de ONA é fator de risco preponderante para o desenvolvimento desta complicação no LES recente. / OBJECTIVE. To evaluate predictive factors for osteonecrosis (ON) development in patients with early Systemic Lupus Erythematosus (SLE). METHODS. Forty-six consecutive SLE patients from an electronic cohort in a Lupus Clinic from the Rheumatology Division in the University of São Paulo were enrolled on this study that occurred between July 2004 and July 2005. Inclusion criteria were female gender, age > 18 years-old and less than 5 years of disease duration. All patients underwent magnetic resonance imaging (MRI) of the hips for ON diagnosis irrespective of symptoms. Clinical variables were obtained through medical records, interview and physical examination. Laboratory variables were: serum lipoproteins, autoantibodies profile, trombophilia and hypofibrinolysis factors. Bone mineral density was acquired through dual energy x-ray absorptiometry. Vertebral fractures were investigated by spine X-rays. RESULTS. ON was found in 10 of 46 patients. Age, disease duration and race did not differ between patients with and without ON. The frequency of clinical features, lipoprotein and auto-antibodies profile and frequency of trombophilia and hypofibrinolysis were also alike in the two groups. Importantly, disease activity (frequency of patients with SLEDAI ?8) in the previous year of ON clinical diagnosis was significantly higher when compared to patients without ON in the previous year of study entrance (60.0% vs. 19.4%, p=0.011). Reinforcing this finding, glucocorticoid cumulative dose used in the previous year of ON diagnosis was also higher compared to SLE without ON in the previous year of study entrance (p=0.045). Differences concerning the densitometric and radiographic data were not observed. Remarkably, in the multivariate analysis only SLEDAI remained as an independent risk factor for ON (OR=6.6, CI=1.07-41.29, p= 0.042). CONCLUSION. This study has clearly revealed that disease activity in the previous year of ON clinical diagnosis is the main predictor factor for the development of this complication in early SLE.

Introdução: Pancreatite é uma manifestação incomum e com risco de vida no lúpus eritematoso sistêmico juvenil (LESJ). Objetivo: Estudar a classificação da pancreatite em pacientes com LESJ de acordo com as definições do Grupo Internacional de Estudos de Pancreatite Pediátrica (INSPPIRE) e determinar prevalência geral, características clínicas, alterações laboratoriais e prognóstico do primeiro episódio. Métodos: Um estudo de coorte retrospectivo multicêntrico incluiu 852 pacientes com LESJ estudados em 10 serviços de referência terciária de reumatologia pediátrica. Resultados: Pancreatite foi diagnosticada em 22 de 852 (2.6%) pacientes com LESJ. Foram classificados como pancreatite aguda em 20 (91%), pancreatite aguda recorrenteem 2 (9%), e nenhum deles apresentou pancreatite crônica. Nenhum deles tinha cálculos biliares, pancreatite traumática, ou relatou o uso de álcool e/ou tabagismo. A comparação dos pacientes com pancreatite (primeiro episódio) e sem esta complicação, revelou uma menor duração da doença [1 (0-10) vs. 4 (0-23) anos, P < 0,0001] e maior mediana do Índice de Atividade de Doença do LES 2000 [21 (0-41) vs. 2 (0-45), P < 0,0001]. A frequência de febre (P < 0,0001), perda de peso (P < 0,0001), serosite (P < 0,0001), nefrite (P < 0,0001), hipertensão arterial (P < 0,0001), insuficiência renal aguda (P < 0,0001), síndrome de ativação macrofágica (P < 0,0001), e morte (P=0,001) foram maiores em pacientes com pancreatite. A freqüência de metilprednisolona endovenosa (P < 0,0001) e a mediana da prednisona [55 (15-60) vs. 11 (1-90) mg/dia, P < 0,0001] foram significantemente maiores em pacientes com pancreatite. Dois pacientes apresentavam pancreatite aguda recorrente com dois episódios distintos, com intervalo sem dor entre os dois episódios de 1 e 4 anos. Conclusão: Este foi o primeiro estudo classificando a pancreatite usando as definições do Grupo Internacional de Estudos de Pancreatite Pediátrica em pacientes com LESJ mostrando uma predominância da pancreatite aguda associado ao tratamento com glicocorticóide e atividade grave da doença / Introduction: Pancreatitis is a rare and a life-threatening systemic lupus erythematosus (SLE) manifestation in childhood-onset SLE (cSLE). Objective: To study the classification of pancreatitis in cSLE according to the International Study Group of Pediatric Pancreatitis and determine the overall prevalence, clinical features, laboratory, and first episode outcomes. Methods: A multicenter cohort study in 10 pediatric rheumatology centers, included 852 patients with cSLE. Results: Pancreatitis was diagnosed in 22 of 852 (2.6%) patients with cSLE. It was classified as acute pancreatitis in 20 (91%), acute recurrent pancreatitis in 2 (9%), and none of them had chronic pancreatitis. None of them had gallstones, traumatic pancreatitis, or reported alcohol/tobacco use. The comparison of patients with pancreatitis (first episode) and without this complication revealed a shorter disease duration [1 (0-10) vs. 4 (0-23) anos, P<0.0001] and higher median of Systemic Lupus Erythematosus Disease Activity Index 2000 [21 (0-41) vs. 2 (0-45), P < 0.0001]. The frequencies of fever (P < 0.0001), weight loss (P < 0.0001), serositis (P < 0.0001), nephritis (P < 0.0001), arterial hypertension (P < 0.0001), acute renal failure (P < 0.0001), macrophage activation syndrome (P < 0.0001), and death (P=0.001) were also higher in patients with pancreatitis. The frequencies of intravenous methylprednisolone use (P < 0.0001) and the median of prednisone dose [55 (15-60) vs. 11 (1-90) mg/dia, P<0.0001] were significantly higher in patients with pancreatitis. Of note, the 2 patients with acute recurrent pancreatitis had 2 episodes, with pain free interval of 1 and 4 years. Conclusions: This was the first study characterizing pancreatitis using the International Study Group of Pediatric Pancreatitis standardized definitions in patients with cSLE showing that the predominant form is acute pancreatitis seen in association with glucocorticoid treatment and active severe disease

Introdução: Os anticorpos antiproteína P ribossomal (anti-P) são considerados marcadores sorológicos específicos do Lúpus Eritematoso Sistêmico (LES) e estão associados a acometimento hepático nesta doença. As semelhanças entre a hepatite autoimune (HAI) e a hepatite associada ao LES levou ao questionamento se o anticorpo anti-P também estaria presente na HAI. Objetivo: Avaliar a frequência e significância clínica do anticorpo anti-P em uma grande coorte de pacientes com HAI. Métodos: Foram analisados os soros de 96 pacientes com HAI, coletados no diagnóstico e comparados com 82 soros de indivíduos saudáveis. Todos os soros foram testados para a presença do anticorpo anti-P pelo método de ELISA, do anticorpo anti-DNA de dupla fita pelo método de imunofluorescência indireta usando Crithidia luciliae e do anticorpo anti-Sm pelo método de ELISA. Os critérios de exclusão adotados foram a presença de outros anticorpos específicos de LES como o anti-DNA de dupla fita (n=1) e o anti-Sm (n=2) ou se o paciente apresentasse o diagnóstico de LES definido pelo Colégio Americano de Reumatologia (n=0). Os prontuários médicos foram revisados para dados demográficos, clínicos e resultados de exames laboratoriais relacionados a hepatopatia e anticorpos específicos de HAI. Resultado: Títulos moderados ou alto (> 40 U) de anti-P foram encontrados em 9,7% (9/93) dos pacientes com HAI e em nenhum dos controles (p = 0,003). No diagnóstico, os pacientes com anti-P positivo ou negativo apresentavam características demográficas/clínicas semelhantes, como a frequência de cirrose (44,4% vs 28,5%, p = 0,44) e exames laboratoriais relacionados a hepatite (p > 0,05). Entretanto, ao final do seguimento destes pacientes (média de 10,2 ± 4,9 anos), os pacientes positivos para anticorpos anti-P apresentaram uma maior frequência de cirrose quando comparados a pacientes negativos para anti-P (100% vs 60%, p = 0,04). Conclusão: a demonstração da presença do anticorpo anti-P em pacientes com HAI sem evidência de LES sugere um mecanismo comum de acometimento hepático nestas duas doenças. Além disso, a presença deste anticorpo parece predizer um pior prognóstico nos pacientes com HAI / Background: Autoantibodies to ribosomal P proteins (anti-rib P) are specific serological markers for systemic lupus erythematosus (SLE) and are associated with liver involvement in this disease. The similarity in autoimmune background between autoimmune hepatitis (AIH) and SLE- associated hepatitis raises the possibility that anti-rib P antibodies might also have relevance in AIH. Aims: To evaluate the frequency and clinical significance of anti-rib P antibodies in a large AIH cohort. Methods: Sera obtained at diagnosis of 96 AIH patients and of 82 healthy controls were tested for IgG anti-ribosomal P protein by ELISA. All of the sera were also screened for other lupus-specific autoantibodies, three patients with the presence of anti-dsDNA (n=1) and anti-Sm (n = 2) were excluded. Results: Moderate to high titers (> 40 U) of anti-rib P antibody were found in 9.7% (9/93) of the AIH patients and none of the controls (P = 0.003). At presentation, AIH patients with and without anti-rib P antibodies had similar demographic/clinical features, including the frequency of cirrhosis (44.4% vs. 28.5%, P = 0.44), hepatic laboratorial findings (p > 0.05). Importantly, at the final observation (follow-up period 10.2 ± 4.9 years), the AIH patients with anti-rib P had a significantly higher frequency of cirrhosis compared to the negative group (100% vs. 60%, P = 0.04). Conclusion: The novel demonstration of anti-rib P in AIH patients without clinical or laboratory evidence of SLE suggests a common underlying mechanism targeting the liver in these two diseases. In addition, this antibody appears to predict the patients with worse AIH prognoses

Nas últimas décadas, a molécula HLA-G despontou como uma importante molécula imunossupressora. O fato de a molécula HLA-G estar envolvida em diversos mecanismos de imunorregulação e, considerando sua expressão em doenças inflamatórias, sugere a possibilidade de um papel dessa molécula na patogênese e no curso de doenças reumatológicas. Com base nisso, esta tese teve como objetivo avaliar a influência da molécula HLA-G, bem como das variantes genéticas do gene HLA-G na suscetibilidade e no curso de doenças reumatológicas, buscando correlacionar fatores genéticos, moleculares, clínicos e imunológicos. Neste trabalho, avaliamos a influência de variantes alélicas da região 3’ não traduzida do gene HLA-G na suscetibilidade e curso do lúpus eritematoso sistêmico (LES), na suscetibilidade à artrite reumatóide (AR) e avaliamos a expressão de HLA-G solúvel (sHLA-G) em pacientes com AR e artrite idiopática juvenil (AIJ). Observamos que o mesmo haplótipo (D/G) parece estar associado tanto à suscetibilidade ao LES quanto à AR, apontando para o gene HLA-G como um potencial fator de suscetibilidade comum às duas doenças. Em AR, observamos maiores níveis de HLA-G solúvel no líquido sinovial de pacientes fator reumatóide-negativos (FR-) em comparação com pacientes FR+, e diferentes padrões de correlação entre os níveis plasmáticos de sHLA-G e parâmetros de atividade de doença após estratificarmos os grupos de pacientes para positividade para FR e gênero. Nossas observações, portanto, colocam a molécula e o gene HLA-G como elementos diretamente envolvidos na patogênese e curso dessas doenças e encorajam estudos futuros que procurem elucidar o papel da molécula HLA-G no curso de doenças reumatológicas. / In the last decades, HLA-G has emerged as a major immunosuppressive molecule. The fact that HLA-G is involved in various mechanisms of immunoregulation and given its expression in inflammatory diseases suggests the possibility of a role of this molecule in the pathogenesis and course of rheumatic diseases. This thesis aimed to evaluate the influence of HLA-G, as well as genetic variants of the HLA-G gene in the susceptibility and course of rheumatic diseases, seeking to correlate genetic, molecular, clinical and immunological factors. We evaluated the influence of allelic variants of the HLA-G gene 3 'untranslated region (3”UTR) in susceptibility and course of systemic lupus erythematosus, in the susceptibility to rheumatoid arthritis and we have also evaluated the expression of soluble HLA-G in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). We noted that the same haplotype (D/G) seems to be associated with susceptibility to RA and SLE, pointing to the HLA-G gene as a potential common susceptibility factor to both diseases. In RA, we observed higher levels of soluble HLA-G (sHLA-G) in synovial fluid (SF) from rheumatoid factor negative (RF-) patients as compared to RF+ patients, and different patterns of correlation between sHLA-G plasma levels and disease activity parameters after stratifying patient groups for RF positivity and gender. Our observations, therefore, put the gene and molecule HLA-G as directly involved elements in the pathogenesis and course of these diseases and encourage future studies that seek to elucidate the role of HLA-G in the course of rheumatic diseases.

A vacina contra hepatite B tem sido implicada como um desencadeador de doenças auto-imunes, mas ainda não existem estudos prospectivos no lúpus. Assim, avaliamos prospectivamente a segurança e eficácia da imunização com a vacina recombinante contra hepatite B (Euvax B® - LG) em pacientes com diagnóstico de lúpus. Foram selecionadas 28 pacientes com a doença inativa (SLEDAI<4), com idade entre 18 e 50 anos e sorologia negativa para o vírus da hepatite B (VHB). Os critérios de exclusão foram o uso de prednisona >=20 mg/dia e drogas imunossupressoras, anti-dsDNA e anticardiolipina negativos. Os dados clínicos e laboratoriais foram coletados na entrada do estudo e um mês após cada dose da vacina. Além disso, obtivemos dados do ano anterior usando o prontuário eletrônico padronizado. A média de idade foi de 34 ± 7,7 anos e a média da duração da doença foi de 10,4 ± 6,7 anos. Soroconversão adequada foi atingida no final do estudo (93%), embora tenhamos observado uma baixa freqüência após a primeira dose (4%) e após a segunda dose (54%). Nenhuma alteração significativa na média de SLEDAI foi detectada após cada dose durante o estudo (0,14 ± 0,52 vs. 0 vs. 0,61 ± 1,66 vs. 0,36 ± 1,34, p=0,11). Reforçando estes achados, os 11% de atividade de doença durante o período de vacinação foi semelhante aos 21% observados no ano anterior (p=0,46). Além disso, a média da dose de prednisona na entrada foi comparável à dose do final do estudo (2,86 ± 3,06 vs. 4,64 ± 8,25 mg/d, p=0,32). A freqüência do uso de terapia imunossupressora no período da vacinação (11%) foi semelhante aos 14% observados no ano anterior (p=0,66). A vacinação contra hepatite B apresentou uma resposta de anticorpos protetores adequada e foi segura nos pacientes com lúpus inativo. / Hepatitis B vaccination has been implicated as a potential trigger for autoimmune diseases but there are no prospective studies in lupus. We therefore assessed prospectively the safety and efficacy of immunization with recombinant DNA hepatitis B vaccine (Euvax B® - LG) in SLE patients. Twenty-eight consecutive inactive SLE patients (SLEDAI<4), age between 18-50 years and negative serology for hepatitis B virus (HBV) were selected. Exclusion criteria were prednisone > 20mg/day and immunosuppressive drugs. Clinical and laboratorial assessments were obtained at study entry and one month after the three doses. In addition, a previous one year evaluation was performed using a standard electronic protocol. The mean age was 34 ± 7.7 years and disease duration was 10.4 ± 6.7 years. An adequate seroconversion was achieved at the end of the study (93%), although a lower frequency after the first (4%) and second dose (54%) was observed. No significant change in mean SLEDAI score was detected after each dose throughout the study (0.14 ± 0.52 vs. 0 vs. 0.61 ± 1.66 vs. 0.36 ± 1.34, p=0.11). Reinforcing these findings, the 11% flares during vaccination was similar to the 21% observed in the previous year (p=0.46). Furthermore, the mean prednisone dose at study entry was comparable to the end of the study (2.86 ± 3.06 vs. 4.64 ± 8.25 mg/d, p=0.32). In addition, the frequency of immunosuppressive therapy during the vaccination period (11%) was alike to the 14% observed in the previous year before entry (p=0.66). Hepatitis B vaccination was safe in inactive SLE patients with an adequate vaccine response rate.

Objetivos: Avaliar fatores de risco e diferentes métodos diagnósticos para retinopatia nos usuários crônicos do difosfato de cloroquina, portadores de lúpus eritematoso sistêmico. Métodos: Foram avaliados 72 olhos de 36 pacientes consecutivos, seguidos no Serviço de Reumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, entre julho de 2007 e abril de 2008. Dados demográficos e clínicos foram pesquisados para estudar os fatores de alto risco (dose diária acima de 3,0 mg/Kg, dose cumulativa, alterações renais, alterações hepáticas, idade acima de 60 anos) e compará-los com os seguintes métodos diagnósticos: acuidade visual, testes de Amsler com grade branca e vermelha, biomicroscopia da córnea, biomicroscopia do fundo, retinografia, angiofluoresceinografia da retina, campo visual dos 10 graus centrais com mira branca, testes de visão de cores, Panel D15 e HRR. Resultados: Dos 36 pacientes, 34 (94,4 %) eram mulheres. A média de idade foi 39,9±9,8 anos, com tempo de doença igual a 13,9±6,6 anos e tempo de uso da cloroquina igual a 11,9±5,1 anos. Além do uso crônico, os pacientes apresentaram altas doses diárias (4,4±0,4 mg, segundo peso ideal e 5,4±0,6 mg, segundo peso magro) e cumulativas (1092,2±476,6 g). Não foi observada relação entre os fatores de alto risco estudados e maior prevalência de retinopatia. A prevalência de retinopatia, confirmada por alterações bilaterais, centrais ou paracentrais e reprodutíveis nos exames de campo visual, foi de 38.9 %. Outros exames indicados para seguimento, como acuidade visual, biomicroscopia da córnea, biomicroscopia do fundo, teste de Amsler, Panel D15 e angiofluoresceinografia do fundo, não foram capazes de diagnosticar a maioria das alterações confirmadas pelo campo visual. O teste de visão de cores HRR apresentou alta sensibilidade e boa especificidade. A intensidade dos achados no HRR mostrou relação com a intensidade dos achados no campo visual. Conclusão: Foi observada alta prevalência de retinopatia por cloroquina entre os pacientes usuários crônicos da cloroquina. A avaliação desses pacientes deve considerar a realização do exame de campo visual e testes de visão de cores mais específicos para as maculopatias adquiridas, mesmo quando não há suspeita clínica. / Purpose: To evaluate risk factors and screnning methods for retinopathy in systemic lupus erythematosus patients after chronic use of chloroquine. Methods: Seventy-two eyes of 36 consecutive patients, followed in the Division of Rheumatology of Hospital das Clínicas, School of Medicine, São Paulo University, were analised from July 2007 to April 2008. Demographic and clinical data were evaluated in order to study risk factors and compare different ophthalmological methods as following: visual acuity, Amsler grid, corneal biomicroscopy, fundus examination, retinography, fluorescein retinography, visual field, color vision tests. Results: From 36 patients, 34 (94,4 %) were female. The mean age was 39,9± 9,8 years and disease duration was 13,9±6,6 years. Besides chronic use of chloroquine, patients also showed high daily (4,4±0,4 mg) and cumulative (1092,2 ±476,6 g) doses. These high risk factors were not related to higher prevalence of retinopathy. Visual field showed 38.9 % retinopathy prevalence. Other ophthalmological methods failed in detecting most cases. Color vision test HRR was highly sensitive but not so specific in detecting retinopathy. The intensity of alterations in HRR were related to the intensity of visual field alterations. Conclusion: High prevalence of retinopathy in chronic users of chloroquine patients was detected by visual field test, but other screening methods failed in detecting alterations. Ophthalmological assessment of these patients should include visual field and color vision tests specific for acquired maculopathies, even in the absence of clinical alterations.

This medical anthropology dissertation is an intersectional study of the illness experiences of African-American women living with the chronic autoimmune syndrome systemic lupus erythematosus (SLE), commonly known as lupus. Research was conducted in Memphis, Tennessee from 2013 to 2015, with the aim of examining the healthcare resources available to working poor and working class women using public sector healthcare programs to meet their primary care needs. This project focuses on resources available through Tennessee’s privatized public sector healthcare system, TennCare, during the first phases of the Patient Protection and Affordable Care Act (ACA). A critical medical anthropological analysis is used to examine chronically ill women’s survival strategies regarding their daily health and well-being. The objectives of this research were to: 1) understand what factors contribute to poor women’s ability to access healthcare resources, 2) explore how shared illness experiences act as a form of community building, and 3) document how communities of color use illness narratives as a way to address institutionalized racism in the United States. The research areas included: the limits of biomedical objectivity; diagnostic timeline in relation to self-reported medical history; effects of the relationship between socio-economic circumstance and access to consistent healthcare resources, including primary and acute care, as well as access to pharmaceutical interventions; and the role of non-medical support networks, including personal support networks, illness specific support groups, and faith based organizations. Qualitative methods were used to collect data. Methods included: participant observation in support groups, personal homes, and faith based organizations, semi-structured group interviews, and open-ended individual interviews. Fifty-one women living with clinically diagnosed lupus or undiagnosed lupus-like symptoms participated in individual interviews. Additionally twenty-one healthcare workers, including social workers, Medicaid caseworkers, and clinic support staff were interviewed in order to contextualize current state and local health programs and proposed changes to federal and state healthcare policy.

Driving into Yellowstone National Park for the first time is a moving experience. Gazing over the sweeping landscapes, seeing a geyser erupt 80 feet into the air, and having your first ‘wildlife encounter’, whether that be a 2 ton bull bison aggressively wallowing on his dirt mound, snorting and kicking up dust, or watching a pack of 6 wolves move through a valley off in the distance, pausing to howl in search of their companions. Yellowstone staff wishes to manage our park in a way that preserves these remarkable experiences. In order to effectively manage this dynamic ecosystem, it is critical to thoroughly understand how different animal and plant species interact with each other and their environment. Wolves were reintroduced to Yellowstone in 1995-1997 and park researchers and managers are still trying to understand how their presence impacts the ecosystem. In Yellowstone, wolves primarily prey on elk; however, predation on bison has started to increase in recent years. We still know little about how wolves hunt bison and what impacts wolves have had on how bison use their environment. The objective of this study was to better understand the behavioral and ecological interactions of wolves and bison, the most dangerous prey for wolves in North America. Since reintroduction, researchers have collected data on how wolves hunt both elk and bison. I used these data to understand 1) the conditions that allow wolves to capture their most dangerous prey, bison, 2) whether wolves have started preying on bison more often as the bison population increased, and 3) whether wolf reintroduction has limited bison use of Yellowstone’s most extreme high-elevation winter range. Finally, I collaborated with ecologists in Scandinavia to determine how wolf predation was affected by a competitor, the brown bear. My study adds to the current body of work addressing the effects of wolf reintroduction in Yellowstone. This research is unique because it focuses on wolf bison interactions, about which little is known in this system. This research also sheds light on the behavioral relationships at play in a special type of predator-prey interaction: predators that hunt dangerous prey

Cytosolic double stranded DNA (dsDNA) is sensed as a “danger signal” by host cells. Detection of viral and bacterial nucleic acid is emerging as a major route for cells to identify an infection by a pathogen. Recognition of cytoplasmic DNA causes death of some cells and interferon (IFN) and cytokine induction, which are appropriate anti-viral responses. Responses to cytoplasmic DNA may not only be relevant to certain retrovirus, DNA virus and bacterial infections, but could also be generated by reverse transcription of endogenous retro-elements. Introduction of DNA into the cytoplasm of bone marrow derived macrophages (BMM) causes upregulation of MHC Class I, induction of IFNβ and other cytokines and cell death. Both cytokine induction and cell death were independent of recognition of “CpG motifs” through TLR9. In order to determine whether a single receptor was likely to mediate these responses, the types of DNA eliciting these responses was compared. Both cellular activation to produce cytokines and IFNβ, as well as cell death were seen only with dsDNA but not single stranded DNA (ssDNA). Both responses increased with increasing DNA length, with little detectable effect of a double stranded 22bp oligonucleotide (ODN). The sequences of DNA leading to optimal induction of IFNβ and death were different. Although all dsDNA induced death of primary macrophages, poly(dA):(dT) was a particularly potent and rapid pro-death stimulus. In contrast, poly(dA):(dT) was a relatively poor stimulus for IFNβ, even at doses which were minimally toxic, or in cells which are resistant to DNA induced cell death. The alternating co-polymer poly(dA-dT) was the most potent inducer of IFNβ. This data suggests that separate DNA receptors mediate cell death and IFNβ induction in response to dsDNA Transfected dsDNA also rapidly activated caspase 3, a classical pro-apoptotic caspase, in BMM as early as 2½ minutes post-transfection with DNA. Caspase 3 is an effector caspase which is activated by an upstream initiator caspase. Although the apical caspase in the DNA detection system has not been defined, use of Bcl2 overexpressing BMM and caspase 2-/- BMM showed that DNA-dependent caspase 3 activation did not occur via the mitochondrial damage or the caspase 2 activation pathways. The inflammatory caspase, caspase 1 was also activated in response to DNA transfection, although whether caspase 1 is responsible for cleavage of caspase 3 has not been established. Caspase 1 activation suggests the involvement of the inflammasome, which is important for processing pro-inflammatory cytokines such as IL-1β into their biologically active forms. Furthermore, there is recent evidence suggesting that DNA-transfected cells die by a caspase 1-dependent cell death called pyroptosis. Other work in our lab identified the HIN-200 family member and candidate lupus susceptibility factor p202 as a candidate receptor for cytoplasmic dsDNA; p202 bound stably and rapidly to transfected DNA. Here, knockdown studies revealed p202 to be a regulatory protein limiting DNA-induced caspase 1 and 3 activation. Conversely, the related pyrin domain-containing HIN-200 factor AIM2 (p210), a candidate tumour suppressor, was required for caspase 1 and 3 activation by cytoplasmic dsDNA. Recently published work suggests that AIM2 multimerises along the length of the DNA leading to the formation of an inflammasome complex. The pyrin domain of AIM2 recruits the adaptor protein ASC through homotypic pyrin domain interactions. ASC subsequently recruits caspase 1, which results in its auto-activation. The inhibitory effect of p202 on caspase activation is likely to be due to its lack of a pyrin signalling domain. p202 rapidly binds to cytoplasmic DNA, and may reduce the clustering of AIM2 pyrin domains which results in caspase activation. Consistent with this proposal, DNA-dependent caspase activation correlated inversely with p202 expresssion in 3 mouse strains. This work defines HIN-200 proteins as a new class of pattern recognition receptors mediating responses to dsDNA. Work in this thesis aimed to understand the biological role and mechanism of responses to cytoplasmic DNA. Responses to cytoplasmic DNA are likely to be relevant not only to infectious disease but also to autoimmune diseases such as systemic lupus erythmatosus (SLE), where DNA appears to act as an adjuvant, and even tumour progression where there is evidence for a role for active endogenous retro-elements. In addition, responses to DNA may limit transfection efficiency and the efficacy of non-viral gene therapy.