Trabajo de Investigación Requisito para optar al título de Cirujano Dentista / Introducción: El Síndrome de Sjögren (SS) es una enfermedad autoinmune crónica caracterizada por una disminución o pérdida en la producción de secreciones glandulares, que se manifiesta principalmente con síntomas de sequedad ocular y oral, junto con fatiga y dolor musculoesquelético. El SS afecta la cotidianidad y reduce de forma significativa el estado de salud, provocando un cambio importante en el quehacer de las personas, alterando la calidad de vida en múltiples ámbitos. Para comprender mejor la implicancia del SS, resulta necesario analizar la perspectiva del paciente según sus propias experiencias de enfermedad (EE) y la alteración en su calidad de vida, por lo que esta investigación tiene como objetivo determinar el grado de concordancia entre las EE y la asociación entre calidad de vida en relación a salud general y oral en mujeres chilenas con síndrome de Sjögren. Materiales y métodos: Participaron 31 mujeres voluntarias con diagnóstico confirmado de SS entre los rangos de 18 y 70 años, las cuales debieron evaluar 70 experiencias de enfermedad en relación al síndrome, en base a una escala Likert según su grado de acuerdo y desacuerdo. Además, respondieron dos cuestionarios el EQ-5D-5L y OHIP-14Sp. En estos tres instrumentos se utilizaron tablas de frecuencia de datos, análisis estadístico de tendencia central en base a la media y desviación estándar. Para el grado de concordancia de las EE se utilizó la prueba Wilcoxon y para la asociación entre las variables se usó el coeficiente de correlación de Spearman. Resultados: En el 62,9% del total de las afirmaciones, existió concordancia entre las voluntarias. En el EQ-5D-5L las dimensiones con mayores problemas fueron las de “Dolor/Malestar” y “Actividades habituales”, mientras que en el OHIP-14Sp fueron las de “Dolor físico” y “Malestar psicológico”. No se determinó una correlación significativa entre la salud actual y la calidad de vida en relación a salud oral. Conclusiones: Existe una alta concordancia de las experiencias de enfermedad entre las mujeres con SS. Además, la calidad de vida en relación a salud general y oral, sí se ven afectadas, aunque no se observó una asociación entre salud actual y calidad de vida oral. / Adscrito a Proyecto FONIS SA16/0136

Le syndrome sec de Gougerot Sjögren (SGS) est une maladie auto-immune chronique qui présente des dommages progressifs et irréversibles des glandes exocrines lacrymales et salivaires. Cette pathologie affecte entre 0.1 et 3 % de la population et est plus commune chez les femmes avec un ratio de 9 femmes pour 1 homme. Dans la glande salivaire, une infiltration lymphocytaire est observée et est associée avec la destruction de l'épithélium sécrétoire, qui joue un rôle central dans l'initiation et le développement du SGS. Le processus physiopathologique est loin d’être compris et semble dépendant de phénomènes épigénétiques. En effet, des perturbations importantes de la méthylation de l'ADN sont observées dans les cellules épithéliales en lien avec le niveau d’infiltration lymphocytaire des glandes salivaires.L'objectif de ce travail est de mieux comprendre les changements épigénétiques au cours du SGS et en particulier les défauts de méthylation/déméthylation de l’ADN observés dans les Cellules Epithéliales de Glandes Salivaires (SGEC) et leurs rôles dans le développement de la pathologie.Dans ce but, Une étude globale de la méthylation de l'ADN a été réalisée après culture cellulaire destinée à isoler les SGEC de patients SGS. La puce « human methylation 450k » d’Illumina utilisée couvre plus de 485 000 sites CpG du génome. Des analysesbioinformatiques nous ont permis d'obtenir un panel de gènes différentiellement méthylés. Nous avons ainsi mis en évidence l’importance de la voie calcique (déméthylée, connue pour avoir un impact sur la salivation) et de la voie WNT (hyperméthylée). De plus nous avons pu identifier une régulation interféron et montrer l’importance d’un changement du type d'interféron (I à II) lors de l’évolution vers un lymphome de type MALT. En outre, nous montrons qu’il existe une inter-relation forte entre les processus épigénétiques et les facteurs génétiques associés au SGS. Enfin la dernière partie de ce travail met en lumière l’implication d’un environnement inflammatoire dans le contrôle du processus de méthylation/déméthylation de l’ADN dans les cellules épithéliales.Ainsi, les altérations du méthylome des SGECs pourraient contribuer à la pathophysiologie du SGS et à son évolution en un lymphome du MALT, ceci en lien avec son environnement inflammatoire. / Sjögren Syndrome (SjS) is a chronic autoimmune disease characterized by a progressive and irreversible damage of exocrine glands, particularly salivary and lacrymal glands. This pathology affects between 0.1 and 3% of the population and is more common in women with a ratio of 9 women for 1 man. In salivary glands, a lymphocytic infiltration is observed and associated with the destruction of the secretory epithelium, which plays a central role in initiation and development of the SjS. The process remains incompletely clarified and contains a strong epigenetic component. Indeed, important disturbances of the process of DNA methylation are observed in epithelial cells and they are linked with the level of lymphocyte infiltration in salivary glands.The objective of this work is to better understand epigenetic changes during the SjS and in particular the DNA methylation/demethylation defects observed in Salivary Gland Epithelial Cells Epithelial (SGEC) and their roles in the pathology development.For that purpose, a global study of DNA methylation was done on 12 patients SGECs with the Infinium HumanMethylation450 BeadChip (Illumina). The 450k HM allows to cover more than 485,000 CpG sites on the whole genome. Bioinformatic analysis allowed us to obtain genes panels which are differentially methylated during this pathological phenomenon. In an interesting way, we identified the potential involvement of the calcic (hypomethylated, known to impact salivation) and WNT pathways (hypermethylated). Besides we were able to identify interferon regulation and the shift from interferon type I to type II with mucosa associated lymphoid tissue (MALT) lymphoma evolution. Furthermore, the simultaneous genomic–epigenomic analysis revealed significant associations between SjS-associated genetic risk factors and epigenetic modifications. Finally, the last part of this work highlights inflammatory environment involvement to control DNA methylation/demethylation in salivary gland epithelial cells.Altogether, alterations of DNA methylation in SGEC may contribute to SjS pathophysiology and evolution to MALT and this in link with the inflammatory environment.

O HTLV-1 (human T-cell lymphotropic virus type 1) foi o primeiro retrovírus humano a ser identificado. É comprovadamente o agente etiológico da leucemia/linfoma de células T no adulto (ATLL) e da paraparesia espástica tropical ou mielopatia associada ao HTLV (HAM/TSP). Porém se evidencia que o vírus possa estar relacionado a várias outras manifestações sistêmicas. A Síndrome de Sjögren (SS) é uma das desordens que têm sido associada ao HTLV-1. Embora a infecção pelo HTLV seja reconhecidamente endêmica no Brasil, não há informações sobre essa associação na população brasileira. Este trabalho propõe-se a investigar a prevalência de SS em pacientes infectados pelo HTLV e a prevalência de HTLV em pacientes diagnosticados com SS. Exames sorológicos para investigação do HTLV foram realizados em 50 pacientes da Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP) que apresentavam queixas compatíveis com a SS (grupo 1). No Instituto de Infectologia Emílio Ribas foram avaliados 129 pacientes HTLV+ que passaram pelo processo diagnóstico para a SS (grupo 2). Nenhum dos pacientes do grupo 1 apresentou soropositividade para o HTLV. No grupo 2, 46 (35,7%) apresentaram algum grau de xerostomia, 18 (13,95%) apresentaram xeroftalmia, 8 (6,2%) apresentaram hipossalivação, 2 (1,55%) apresentaram fluxo lacrimal alterado e 1 paciente (0,77%) apresentou autoanticorpos reagentes (anti-SSB). Foram executadas biópsias incisionais de glândulas salivares menores em 5 pacientes do grupo 2. Apenas 2 pacientes (1,55%) HTLV+ completaram os critérios para o diagnóstico de SS. A SS mostrou ser três vezes mais prevalente em pacientes HTLV+ do IIER do que nos pacientes que buscaram atendimento no serviço de Otorrinolaringologia da ISCMSP. / HTLV-1 (human T-cell lymphotropic virus type 1) was the first human retrovirus identified. It is proven to be the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and of a neurological disease known as HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). However, there is the evidence that the virus could be related to several other systemic manifestations. Sjögren\'s Syndrome (SS) is one of the disorders that have been associated with HTLV-1. Although HTLV infection is known to be endemic in Brazil, there is no information about this association in Brazilian population. This study proposes to investigate the prevalence of SS among patients infected with HTLV and the prevalence of HTLV among patients diagnosed with SS. Serological tests for HTLV were performed in 50 patients from Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP) with complaints compatible with the SS (group 1). At Institute of Infectious Diseases Emilio Ribas (IIER), 129 HTLV+ patients were evaluated and the diagnostic process for SS was performed (group 2). None of the patients in group 1 was positive for HTLV. In group 2, 46 (35.7%) reported any degree of xerostomia, 18 (13.95%) had xerophtalmia, hyposalivation was present in 8 (6.2%) patients and decrease in tear secretion, in only one patient (0.77%) the auto-antibodies was positive ( Anti-SSB). Incisional biopsies of labial minor salivary glands were executed in 5 patients in group 2. Only 2 HTLV+ patients (1.55%) have fulfilled the classification criteria for SS. SS proved to be three times more prevalent in HTLV patients from IIER than in patients who sought care in the service of Otorhinolaryngology at ISCMSP.

O HTLV-1 (human T-cell lymphotropic virus type 1) foi o primeiro retrovírus humano a ser identificado. É comprovadamente o agente etiológico da leucemia/linfoma de células T no adulto (ATLL) e da paraparesia espástica tropical ou mielopatia associada ao HTLV (HAM/TSP). Porém se evidencia que o vírus possa estar relacionado a várias outras manifestações sistêmicas. A Síndrome de Sjögren (SS) é uma das desordens que têm sido associada ao HTLV-1. Embora a infecção pelo HTLV seja reconhecidamente endêmica no Brasil, não há informações sobre essa associação na população brasileira. Este trabalho propõe-se a investigar a prevalência de SS em pacientes infectados pelo HTLV e a prevalência de HTLV em pacientes diagnosticados com SS. Exames sorológicos para investigação do HTLV foram realizados em 50 pacientes da Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP) que apresentavam queixas compatíveis com a SS (grupo 1). No Instituto de Infectologia Emílio Ribas foram avaliados 129 pacientes HTLV+ que passaram pelo processo diagnóstico para a SS (grupo 2). Nenhum dos pacientes do grupo 1 apresentou soropositividade para o HTLV. No grupo 2, 46 (35,7%) apresentaram algum grau de xerostomia, 18 (13,95%) apresentaram xeroftalmia, 8 (6,2%) apresentaram hipossalivação, 2 (1,55%) apresentaram fluxo lacrimal alterado e 1 paciente (0,77%) apresentou autoanticorpos reagentes (anti-SSB). Foram executadas biópsias incisionais de glândulas salivares menores em 5 pacientes do grupo 2. Apenas 2 pacientes (1,55%) HTLV+ completaram os critérios para o diagnóstico de SS. A SS mostrou ser três vezes mais prevalente em pacientes HTLV+ do IIER do que nos pacientes que buscaram atendimento no serviço de Otorrinolaringologia da ISCMSP. / HTLV-1 (human T-cell lymphotropic virus type 1) was the first human retrovirus identified. It is proven to be the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and of a neurological disease known as HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). However, there is the evidence that the virus could be related to several other systemic manifestations. Sjögren\'s Syndrome (SS) is one of the disorders that have been associated with HTLV-1. Although HTLV infection is known to be endemic in Brazil, there is no information about this association in Brazilian population. This study proposes to investigate the prevalence of SS among patients infected with HTLV and the prevalence of HTLV among patients diagnosed with SS. Serological tests for HTLV were performed in 50 patients from Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP) with complaints compatible with the SS (group 1). At Institute of Infectious Diseases Emilio Ribas (IIER), 129 HTLV+ patients were evaluated and the diagnostic process for SS was performed (group 2). None of the patients in group 1 was positive for HTLV. In group 2, 46 (35.7%) reported any degree of xerostomia, 18 (13.95%) had xerophtalmia, hyposalivation was present in 8 (6.2%) patients and decrease in tear secretion, in only one patient (0.77%) the auto-antibodies was positive ( Anti-SSB). Incisional biopsies of labial minor salivary glands were executed in 5 patients in group 2. Only 2 HTLV+ patients (1.55%) have fulfilled the classification criteria for SS. SS proved to be three times more prevalent in HTLV patients from IIER than in patients who sought care in the service of Otorhinolaryngology at ISCMSP.

A Síndrome de Sjögren primária (SSp) é uma doença autoimune sistêmica de etiologia desconhecida, caracterizada principalmente, pela presença de infiltrado linfocítico nas glândulas exócrinas (salivares e lacrimais) que leva ao quadro de boca seca e olhos secos (síndrome sicca). Apesar das evidências de que o nível de atividade física e das capacidades física e funcional estarem diminuídas na maioria das doenças reumáticas, essas variáveis tem sido pouco estudadas em pacientes com SSp. Assim, o objetivo desse estudo foi avaliar objetivamente o nível de atividade física e as capacidades físicas de pacientes com SSp com baixo nível de atividade da doença, bem como, a possível associação desses fatores com a fadiga, a qualidade de vida, a artralgia e a depressão. Trinta pacientes diagnosticadas com SSp (Vitali et al., 2002) utilizaram acelerômetros por 7 dias consecutivos para avaliação do nível de atividade física, realizaram teste ergoespirométrico, testes de força, testes funcionais, exames laboratoriais, densitometria óssea e responderam a questionários de fadiga, qualidade de vida, depressão e artralgia. Os pacientes com SSp apresentaram menor tempo em atividades físicas moderadas e menor quantidade de passos por dia do que o grupo controle. Os pacientes apresentaram ainda redução da aptidão aeróbia, da força muscular de membros inferiores e superiores, da capacidade funcional e da qualidade de vida, além de fadiga aumentada em comparação com o GC. Não foram encontradas diferenças significativas para a composição corporal, artralgia e depressão entre os grupos. Pacientes com SSp mesmo em baixa atividade da doença mantêm um estilo de vida sedentário e redução das capacidades físicas e qualidade de vida. Faz-se necessária a implementação de estratégias que reduzam o tempo gasto em atividades sedentárias, bem como, a elaboração de programas de exercícios físicos sistematizados de acordo com as características dessa população / Primary Sjögren´s syndrome (PSS) is a systemic autoimune disease of unknown aetiology characterized by lymphocytic infiltration in the exocrine glands (salivary and lacrimal) hwhich leads to dry mouth and dry eyes (sicca syndrome). Despite the evidence that physical activity level and physical and functional capabilities are reduced in most rheumatic diseases, these variables have been poorly studied in patients with pSS. The objective of this study was to objectively assess the physical activity level and the physical capacities of patients with pSS with mild disease activity, as well as the possible association of these factors with fatigue, quality of life, arthralgia and depression. Thirty patients diagnosed with pSS (Vitali et al., 2002) used accelerometers for 7 consecutive days to assess the physical activity level. They performed cardiopulmonary exercise test, strength tests, functional tests, laboratory tests, bone densitometry and answered questionnaires of fatigue, quality of life, depression and arthralgia. Patients with pSS showed less time in moderate physical activities and fewer steps per day than the control group. The patients also showed reduced aerobic conditioning, muscle strength of upper and lower limbs, functional capacity and quality of life, and also increased fatigue compared to the control group. No significant differences were found for body composition, arthralgia and depression between the groups. Patients with pSS, even with mild disease activity, maintain a sedentary lifestyle and reduced physical capacity and quality of life. It is necessary to implement strategies that reduce time spent on sedentary activities, as well as to elaborate physical exercise programs in accordance to the characteristics of this population

A Síndrome de Sjögren primária (SSp) é uma doença autoimune sistêmica de etiologia desconhecida, caracterizada principalmente, pela presença de infiltrado linfocítico nas glândulas exócrinas (salivares e lacrimais) que leva ao quadro de boca seca e olhos secos (síndrome sicca). Apesar das evidências de que o nível de atividade física e das capacidades física e funcional estarem diminuídas na maioria das doenças reumáticas, essas variáveis tem sido pouco estudadas em pacientes com SSp. Assim, o objetivo desse estudo foi avaliar objetivamente o nível de atividade física e as capacidades físicas de pacientes com SSp com baixo nível de atividade da doença, bem como, a possível associação desses fatores com a fadiga, a qualidade de vida, a artralgia e a depressão. Trinta pacientes diagnosticadas com SSp (Vitali et al., 2002) utilizaram acelerômetros por 7 dias consecutivos para avaliação do nível de atividade física, realizaram teste ergoespirométrico, testes de força, testes funcionais, exames laboratoriais, densitometria óssea e responderam a questionários de fadiga, qualidade de vida, depressão e artralgia. Os pacientes com SSp apresentaram menor tempo em atividades físicas moderadas e menor quantidade de passos por dia do que o grupo controle. Os pacientes apresentaram ainda redução da aptidão aeróbia, da força muscular de membros inferiores e superiores, da capacidade funcional e da qualidade de vida, além de fadiga aumentada em comparação com o GC. Não foram encontradas diferenças significativas para a composição corporal, artralgia e depressão entre os grupos. Pacientes com SSp mesmo em baixa atividade da doença mantêm um estilo de vida sedentário e redução das capacidades físicas e qualidade de vida. Faz-se necessária a implementação de estratégias que reduzam o tempo gasto em atividades sedentárias, bem como, a elaboração de programas de exercícios físicos sistematizados de acordo com as características dessa população / Primary Sjögren´s syndrome (PSS) is a systemic autoimune disease of unknown aetiology characterized by lymphocytic infiltration in the exocrine glands (salivary and lacrimal) hwhich leads to dry mouth and dry eyes (sicca syndrome). Despite the evidence that physical activity level and physical and functional capabilities are reduced in most rheumatic diseases, these variables have been poorly studied in patients with pSS. The objective of this study was to objectively assess the physical activity level and the physical capacities of patients with pSS with mild disease activity, as well as the possible association of these factors with fatigue, quality of life, arthralgia and depression. Thirty patients diagnosed with pSS (Vitali et al., 2002) used accelerometers for 7 consecutive days to assess the physical activity level. They performed cardiopulmonary exercise test, strength tests, functional tests, laboratory tests, bone densitometry and answered questionnaires of fatigue, quality of life, depression and arthralgia. Patients with pSS showed less time in moderate physical activities and fewer steps per day than the control group. The patients also showed reduced aerobic conditioning, muscle strength of upper and lower limbs, functional capacity and quality of life, and also increased fatigue compared to the control group. No significant differences were found for body composition, arthralgia and depression between the groups. Patients with pSS, even with mild disease activity, maintain a sedentary lifestyle and reduced physical capacity and quality of life. It is necessary to implement strategies that reduce time spent on sedentary activities, as well as to elaborate physical exercise programs in accordance to the characteristics of this population

Le syndrome de Gougerot-Sjögren (SGS) est une maladie auto-immune systémique. Il se caractérise principalement par une infiltration lymphocytaire des glandes salivaires (GS) et lacrymales responsable d’une sécheresse buccale et oculaire. Par ailleurs,les Toll-like récepteurs (TLR) endosomaux – notamment le TLR9 qui reconnait l’acide désoxyribonucléique (ADN) microbien mais aussi, dans certaines conditions, l’ADN du soi –s’avèrent être importants pour l’activation des lymphocytes B (LB) lors du lupus, une maladie proche du SGS. Nos travaux montrent que la stimulation du TLR9 chez les LB transitionnels,des LB immatures fraichement émigrés de la moelle osseuse, favorise leur différenciation selon la voie des LB de la zone marginale, et entraine la sécrétion d’auto-anticorps. L’analyse des LB infiltrant les GS lors du SGS révèle que ce phénomène pourrait être impliqué dans la physiopathologie de cette maladie. De plus, nous montrons que LL37, un peptide produit dans les GS, pourrait participer à l’activation du TLR9 des LB transitionnels. Enfin, nous avons mis en évidence une inattendue expression du TLR9 à la surface des LB. Si l’étude des conséquences fonctionnelles de cette localisation reste à poursuivre, elle semble avoir un effet négatif sur la stimulation du TLR9 endosomal. En conclusion, ces résultats suggèrent que leTLR9 puisse être une nouvelle cible thérapeutique lors du SGS. / Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease. It is mainly characterized by B cell and T cell infiltration in lacrimal and salivary glands (SG) responsible for eye and mouth dryness. In addition, endosomal Toll-like receptors (TLR) – especially TLR9 which recognizes microbial deoxyribonucleic acid (DNA) and also, under certain conditions, self DNA – are important for B cell activation during lupus, a disease close topSS. Our work shows that TLR9 stimulation on transitional B cells, immature B cells freshly emigrated from bone marrow, promotes their differentiation into marginal zone B cell pathway and drives to auto-antibodies production. Analysis of infiltrating B cells in pSS SG reveals that this phenomenon might be involved in the pathogenesis of the disease.Furthermore, we show that LL37, a peptide produced in the SG, could participate in TLR9activation of transitional B cells. Finally, we demonstrated an unexpected TLR9 expression on B cell surface. If the functional consequences of this localization remain to be more precisely evaluated, it seems that cell surface TLR9 has a negative effect on endosomal TLR9 stimulation. In conclusion, these results suggest TLR9 could be a new therapeutic target incase of pSS.

O HTLV-1 (human T-cell lymphotropic virus type 1) foi o primeiro retrovírus humano a ser identificado. O HTLV-1 tem a capacidade de ativar e gerar uma intensa resposta inflamatória, podendo levar a alterações em diversos tecidos que mimetizam uma doença autoimune. Do complexo de doenças associadas ao HTLV-1, a Síndrome de Sjögren (SS) figura entre as mais estudadas. No entanto, nenhuma relação definitiva foi ainda estabelecida. Este trabalho propõe-se a investigar indícios da presença do HTLV-1 em glândulas salivares menores de pacientes infectados por esse retrovírus e comparar as alterações morfológicas em glândulas salivares menores de pacientes com HTLV-1 e de pacientes com SS não infectados. Amostras de glândula salivar menor foram coletadas de 14 pacientes HTLV+ que apresentavam síndrome seca (grupo de estudo) e 5 pacientes diagnosticados com SS e negativos para o HTLV (grupo controle). No grupo de estudo, o infiltrado inflamatório visto era composto principalmente por linfócitos T CD4+, no grupo controle a população majoritária foi de linfócitos B CD20+. Alterações morfológicas como fibrose e infiltração gordurosa foram mais comumente vistas nas amostras do grupo de estudo, sendo a diferença estatisticamente significativa (p=0,038 e 0,033 respectivamente). Na análise por PCR 11 (78,57%) dos casos do grupo de estudo foi detectado o gene tax e/ou rex do HTLV-1, no entanto 4 (80%) das amostras do grupo controle também foram positivas. O HTLV-1 mostra indícios de estar presente nas glândulas salivares de indivíduos com síndrome seca, no entanto pacientes HTLV-1+ apresentam alterações morfológicas em padrões diferentes dos vistos em pacientes com SS, denotando uma provável diferença no processo de ativação imunológica. / Human T-cell lymphotropic virus type I (HTLV-1) was the first human retrovirus to be discovered. HTLV-1 has the ability to activate and generate an intense inflammatory response, which can lead to changes in several tissues that mimic an autoimmune disease Of the complex of diseases associated with HTLV-1, Sjögren\'s Syndrome (SS) is among the most studied. The aim of this study is to investigate the presence of HTLV-1 in the minor salivary glands of patients infected with this retrovirus and to compare the morphological alterations in the salivary glands of patients with HTLV-1 and patients with SS uninfected. Minor salivary gland samples were obtained from 14 HTLV + patients with dry syndrome (study group) and 5 patients diagnosed with SS and HTLV negative (control group). In the study group, the inflammatory infiltrate was mainly composed of CD4+ T lymphocytes, in the control group the majority population was of CD20+ B lymphocytes. Morphological changes such as fibrosis and adipose tissue infiltration were more common in the study group, the difference was statistically significant (p = 0.038 and 0.033, respectively). The HTLV-1 tax and/or rex genes were detected by PCR in 11 (78.57%) patients of the study group, but 4 (80%) samples from the control group were also positive. HTLV-1 shows signs of being present in the salivary glands of individuals with dry syndrome however, HTLV-1+ patients present morphological alterations in different patterns from those observed in SS patients, denoting a probable difference in the immunological activation process.

BAFF, «facteur d'activation des lymphocytes B (LB) » contribue à l'expansion des LB autoréactifs de faible affinité lors de la mise en place de la tolérance. Cependant, les mécanismes menant à la surexpression de BAFF dans les maladies auto-immunes ne sont pas compris. Nous avons découvert un nouveau variant de BAFF, 4BAFF (dans lequel l'exon 4 est épissé), qui agit comme un facteur de transcription de son propre gène et participe à sa régulation. Ainsi, 4BAFF est préférentiellement observé dans les cellules isolées de patients atteints de maladies auto-immunes. De plus, 4BAFF régule un grand nombre de gènes associés à la réponse immunitaire innée et à la régulation de l’apoptose. Une autre constatation importante est que 4BAFF est un élément clé pour comprendre l’activité des LB régulateurs. Notre travail présente un concept entièrement nouveau suggérant qu'une cytokine peut être régulée par l'activité de l'un de ses variants d'épissage. Par ailleurs, nous avons observé que les cellules épithéliales expriment le récepteur de BAFF : BR3. Le blocage de BR3 se traduit par la translocation nucléaire de PKC et l'apoptose des cellules épithéliales. Par un effet autocrine, nous démontrons que seules certaines formes de BAFF participent à la survie des cellules épithéliales. Enfin , nous avons étudié les conséquences de l'expression du TLR9 à la surface des LB et démontrons que ce TLR9 membranaire ne fixe pas le CpG et agit comme un co-récepteur négatif du BCR. En effet, l'activation des LB par le CpG capté au niveau endosomal, est inhibée par l’action d’un anticorps anti-TLR9 se fixant au niveau membranaire. Tous ces résultats contribuent à une meilleure compréhension des mécanismes impliqués dans l'immunopathologie des maladies autoimmunes avec des applications potentielles en thérapeutique. / Elevated expression of ‘B cell activating factor’ (BAFF), a potent B cell survival factor contributes to the expansion of low-affinity self-reactive B cells during the establishment of tolerance. However, mechanisms leading to BAFF over-expression in autoimmune diseases are not understood. We reported the discovery of a new variant for BAFF, 4BAFF in humans (in which exon 4 is excised) or 5BAFF in mice (in which exon 5 is excised), which acts as a transcription factor of the full-length form of BAFF, and which is preferentially found in cells isolated from patients with autoimmune diseases. When transfected in human B cells, D4BAFF upregulates a large number of genes associated with immune response and especially innate immunity and regulation of apoptotis. Furthermore D4BAFF acts, in association with p50 from the NF- B pathway, as a transcription factor for its own parent gene. Another important finding is that 4BAFF is an important component of the efficacy of regulatory B cell activity. Our work introduces an entirely novel concept in biology suggesting that a human cytokine gene can be transcriptionally regulated by the activity of one of its own splice variants.We have also tried to understand the complexity of the various forms of BAFF. We observed that epithelial cells expressed BAFF-receptor (BR3) and produce BAFF suggesting autocrine properties. Blocking BR3 results in nuclear translocation of PKC promoting epithelial cell apoptosis.Furthermore, only some forms of BAFF are required for epithelial cell survival. Finally, we studied the consequences of the expression of TLR9 on the B cell surface and demonstrated that TLR9 acts as a co-receptor of the B cell receptor to influence B cell fate independently of CpG binding. We show that CpG activation of B cells, acting synergistically with BCR signals, was inhibited by anti-TLR9 stimulation. Induction of CD25 expression and proliferation of B cells were thus down-regulated by engagement of cell surface TLR9. Overall, our results indicate that TLR9 expressed on B cell plasma membrane might be a negative regulator of endosomal TLR9, and could provide a novel control by which activation of autoreactive B cells is restrained. All these findings contribute to a better understanding on immunopathology of autoimmune diseases with potential applications in therapy.

O HTLV-1 (human T-cell lymphotropic virus type 1) foi o primeiro retrovírus humano a ser identificado. O HTLV-1 tem a capacidade de ativar e gerar uma intensa resposta inflamatória, podendo levar a alterações em diversos tecidos que mimetizam uma doença autoimune. Do complexo de doenças associadas ao HTLV-1, a Síndrome de Sjögren (SS) figura entre as mais estudadas. No entanto, nenhuma relação definitiva foi ainda estabelecida. Este trabalho propõe-se a investigar indícios da presença do HTLV-1 em glândulas salivares menores de pacientes infectados por esse retrovírus e comparar as alterações morfológicas em glândulas salivares menores de pacientes com HTLV-1 e de pacientes com SS não infectados. Amostras de glândula salivar menor foram coletadas de 14 pacientes HTLV+ que apresentavam síndrome seca (grupo de estudo) e 5 pacientes diagnosticados com SS e negativos para o HTLV (grupo controle). No grupo de estudo, o infiltrado inflamatório visto era composto principalmente por linfócitos T CD4+, no grupo controle a população majoritária foi de linfócitos B CD20+. Alterações morfológicas como fibrose e infiltração gordurosa foram mais comumente vistas nas amostras do grupo de estudo, sendo a diferença estatisticamente significativa (p=0,038 e 0,033 respectivamente). Na análise por PCR 11 (78,57%) dos casos do grupo de estudo foi detectado o gene tax e/ou rex do HTLV-1, no entanto 4 (80%) das amostras do grupo controle também foram positivas. O HTLV-1 mostra indícios de estar presente nas glândulas salivares de indivíduos com síndrome seca, no entanto pacientes HTLV-1+ apresentam alterações morfológicas em padrões diferentes dos vistos em pacientes com SS, denotando uma provável diferença no processo de ativação imunológica. / Human T-cell lymphotropic virus type I (HTLV-1) was the first human retrovirus to be discovered. HTLV-1 has the ability to activate and generate an intense inflammatory response, which can lead to changes in several tissues that mimic an autoimmune disease Of the complex of diseases associated with HTLV-1, Sjögren\'s Syndrome (SS) is among the most studied. The aim of this study is to investigate the presence of HTLV-1 in the minor salivary glands of patients infected with this retrovirus and to compare the morphological alterations in the salivary glands of patients with HTLV-1 and patients with SS uninfected. Minor salivary gland samples were obtained from 14 HTLV + patients with dry syndrome (study group) and 5 patients diagnosed with SS and HTLV negative (control group). In the study group, the inflammatory infiltrate was mainly composed of CD4+ T lymphocytes, in the control group the majority population was of CD20+ B lymphocytes. Morphological changes such as fibrosis and adipose tissue infiltration were more common in the study group, the difference was statistically significant (p = 0.038 and 0.033, respectively). The HTLV-1 tax and/or rex genes were detected by PCR in 11 (78.57%) patients of the study group, but 4 (80%) samples from the control group were also positive. HTLV-1 shows signs of being present in the salivary glands of individuals with dry syndrome however, HTLV-1+ patients present morphological alterations in different patterns from those observed in SS patients, denoting a probable difference in the immunological activation process.