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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
11

Autophagie comme cible thérapeutique potentielle pour le syndrome de Sjögren / Autophagy as a potential therapeutic target for Sjögren's syndrome

Li, Baihui 13 September 2017 (has links)
Le syndrome de Sjögren (SS) est l'une des maladies autoimmunes (MAI) systémiques les plus fréquentes chez l’Homme. Cette maladie est caractérisée par une infiltration lymphocytaire dans les glandes exocrines conduisant à des symptômes dits de « yeux secs » et à la bouche sèche. Il n’existe actuellement aucun traitement curatif pour cette maladie. Le peptide P140 a été démontrée comme un outil thérapeutique efficace chez les patients atteints d'un lupus érythémateux disséminé (LED) et des souris modèles développant un lupus.L'autophagie est une voie intracellulaire conservée qui joue un rôle central dans le maintien de l'homéostasie cellulaire. En outre, l'autophagie a été démontrée comme un mécanisme de régulation de l'autoimmunité. Les effets bénéfiques du peptide P140 dans le lupus semblent étroitement liés à son effet d'inhibition de l’autophagie qui est hyper-activée dans le lupus. A ce jour, très peu de données sont connues concernant l'autophagie dans le SS. Le sujet de ma thèse porte i. sur l’étude et la compréhension des phénomènes de l’autophagie dans le SS et ii. sur l’effet éventuel du peptide P140 dans cette maladie.Dans cette étude, nous avons d’abord montré des effets protecteurs du P140 contre le SS dans les souris modèle MRL/lpr, comme en témoignent l’amélioration de l'inflammation, une diminution de l'infiltration lymphocytaire dans les SG de souris et une baisse des niveaux d'autoanticorps circulants. Nous avons également constaté que l'autophagie et les lysosomes étaient défectueux dans les SG des souris MRL/lpr et que le P140 rétabli le flux autophagique et l'acidité lysosomale. Ces résultats suggèrent que l'autophagie défectueuse et des défauts des lysosomes pourraient contribuer à la pathologie du SS et que les effets thérapeutiques de P140 pourraient être liés à son effet sur l'autophagie et les lysosomes.Les résultats obtenus dans le cadre de cette thèse nous offrent des informations décisives sur la pathogenèse de SS et suggèrent que l'autophagie pourrait être une cible thérapeutique de choix dans le SS. Au-delà, les effets protecteurs de P140 dans le modèle de souris SS nous éclairent sur l'application thérapeutique du P140 dans d'autres MAIs. / Sjögren's syndrome (SS) is one of the most common systemic autoimmune diseases (AIDs) in human. This disease is characterized by lymphocytic infiltration in the exocrine glands which leads to symptoms named dry eyes and dry mouth. There is no cure for SS currently. P140 peptide has been demonstrated to be an effective therapeutic tool in patients with systemic lupus erythematosus (SLE) and lupus mouse model. Autophagy is a conserved intracellular pathway that plays a central role in maintaining cellular homeostasis. In addition, autophagy has been demonstrated to be a mechanism of autoimmune regulation. The beneficial effects of P140 peptide in lupus seem to be closely related to its inhibitory effect on autophagy which is overactivated in lupus. However, the role of autophagy in SS is largely unknown. The aim of my thesis is: 1, to study the role of autophagy in SS and 2, to examine the possible effect of the P140 peptide in this disease. In this study, we first demonstrated the protective effects of P140 against SS in MRL/lpr mouse model, as evidenced by ameliorated inflammation, decreased lymphocyte infiltration in mouse salivary glands (SGs), as well as decreased levels of circulating autoantibodies. We also found that autophagy and lysosomes were defective in SGs of MRL/lpr mice and that P140 restored the autophagic flux and lysosomal acidity. These results suggest that defective autophagy and lysosome dysfunction may contribute to the pathology of SS and that the therapeutic effects of P140 may be related to its effect on autophagy and lysosomes. The results obtained in this study provide us valuable information about the pathogenesis of SS, and suggest that autophagy could be a potential therapeutic target in SS. Moreover, the protective effects of P140 in SS mouse model shed light on the therapeutic application of P140 in other AIDs.
12

Prevalência de Disfunção Temporomandibular e análise comparativa do perfil psicoemocional, da qualidade de vida e da presença de dores orofaciais em mulheres com Síndrome de Sjögren / Prevalence of Temporomandibular Disorder and comparative analysis of the psychoemotional profile, quality of life and the presence of orofacial pain in Sjögren\'s Syndrome women

Nunes, Thaís Borguezan 20 September 2016 (has links)
O objetivo do estudo foi avaliar a prevalência de Disfunção Temporomandibular e fazer uma análise comparativa do perfi l psicoemocional, da qualidade de vida e da presença de dores orofaciais em mulheres com Síndrome de Sjögren (SS) primária. Cinquenta e três pacientes do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) diagnosticadas de acordo com os critérios propostos pelo American-European Consensus Group (AECG) foram selecionadas e aceitaram participar da pesquisa. Foram aplicados os questionários RDC/TMD para diagnosticar a Disfunção Temporomandibular, DN4 para classifi car o tipo de dor quando presente, BDI para avaliar de forma global a intensidade e localização da dor presente e sua interferência nas atividades de vida diária, SF-36 para avaliar a percepção da paciente quanto ao seu estado geral e sua qualidade de vida, EADS- 21 para diagnosticar fenômenos de ansiedade, estresse e depressão e EPCD para verifi car os pensamentos catastrófi cos para a dor. As pacientes também foram classifi cadas de acordo com ESSDAI para avaliar a atividade da doença SS e de acordo com ESSPRI para avaliar os sintomas de fadiga, secura e dor. Segundo o questionário RDC/TMD, 49,1% das pacientes com SS têm dor miofascial, 9,37% têm deslocamento de disco e 13,2% têm artralgia, 50,9% têm dor na face, 58,5% têm dor de cabeça, 35,8% têm estalo, 17% têm crepitação, 45,3% têm bruxismo, 60,4% têm apertamento diurno e 41,5% têm zumbido. Quanto ao questionário BPI, 74,53% das pacientes relataram melhora da dor com o tratamento instituído. Quanto ao questionário DN4, 11,3% têm dor neuropática. Quanto ao questionário SF-36, todos os domínios tiveram pontuação menor que 50 pontos, exceto os Domínios Capacidade Funcional (52,45 pontos), Aspectos Sociais (60,57 pontos) e Saúde Mental (65,96 pontos). De acordo com o EADS-21, o Domínio Estresse teve maior média (6,02 pontos), seguido por Ansiedade (4,51 pontos) e Depressão (3,53 pontos). O Score EPCD foi de 1,26 pontos e a maioria dos pacientes (83%) teve baixa catastrofi zação. Cerca de 51% das pacientes têm baixa atividade da doença SS (Score ESSDAI =2,7) e 67,9% têm alto nível de sintoma incapacitante (Score ESSPRI>=5). O estudo mostrou que os principais fatores contribuintes para a pior qualidade de vida em pacientes com SS primária são fadiga, depressão, ansiedade, xerose, dor e estresse. / Sjögren\'s Syndrome (SS) is a chronic autoimmune disease with progressive evolution, whose clinical manifestations are extremely variable, aff ecting local and specifi c organs or presenting as a systemic condition. Dryness, pain, somatic and mental fatigue are the main symptoms in caucasian women aged between 40 to 60 years.The aim of this study was to evaluate the prevalence of Temporomandibular Disorders and make a comparative analysis of the psychoemotional profi le, quality of life and the presence of orofacial pain in women with primary Sjögren\'s Syndrome. Fifty-three patients of the Clinics Hospital of Medical School of University of São Paulo diagnosed according to the AECG criteria for primary SS were selected and examined with RDC/TMD to diagnose Temporomandibular Disorders, DN4 to diagnose neurophatic pain, BPI to assess globally the intensity and location of pain and how this symptom interferes with activities of daily living, SF-36 to evaluate the perception of the patient about their general health and quality of life, EADS-21 to diagnose anxiety, stress and depression and PCS to check the catastrophic thoughts for pain.The patients were also classifi ed according to ESSDAI to evaluate the activity of primary SS and to ESSPRI symptoms of fatigue, dryness and soreness. According to the RDC / TMD, 49.1% of patients with Sjögren\'s syndrome have myofascial pain, 9.37% have disc displacement and 13.2% have arthralgia; 50.9% have pain in the face, 58.5% headache, 35.8% clicking, 17% crepitus, 45.3% bruxism, 60.4% daytime clenching and 41.5% tinnitus. The BPI showed that 74.53% of patients reported improvement in pain with the treatment. According to DN4, 11.3% have neuropathic pain. As for the SF-36, all areas have lower scores 50 points, except the Functional Capacity (52.45 points), Social Aspects (60.57 points) and Mental Health (65.96 points). According to DASS-21, Stress had higher mean (6.02 points), followed by Anxiety (4.51 points) and Depression (3.53 points). The PCS score was 1.26 points and the majority of patients (83%) had low catastrophizing. Nearly 51% have low disease activity (Score ESSDAI = 2.7) and 67.9% has a high level of incapacitating symptom (Score ESSPRI>=5). The study showed that the main factors contributing to the worst quality of life in patients with primary Sjögren\'s Syndrome are fatigue, depression, anxiety, xerosis, pain and stress.
13

Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases

Lövgren, Tanja January 2006 (has links)
<p>Patients with systemic lupus erythematosus (SLE) have elevated levels of interferon (IFN)-α in blood and IFN-α-producing cells in tissues. In the present thesis, we investigate the mechanisms behind the upregulated IFN-α-production in SLE and also show that the IFN-α system is activated in primary Sjögren’s syndrome (pSS), with IFN-α-producing cells in the major affected organ, the salivary glands. The IFN-α is a type I IFN, a family of cytokines counteracting especially viral infections, by acting directly on infected cells, and via many immunomodulatory effects. The latter may also contribute to autoimmune processes.</p><p>The type I IFNs are usually produced upon recognition of microbial structures. In SLE, however, DNA-containing immune complexes (ICs) that induce IFN-α production are found. Many autoantibodies in SLE and pSS are directed to nucleic acids or to DNA/RNA-binding proteins. We show that also RNA in complex with autoantibodies from SLE or pSS patients (RNA-IC) induces IFN-α-production. The RNA could be either in the form of RNA-containing material released from apoptotic or necrotic cells or as a pure RNA-containing autoantigen, the U1 small nuclear ribonucleoprotein particle. </p><p>The IFN-α-production induced by RNA-IC occurred in plasmacytoid dendritic cells (PDCs), also termed natural IFN-producing cells (NIPCs), via binding to Fcγ-receptor IIa, endocytosis and triggering of Toll-like receptors (TLRs), probably TLR7 and TLR9. The RNA-IC may also have other effects, and we found that they induce prostaglandin E2 (PGE2) production in monocytes and tumor necrosis factor (TNF)-α in both monocytes and NIPC/PDC. The PGE2 downregulated the IFN-α induction in NIPC/PDC, and the IFN-α induction was increased in monocyte-depleted cell cultures. </p><p>The findings presented in this thesis aids in the understanding of the mechanisms behind the activated IFN-α system in SLE and other autoimmune diseases, and shows that also pSS is one of these diseases.</p>
14

Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases

Lövgren, Tanja January 2006 (has links)
Patients with systemic lupus erythematosus (SLE) have elevated levels of interferon (IFN)-α in blood and IFN-α-producing cells in tissues. In the present thesis, we investigate the mechanisms behind the upregulated IFN-α-production in SLE and also show that the IFN-α system is activated in primary Sjögren’s syndrome (pSS), with IFN-α-producing cells in the major affected organ, the salivary glands. The IFN-α is a type I IFN, a family of cytokines counteracting especially viral infections, by acting directly on infected cells, and via many immunomodulatory effects. The latter may also contribute to autoimmune processes. The type I IFNs are usually produced upon recognition of microbial structures. In SLE, however, DNA-containing immune complexes (ICs) that induce IFN-α production are found. Many autoantibodies in SLE and pSS are directed to nucleic acids or to DNA/RNA-binding proteins. We show that also RNA in complex with autoantibodies from SLE or pSS patients (RNA-IC) induces IFN-α-production. The RNA could be either in the form of RNA-containing material released from apoptotic or necrotic cells or as a pure RNA-containing autoantigen, the U1 small nuclear ribonucleoprotein particle. The IFN-α-production induced by RNA-IC occurred in plasmacytoid dendritic cells (PDCs), also termed natural IFN-producing cells (NIPCs), via binding to Fcγ-receptor IIa, endocytosis and triggering of Toll-like receptors (TLRs), probably TLR7 and TLR9. The RNA-IC may also have other effects, and we found that they induce prostaglandin E2 (PGE2) production in monocytes and tumor necrosis factor (TNF)-α in both monocytes and NIPC/PDC. The PGE2 downregulated the IFN-α induction in NIPC/PDC, and the IFN-α induction was increased in monocyte-depleted cell cultures. The findings presented in this thesis aids in the understanding of the mechanisms behind the activated IFN-α system in SLE and other autoimmune diseases, and shows that also pSS is one of these diseases.
15

Changes of the immune system in the pathogenesis of primary Sjögren's syndrome / Imuninės sistemos pokyčiai pirminio Sjögreno sindromo patogenezėje

Sūdžius, Gintaras 20 December 2013 (has links)
There are many studies done to determine factors what can cause susceptibility to Sjögren's syndrome. Despite intensive research of the immune system, the model of the Sjögren's syndrome pathogenesis is not completely clear. Lymphopenia is a common symptom found in the pSS patients. Numerous studies are performed in order to determine the causes of lymphopenia, but there is a lack of detailed studies to reveal which cell population counts increase or decrease. Scarce studies are done to associate the changes in the immune cell population and the expression of humoral factors in the peripheral blood of pSS patients. The aim of dissertation work was to investigate the changes of the components of the systemic immune response in the peripheral blood of patients with primary Sjögren's syndrome (pSS) with different manifestations of the disease. In this study, a comprehensive analysis of B, NK and T cell populations and humoral factors in the peripheral blood of pSS patients was performed. For the first time the expression of CD57 and CD27 markers on CD8+ T cell population was analyzed. For the first time Th17/Th1-like cells in the peripheral blood of pSS patients were identified and imbalance in the distribution of T helper cell population was revealed. It can be explained by the significant increase of Th17/Th1-like lymphocyte population. The levels of IL-27 and IL-35 in sera of pSS patients were measured (not in the model system) for the first time as well. Primary Sjögren’s... [to full text] / Pastaruoju metu ypatingai intensyviai tiriami veiksniai, kurie gali paskatinti išsivystyti sindromą. Nepaisant intensyvių imuninės sistemos tyrimų, Sjögreno sindromo (SS) patogenezės modelis nėra pilnai aiškus. Pirminiu Sjögreno sindromu (pSS) sergančiųjų kraujyje būdinga limfopenija. Siekiant nustatyti to priežastis atlikta nemažai tyrimų, tačiau trūksta detalesnių tyrimų, atskleidžiančių kokių ląstelių populiacijų padaugėja/sumažėja, bei kokių ląstelių subpopuliacijų sąskaita, tai vyksta. Trūksta tyrimų, kurie susietų imuninės sistemos ląstelių populiacijų pokyčius ir humoralinių veiksnių raišką. Šio darbo tikslas buvo įvertinti pirminiu Sjögreno sindromu sergančių pacientų su skirtinga ligos raiška sisteminio imuninio atsako komponentų pokyčius periferiniame kraujyje. Darbe buvo atlikta kompleksinė, detali B, NK, T limfocitų populiacijų, jų subpopuliacijų ir humoralinių veiksnių analizė sergančių pSS pacientų periferiniame kraujyje. Pirmą kartą pSS pacientų periferiniame kraujyje tirtos CD8+ limfocitų populiacijos pagal jų ekspresuojamus CD57 ir CD27 žymenis. Pirmą kartą pSS pacientuose, o ne modelinėse sistemose, ištirta IL-27 ir IL-35 raiška kraujo serume. Pirmą kartą identifikuoti Th17/Th1-like limfocitai pSS pacientų periferiniame kraujyje. Nustatyta, kad pacientų sergančių pSS periferiniame kraujyje Th limfocitų populiacijų pusiausvyra yra sutrikusi, ir to priežastimi reikšmingas Th17/Th1-like limfocitų populiacijos pagausėjimas. Sergantiesiems pirminiu Sjögreno... [toliau žr. visą tekstą]
16

Imuninės sistemos pokyčiai pirminio Sjögreno sindromo patogenezėje / Changes of the immune system in the pathogenesis of primary Sjögren's syndrome

Sūdžius, Gintaras 20 December 2013 (has links)
Pastaruoju metu ypatingai intensyviai tiriami veiksniai, kurie gali paskatinti išsivystyti sindromą. Nepaisant intensyvių imuninės sistemos tyrimų, Sjögreno sindromo (SS) patogenezės modelis nėra pilnai aiškus. Pirminiu Sjögreno sindromu (pSS) sergančiųjų kraujyje būdinga limfopenija. Siekiant nustatyti to priežastis atlikta nemažai tyrimų, tačiau trūksta detalesnių tyrimų, atskleidžiančių kokių ląstelių populiacijų padaugėja/sumažėja, bei kokių ląstelių subpopuliacijų sąskaita, tai vyksta. Trūksta tyrimų, kurie susietų imuninės sistemos ląstelių populiacijų pokyčius ir humoralinių veiksnių raišką. Šio darbo tikslas buvo įvertinti pirminiu Sjögreno sindromu sergančių pacientų su skirtinga ligos raiška sisteminio imuninio atsako komponentų pokyčius periferiniame kraujyje. Darbe buvo atlikta kompleksinė, detali B, NK, T limfocitų populiacijų, jų subpopuliacijų ir humoralinių veiksnių analizė sergančių pSS pacientų periferiniame kraujyje. Pirmą kartą pSS pacientų periferiniame kraujyje tirtos CD8+ limfocitų populiacijos pagal jų ekspresuojamus CD57 ir CD27 žymenis. Pirmą kartą pSS pacientuose, o ne modelinėse sistemose, ištirta IL-27 ir IL-35 raiška kraujo serume. Pirmą kartą identifikuoti Th17/Th1-like limfocitai pSS pacientų periferiniame kraujyje. Nustatyta, kad pacientų sergančių pSS periferiniame kraujyje Th limfocitų populiacijų pusiausvyra yra sutrikusi, ir to priežastimi reikšmingas Th17/Th1-like limfocitų populiacijos pagausėjimas. Sergantiesiems pirminiu Sjögreno... [toliau žr. visą tekstą] / There are many studies done to determine factors what can cause susceptibility to Sjögren's syndrome. Despite intensive research of the immune system, the model of the Sjögren's syndrome pathogenesis is not completely clear. Lymphopenia is a common symptom found in the pSS patients. Numerous studies are performed in order to determine the causes of lymphopenia, but there is a lack of detailed studies to reveal which cell population counts increase or decrease. Scarce studies are done to associate the changes in the immune cell population and the expression of humoral factors in the peripheral blood of pSS patients. The aim of dissertation work was to investigate the changes of the components of the systemic immune response in the peripheral blood of patients with primary Sjögren's syndrome (pSS) with different manifestations of the disease. In this study, a comprehensive analysis of B, NK and T cell populations and humoral factors in the peripheral blood of pSS patients was performed. For the first time the expression of CD57 and CD27 markers on CD8+ T cell population was analyzed. For the first time Th17/Th1-like cells in the peripheral blood of pSS patients were identified and imbalance in the distribution of T helper cell population was revealed. It can be explained by the significant increase of Th17/Th1-like lymphocyte population. The levels of IL-27 and IL-35 in sera of pSS patients were measured (not in the model system) for the first time as well. Primary Sjögren’s... [to full text]
17

Les lymphocytes B producteurs d'interleukine 10 chez les sujet sains et chez les patients atteints de Polyarthrite rhumatoïde ou de syndrome de Sjögren : comment fonctionnent-ils et comment optimiser leur nombre et leurs fonctions ? / IL-10 producing B cells in healthy subjects and patients with rheumatoid arthritis or Sjögren's syndrome : how do they work and how to optimize their number and functions ?

Mielle, Julie 16 November 2018 (has links)
La polyarthrite Rhumatoïde (PR) et le syndrome de Sjögren primitif (pSS) sont des deux maladies auto-immunes invalidantes pour lesquelles il n’existe à ce jour pas de traitement permettant la guérison des patients. Bien que les lymphocytes B soient impliqués dans le développement ces pathologies, l’existence de lymphocytes B capables de réguler l’inflammation est maintenant largement reconnue. Ces lymphocytes B régulateurs (Bregs) sont capables à la fois d’induire des lymphocytes T régulateurs et d’empêcher le développement de lymphocytes T pro-inflammatoires. In vivo, le transfert de ces Bregs est protecteur dans de nombreux modèles murins de maladies auto-immunes suggérant ainsi que promouvoir ces Bregs serait prometteur pour traiter les patients atteints de PR ou pSS. Cependant, il n’existe à ce jour pas de marqueur spécifique des Bregs, ce qui complique leur étude. Comme leurs fonctions régulatrices sont principalement médiées par l’IL-10, une cytokine anti-inflammatoire, les Bregs peuvent être définis par leur capacité à produire de l’IL-10 après activation par des composés bactériens, notamment CpG, motifs mimant l’ADN microbien. Ces Bregs sont appelés B10+. Toutefois, les fonctions de ces B10+ ne sont pas bien définies chez l’homme. Ainsi, nous ignorons si la seule production d’IL-10 est suffisante pour définir les Bregs.Cette thèse a donc pour premier objectif de définir les fonctions les B10+ stimulés par CpG chez les individus sains et chez les patients, afin de déterminer si la production d’IL-10 était un bon marqueur des Bregs. Nous avons montré que les B10+ induits par CpG étaient capables d’induire des lymphocytes T régulateurs (Tregs et Tr1) mais ne diminuaient pas la proportion de lymphocytes T pro-inflammatoires (Th1 et LT-TNFα+). Chez les patients PR et pSS, les B10+ induisaient des Tregs et Tr1 mais chez les patients PR, ils induisaient également des Th1. Ces résultats suggèrent que la production d’IL-10 seule ne suffit pas à récapituler toutes les fonctions régulatrices des Bregs, et que le stimulus CpG impacte probablement leur fonctions.Pour mieux comprendre les mécanismes contrôlant la production d’IL-10 des lymphocytes B et pouvoir proposer d’autres stimuli pour les générer, nous avons étudié l’effet de l’acétate, un composé produit par les bactéries commensales, sur la génération des B10+. L’acétate était capable d’induire des B10+ chez la souris et chez l’homme. D’autre part, nous avons également étudié le métabolisme cellulaire de ces B10+. Nous avons montré que la glutamine était un nutriment essentiel à la génération des B10+ et à leurs fonctions régulatrices. En définitive, ce travail a permis de définir les fonctions des B10+ induits par CpG, de caractériser leur métabolisme et de proposer de un stimulus alternatif pour générer les B10+. / Rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) are two debilitating autoimmune diseases. There is currently no treatment to cure patients. Although B lymphocytes are involved in the development of these pathologies, the existence of B cells capable of regulating inflammation is now widely recognized. These regulatory B cells (Bregs) are able of both inducing regulatory T cells and preventing the development of pro-inflammatory T cells. In vivo, the transfer of these Bregs is protective in many mouse models of autoimmune diseases thus suggesting that promoting these Bregs would be promising for treating patients with RA or pSS. However, there is currently no specific marker for Bregs, which largely hinders their study. Since their regulatory functions are mainly mediated by IL-10, an anti-inflammatory cytokine, Bregs can be defined by their ability to produce IL-10 after activation by bacterial compounds, including CpG. Those Bregs are called B10+ cells. However, the functions of these B10+ cells are not well defined in humans. We do not know whether IL-10 production is a sufficient marker to define Bregs.The main goal of this thesis was to define CpG-induced B10+ cell functions in healthy individuals and patients, to determine whether IL-10 production was a good marker for Bregs. We showed that CpG-induced B10+ cells were able to induce regulatory T cells (Tregs and Tr1) but did not decrease the proportion of pro-inflammatory T cells (Th1 and LT-TNFα +). In RA and pSS patients, B10+ cells induced Tregs and Tr1 but in RA patients they also induced Th1. These results shows that IL-10 production alone does not recapitulate all the Breg functions and that CpG stimulation might impact their functions.To better understand the mechanisms controlling IL-10 production by B cells, and to be able to propose other stimuli to generate them, we studied the effect of acetate, a compound produced by commensal bacteria, on B10+ cells generation. Acetate was able to induce B10+ cells in mice and humans. Besides, we studied B10+ cell metabolism. We have showed that glutamine was an essential nutrient for B10+ cell generation and for their regulatory functions. This work has made it possible to define the CpG-induced B10+ cell functions, to characterize their metabolism and to propose an alternative stimulus to generate B10+ cells.
18

Buněčná a molekulární charakterizace selhaných transplantátů lidské rohovky. Role matrix metaloproteináz při opakované keratolýze lidské rohovky. / Cell and Molecular Characterization of Failed Human Corneal Grafts. The Role of Matrix Metalloproteinases in Recurrent Corneal Melting.

Brejchová, Kristýna January 2011 (has links)
The aim of this work was to investigate the contribution of matrix metalloproteinases (MMPs) to recurrent corneal melting. Twenty three melted corneas from seven patients were separated into three groups: a) patients with primary Sjögren's syndrome, b) those with rheumatoid arthritis and c) those with other corneal melting underlying pathologies. Eleven cadaverous corneas served as controls. The presence of MMP-1, -2, -3, -7, -8, -9, and -13 was detected using indirect enzyme immunohistochemistry. The active forms of MMP-2 and -9 and MMP- 3 and -7 were examined by gelatin and casein zymography, respectively. The concentrations of active MMP-1 and -3 were measured using activity assays. Increased immunostaining intensity for MMP-1, -2, -3, -7, -8 and -9 was shown in the corneal epithelium and the stroma of almost all melted corneas from all three groups compared to the negative or slightly positive staining of the controls. In the endothelium, immunostaining for MMP-2 and MMP-9 was increased in most specimens of groups II and III and group I, respectively. A markedly higher level of active MMP-2 was detected in six, and active MMP-9 in all, pathologic specimens compared to the controls. In contrast to the completely negative controls, the proenzymes of MMP-3 and -7 were detected in almost all melted...
19

Role of salivary gland epithelial cells in the differentiation and activation of T lymphocytes in primary Sjögren's syndrome / Etude du rôle des cellules épithéliales des glandes salivaires dans la différenciation et l'activation des lymphocytes T au cours du Syndrome de Sjögren primitif

Gong, Ya-Zhuo 13 September 2013 (has links)
Le syndrome de Sjögren primitif (SJp) est une pathologie auto-immune caractérisée par une sécheresse occulobuccale, un infiltrat lymphocytaire des glandes salivaires, ainsi qu'une production d'auto-anticorps. Les cellules épithéliales salivaires (SGEC) des patients atteints de SSp expriment les molécules impliquées dans les réponses immunitaires et jouent le rôle des cellules présentatrices d’antigènes. Les lymphocytes T folliculaires (LTf) jouent un rôle important en activant les lymphocytes B via la sécrétion d’interleukine (IL)-21. Une augmentation de la proportion de LTf est observée dans le sang des patients ayant un SJp. Nous avons fait l’hypothèse que les SGECs des patients pouvaient induire la différenciation des lymphocytes T naïfs (LTn) en LTf. Nous avons montré que les SGECs sont capables d’induire la différenciation des LTn en LTf via des facteurs solubles tel l’IL-6. La sécrétion d’IL-21 par les LTf nécessite un contact cellulaire impliquant en partie ICOSL.La voie de costimulation OX40/OX40L est impliquée dans plusieurs maladies autoimmunes. Les polymorphismes d’OX40L sont une prédisposent au SJp. Nous avons étudié le rôle pathogène de la voie OX40/OX40L chez les patients SJp. Notre résultats ont montrés une surexpression d’OX40L et d’OX40 dans les glandes salivaires des patients atteint de SJp. Les cocultures des LTn avec les SS SGECs ou contrôle SGECs augmentent l'expression d’OX40 par les LT. Les SS SGECs favorisent la survie et la prolifération des LT via la voie d’OX40/OX40L. Ces résultats démontrent l'implication d’OX40 et d’OX40L dans la pathogénie du SJp et confirment le rôle important des SGECs dans l’épithelite auto-immune du SJp. / The primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by dry mouth and dry eyes. Salivary gland epithelial cells (SGECs) of patients with pSS express the molecules involved in immune responses and act as antigen presenting cells. Follicular helper T cells (Tfh) secrete IL-21 whose augmented secretion is a hallmark of several autoimmunediseases. Here we investigated whether SGECs were capable to induce Tfh differentiation. We report that IL-6 and ICOSL expression by SGECs contributes to naïve CD4+ T differentiation into Tfh cells, as evidenced by their acquisition of a specific phenotype, characterized by Bcl-6, ICOS and CXCR5 expression and IL-21 secretion, but also but by their main functional feature: the capacity to enhance B lymphocytes survival. OX40/OX40L interaction is a pivotal costimulatory pathway. Polymorphisms of OX40L are involved in the genetic predisposition to pSS. We therefore investigated the pathogenic role of OX40/OX40L pathway in pSS. We demonstrated that the proportion of circulating CD4+ T cells expressing OX40 was elevated in patients with pSS and correlated with systemic disease activity. In salivary glands of patients with pSS, epithelial cells overexpressed OX40L and the expression of OX40L and OX40 was respectively evidenced on infiltrating B and T cells. Coculture of T cells with SGECs increased the expression of OX40 by CD4+ T cells promoted T cell survival and proliferation through OX40/OX40L interaction. These studies demonstrate emphasizes unknown pathogenic roles of SGECs and suggests that Tfh, IL-21 and OX40L might be therapeutic targets in pSS.
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Prevalência de Disfunção Temporomandibular e análise comparativa do perfil psicoemocional, da qualidade de vida e da presença de dores orofaciais em mulheres com Síndrome de Sjögren / Prevalence of Temporomandibular Disorder and comparative analysis of the psychoemotional profile, quality of life and the presence of orofacial pain in Sjögren\'s Syndrome women

Thaís Borguezan Nunes 20 September 2016 (has links)
O objetivo do estudo foi avaliar a prevalência de Disfunção Temporomandibular e fazer uma análise comparativa do perfi l psicoemocional, da qualidade de vida e da presença de dores orofaciais em mulheres com Síndrome de Sjögren (SS) primária. Cinquenta e três pacientes do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) diagnosticadas de acordo com os critérios propostos pelo American-European Consensus Group (AECG) foram selecionadas e aceitaram participar da pesquisa. Foram aplicados os questionários RDC/TMD para diagnosticar a Disfunção Temporomandibular, DN4 para classifi car o tipo de dor quando presente, BDI para avaliar de forma global a intensidade e localização da dor presente e sua interferência nas atividades de vida diária, SF-36 para avaliar a percepção da paciente quanto ao seu estado geral e sua qualidade de vida, EADS- 21 para diagnosticar fenômenos de ansiedade, estresse e depressão e EPCD para verifi car os pensamentos catastrófi cos para a dor. As pacientes também foram classifi cadas de acordo com ESSDAI para avaliar a atividade da doença SS e de acordo com ESSPRI para avaliar os sintomas de fadiga, secura e dor. Segundo o questionário RDC/TMD, 49,1% das pacientes com SS têm dor miofascial, 9,37% têm deslocamento de disco e 13,2% têm artralgia, 50,9% têm dor na face, 58,5% têm dor de cabeça, 35,8% têm estalo, 17% têm crepitação, 45,3% têm bruxismo, 60,4% têm apertamento diurno e 41,5% têm zumbido. Quanto ao questionário BPI, 74,53% das pacientes relataram melhora da dor com o tratamento instituído. Quanto ao questionário DN4, 11,3% têm dor neuropática. Quanto ao questionário SF-36, todos os domínios tiveram pontuação menor que 50 pontos, exceto os Domínios Capacidade Funcional (52,45 pontos), Aspectos Sociais (60,57 pontos) e Saúde Mental (65,96 pontos). De acordo com o EADS-21, o Domínio Estresse teve maior média (6,02 pontos), seguido por Ansiedade (4,51 pontos) e Depressão (3,53 pontos). O Score EPCD foi de 1,26 pontos e a maioria dos pacientes (83%) teve baixa catastrofi zação. Cerca de 51% das pacientes têm baixa atividade da doença SS (Score ESSDAI =2,7) e 67,9% têm alto nível de sintoma incapacitante (Score ESSPRI>=5). O estudo mostrou que os principais fatores contribuintes para a pior qualidade de vida em pacientes com SS primária são fadiga, depressão, ansiedade, xerose, dor e estresse. / Sjögren\'s Syndrome (SS) is a chronic autoimmune disease with progressive evolution, whose clinical manifestations are extremely variable, aff ecting local and specifi c organs or presenting as a systemic condition. Dryness, pain, somatic and mental fatigue are the main symptoms in caucasian women aged between 40 to 60 years.The aim of this study was to evaluate the prevalence of Temporomandibular Disorders and make a comparative analysis of the psychoemotional profi le, quality of life and the presence of orofacial pain in women with primary Sjögren\'s Syndrome. Fifty-three patients of the Clinics Hospital of Medical School of University of São Paulo diagnosed according to the AECG criteria for primary SS were selected and examined with RDC/TMD to diagnose Temporomandibular Disorders, DN4 to diagnose neurophatic pain, BPI to assess globally the intensity and location of pain and how this symptom interferes with activities of daily living, SF-36 to evaluate the perception of the patient about their general health and quality of life, EADS-21 to diagnose anxiety, stress and depression and PCS to check the catastrophic thoughts for pain.The patients were also classifi ed according to ESSDAI to evaluate the activity of primary SS and to ESSPRI symptoms of fatigue, dryness and soreness. According to the RDC / TMD, 49.1% of patients with Sjögren\'s syndrome have myofascial pain, 9.37% have disc displacement and 13.2% have arthralgia; 50.9% have pain in the face, 58.5% headache, 35.8% clicking, 17% crepitus, 45.3% bruxism, 60.4% daytime clenching and 41.5% tinnitus. The BPI showed that 74.53% of patients reported improvement in pain with the treatment. According to DN4, 11.3% have neuropathic pain. As for the SF-36, all areas have lower scores 50 points, except the Functional Capacity (52.45 points), Social Aspects (60.57 points) and Mental Health (65.96 points). According to DASS-21, Stress had higher mean (6.02 points), followed by Anxiety (4.51 points) and Depression (3.53 points). The PCS score was 1.26 points and the majority of patients (83%) had low catastrophizing. Nearly 51% have low disease activity (Score ESSDAI = 2.7) and 67.9% has a high level of incapacitating symptom (Score ESSPRI>=5). The study showed that the main factors contributing to the worst quality of life in patients with primary Sjögren\'s Syndrome are fatigue, depression, anxiety, xerosis, pain and stress.

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