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.

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.

Orientador: Cláudia Valéria Seullner Brandão / Resumo: O objetivo deste estudo foi comparar e avaliar a aplicação de célula tronco mesenquimal de tecido adiposo (CTM-TA) e plasma rico em plaquetas aquecido alogênico (PRP-AA) perilacrimal em cães com ceratoconjuntivite seca (CCS), bem como, se há diferença na resposta segundo o grau de gravidade da afecção. Foram analisados 20 cães com produção lacrimal <15mm/min e distribuídos aleatoriamente em dois grupos (n=10). O grupo 1 tratado com CTM-TA (5x106 e 3x106 células) (GCTM-TA) e com grupo 2 PRP-AA (0,7mL e 0,3mL) (GPRP-AA), ambos injetados perilacrimal nas glândulas lacrimal principal e da terceira pálpebra, respectivamente. Todos os olhos foram avaliados em quatro momentos (M0 M15, M30, M60 dias). As variáveis avaliadas foram: osmolaridade da lágrima; teste lacrimal de Schirmer (TLS); sensibilidade corneal; tempo de ruptura do filme lacrimal (TRFL); pressão intraocular; espessura corneal; e biopsia da conjuntiva bulbar, além das variáveis clínico-oftalmológicas. Houve melhora nos dois grupos a partir de M15 (p<0,05) na qualidade do filme lacrimal, avaliada por meio da osmolaridade e TRFL, sem diferença entre os grupos. A produção de lágrima aumentou, entretanto notou-se diferença significativa nos animais com CCS discreta no GPRP-AA a partir do M30, e nos cães com CCS grave no GCTM-TA a partir do M30 e no GPRP-AA a partir do M60. Verificou-se melhora dos sinais clínicos da inflamação em ambos os grupos. Aplicação única perilacrimal de CTM-TA e PRP aquecido alogênicos normaliza a ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aim of the study was to compare and evaluate the application of allogenic mesenchymal stem cell adipose tissue derived (MSCs-AD) and inativate platelet-rich plasma allogenic (PRP-IA), perilacrimal in dogs with keratoconjunctivitis sicca (KCS), and if there is difference in the response according to the degree of severity of the condition. Twenty dogs with lacrimal production <15mm/min randomly assigned to two groups were used. Group treated with MSCs-AD (5x106 and 3x106) (GMSCs-AD) and with PRP-IA (0.7ml and 0.3ml) (GPRP-IA), both intralacrimal in the main lacrimal glands and third eyelid, respectively. The eyes were evaluated in four moments after application (M0 M15, M30, M60). The variables evaluated were: tear osmolarity e; Schirmer's tear test (STT); sensitivity corneal; tear film break time (TBUT); intraocular pressure; corneal thickness; and biopsy of the bulbar conjunctiva, in addition to clinical-ophthalmologic variables. There was improvement in two groups at M15 (p <0.05) on tear film quality, assessed by osmolarity and TBUT, with there was no difference between groups. STT increased, however, statistical difference was only observed in animals with mild KCS in the GPRP-IA from the M30 and in the intense KCS at M30 in the G MSCs-AD and at M60 in the GPRP-IA. There was an improvement in the clinical signs of inflammation in both groups. The unique Intralacrimal application of MSCs-AD and PRP-IA normalizes tear film quality and improves clinical signs of inflamma... (Complete abstract click electronic access below) / Doutor

<p>Primary Sjögren's syndrome (pSS) is a chronic inflammatory connective tissue disease of unknown etiology. The disease primarily involves salivary and lacrimal glands which results in oral and ocular dryness (sicca symptoms). A wide spectrum of extraglandular features from various organs may be seen. </p><p>In this thesis, the frequency of psychiatric symptoms in women with primary Sjögren's syndrome was studied and an attempt was made to assess how these symptoms might influence their well being and quality of life. The main finding was that the women with pSS suffered significantly more often from symptoms of anxiety and depression when compared with age matched, healthy females and female patients with rheumatoid arthritis. The physical and mental well-being of the patients with pSS was significantly reduced compared to patient controls. </p><p>The possible link of psychiatric symptoms to the altered function of the hypothalamic-pituitary-gonadal axis and adrenal androgen secretion was elucidated. Women with pSS have intact cortisol synthesis but reduced serum concentrations of dehydroepiandrosterone sulphate (DHEA-S) (p<0.05) and an increased cortisol/DHEA-S ratio (p<0.05), compared to healthy controls. These findings may reflect a constitutional or disease-meditated influence on adrenal steroid synthesis. Positive correlation was found between DHEA-S serum levels and quality of sexual life (p<0.01) and mental well-being (p<0.01) in women with pSS. </p>

Primary Sjögren's syndrome (pSS) is a chronic inflammatory connective tissue disease of unknown etiology. The disease primarily involves salivary and lacrimal glands which results in oral and ocular dryness (sicca symptoms). A wide spectrum of extraglandular features from various organs may be seen. In this thesis, the frequency of psychiatric symptoms in women with primary Sjögren's syndrome was studied and an attempt was made to assess how these symptoms might influence their well being and quality of life. The main finding was that the women with pSS suffered significantly more often from symptoms of anxiety and depression when compared with age matched, healthy females and female patients with rheumatoid arthritis. The physical and mental well-being of the patients with pSS was significantly reduced compared to patient controls. The possible link of psychiatric symptoms to the altered function of the hypothalamic-pituitary-gonadal axis and adrenal androgen secretion was elucidated. Women with pSS have intact cortisol synthesis but reduced serum concentrations of dehydroepiandrosterone sulphate (DHEA-S) (p&lt;0.05) and an increased cortisol/DHEA-S ratio (p&lt;0.05), compared to healthy controls. These findings may reflect a constitutional or disease-meditated influence on adrenal steroid synthesis. Positive correlation was found between DHEA-S serum levels and quality of sexual life (p&lt;0.01) and mental well-being (p&lt;0.01) in women with pSS.

This dissertation examines Lennart Sjögren’s conception of life as revealed through his poetry and other written documents. Light is shed on his writings in three chapters, with an Introduction that opens the investigations, and a Conclusion that sums up the findings. His collection of poetry Ur männisovärlden (2008, From the world of the living) is commented upon in an epilogue. Chapter Two analyses the collection Havet (1974, The Sea), focussing on Sjögren’s view of nature and his imagery. A religious tone can be apparent throughout the poems. In earlier centuries, poems about migratory birds often gained in authenticity via their Christian context. In a secularised age, ecological insights add to the credibility of the poems. Chapter Three is an analysis and interpretation of Sjögren’s collection of poems Fågeljägarna (1997, The Bird Catchers), as well as of the intra- and intertexts that the reader meets in his writings and that, for various reasons, serve to make Sjögren’s poetic voice so distinctive. In a series of subsections the uniqueness of Fågeljägarna is defined by means of a comparison with ecology, secularisation (secularism), nihilism, religion and mythology. In addition, there is a discussion of the “poetry of place” and a final analysis of what unites and divides Sjögren and K. E. Løgstrup, regarding a poetic understanding of life. Independent of the ideological direction that is identi-fied, this cycle of poems is marked by an elegiac mood. The poem “Dagen före plöjarens kväll” (1984, “The Day before the Plough-man’s Evening”) from the eponymous collection of poems is an example of an ekphrasis (a transformation of images). Chapter Four makes a close reading of this poem, for which Pieter Bruegel the Elder’s picture “Landscape with the Fall of Icarus” is a model. Four interpretative hypotheses are advanced: a moral, ontological, theological and a folkloristic one. The interpretation of the poem points out that the dialogue is not merely the poet’s private affair – the reader is also invited to take an active part in the discussion, now with the picture and the ekphrasis as prerequisites. The chapter contains a further three analyses of ekphrasis dealing with other poems from the collection Dagen före plöjarens kväll.

Le syndrome de Sjögren primitif (SSp) est une maladie auto-immune (MAI) systémique ayant des caractéristiques communes avec le lupus érythémateux. Ces caractéristiques incluent des mécanismes physiopathologiques et des facteurs de predispositions génétiques. Notre équipe et d'autres groupes ont pu mettre en evidence une signature interféron (IFN) dans les glandes salivaires et les PBMCs de patients ayant un SSp. Cette découverte a permis de mettre en évidence de nouvelles voies à explorer dans la pathogénie du SLE et SSp en permettant la focalisation des recherches sur le rôle de l'immunité innée et de la voie IFN.Nous avons confirmé le rôle de 2 gènes importants dans le SSp, impliqués dans les voies des IFN. Le premier est IRF5 sur la voie IFN de type I et STAT4 sur la voie IFN de type II. Nous avons pu mettre en évidence une fonctionnalité de l'allèle à risque d'IRF5 (Polymorphisme Indel situé dans le promoteur). Concernant STAT4, son expression n'était pas altérée par le SNP associé à la maladie. Toutefois, l'ARNm de STAT4 était corrélé à l'expression des gènes IFN de type I. Les dérégulations épigénétique pourraient jouer un rôle important dans la pathogénie de nombreuses MAI, en particulier la méthylation de l'ADN qui est hautement liée à l'extinction de l'expression des gènes. Nous avons étudié la méthylation du promoteur d'IRF5 et nous n'avons pas trouvé de régulation de ce promoteur par le méthylation. Une analyse de la méthylation avec une approche globale du méthylome est en cours dans notre équipe et permettra d'identifier de gènes cibles d'une dérégulation épigénétique pouvant être impliqués dans les MAI.Nous avons essayé de comprendre la relation entre STAT4 et gènes IFN de type I. Ainsi, nous rapportons que l'IL-12 induit spécifiquement l'IFN de type I par intéraction entre deux partenaires cellulaires, les lymphocytes T CD4+ et les cellules dendritiques plasmacytoïdes. Ces résultats pourraient expliquer l'implication des polymorphismes de STAT4 dans les MAI dépendantes de l'IFN de type I. Ces résultats suggèrent également que les MAI dépendantes des IFN de type I et II ne s'opposent pas. Elles seraient seulement le Yin et le Yang d'un facteur d'activation commun, STAT4, capable d'induire les IFNs de type I et II.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, which primarily affects middle-aged women. The liver histology is characterized by inflammation and destruction of the intrahepatic bile ducts as well as a high frequency of granuloma. Although the etiology is unknown, the occurrence of associated multiorganic abnormalities such as Sjogren's syndrome, scleroderma, rheumatic disorders and thyroid gland diseases have been cited as evidence favouring an autoimmune background. Addison and Gull in 1851 described the first patient with jaundice and xanthomatosis. PBC was first mentioned in 1876 as an entity by Hanot. PBC was considered to be a rare disease until in 1973 Sherlock and Scheuer described 100 patients. Since then a greater awareness of the disease combined with a wider use of laboratory screening methods has led to the discovery of an increasing number of patients with PBC. In an epidemiological investigation of PBC in the northern part of Sweden a point prevalence of 151 per 106 was found, which is the highest so far reported, and the mean annual incidence amounted to 13.3 per 106. Asymptomatic PBC was present in more than one third of the patients which is consistent with the finding in other epidemiological investigations and is supposed to explain the higher prevalence of PBC and the better prognosis. Nevertheless 25 patients died during the study period, 14 as a direct consequence of the liver disease. Chronic intrahepatic cholestasis has been reported in sarcoidosis and, moreover, a high frequency of liver granuloma is found. The implication of the present study is that a negative Kveim test in combination with positive mitochondrial antibodies is accurate in differentiating PBC from sarcoidosis. Multisystem involvement is frequently observed in PBC and the present study confirms this. In the prospective investigation of 26 PBC patients 50 % had arthropathy considered to be associated with PBC. Rheumatoid arthritis was found in 5 patients, who all had symptoms of liver disease in addition. Lung function impairment was present in 56% (1 asymptomatic PBC). Most commonly a reduced diffusion capacity was found (36%). Bronchial asthma was present in three patients, and severe lung emphysema in one. Features of Sjogren's syndrome was found in 73% (3 asymptomatic PBC). In 6 patients keratoconjunctivitis sicca (KCS) was evident with the rose bengal test demonstrating corneal staining and a Schirmer test of less than 5 mm. Radiological findings of sialectasia were demonstrated in 6 patients, of whom 5 had KCS as well. The ultimate treatment in PBC is liver transplantation and to calculate the need for that, good epidemiological surveys are needed, and also indicators of hepatocellular function. The present investigation indicates that determination of the von Willebrand factor could be used for this purpose. / <p>Härtill 6 uppsatser</p> / digitalisering@umu

Le syndrome de Gougerot-Sjögren (SGS) est une maladie autoimmune (MAI) systémique inflammatoire chronique caractérisée principalement par la diminution des secrétions salivaires et lacrymales, aboutissant à une sécheresse de la bouche et des yeux. Elle affecte principalement les femmes autour de la ménopause. Au niveau physiologique, le tissu épithélial des glandes salivaires (GS) est infiltré par des lymphocytes, ce qui provoque l'apoptose des cellules épithéliales (CE). L'épigénétique pouvant jouer un rôle important dans le développement des MAI comme le SGS, nous avons analysé l'expression d'éléments rétroviraux endogènes humains (HERV) et des microARN. Par ailleurs, afin de mieux comprendre les mécanismes cellulaires et moléculaires impliqués dans les interactions lymphocytes-CE au niveau de la GS pathologique, nous avons mis en place un modèle de co-culture in vitro entre des CE et des lymphocytes B ou T (LB, LT). Nous avons également étudié le rôle de BAFF sur les CE qui expriment l'un de ses récepteurs, BR3.Dans un premier temps, nous avons montré que dans les GS des patients, les HERV et les miARN ont un profil d'expression distinct de celui des personnes saines, montrant ainsi une participation de l'épigénétique dans la pathologie. Dans un deuxième temps, nous avons montré que les CE entrent en apoptose suite à l'interaction directe avec les lymphocytes B etT, en faisant intervenir la voie Fas pour les LT et la voie de la PKCδ pour les LB. En lien avec l'apoptose induite par les LB, nous avons démontré que BAFF est impliqué dans la survie des CE, et que le blocage de sa signalisation ou la sous-expression de son récepteur conduit à la mort des CE. Nous pouvons supposer que les LB entrent en compétition avec les CE pour le signal de survie apporté par BAFF, et que les CE qui s'en trouvent privées meurent. Finalement, nous avons montré que plusieurs formes de BAFF sont produites parles CE et reconnues de manière différente par les anticorps anti-BAFF. Il pourrait s'agir d'isoformes plus ou moins glycosylés ou de variants de BAFF. Cependant d'autres études sont nécessaires afin de les identifier.

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.