A Artrite Reumatóide (AR) é uma doença auto-imune, crônica e inflamatória cujas manifestações são notadas, principalmente, nas articulações. Um ponto de extrema importância nesta doença é a necessidade de diagnostico e início do tratamento dos pacientes o mais rápido possível, para que os danos às articulações e erosões ósseas sejam evitados, pois estes danos ocorrem no início da doença e são, muitas vezes, irreversíveis. O presente projeto teve como objetivo a construção de um sistema computacional via Web para o auxílio ao diagnóstico de pacientes portadores de artrite reumatóide, através da utilização de técnicas de inteligência artificial, como Redes Neurais Artificiais, Árvores de Decisão e Algoritmos Genéticos, e o sistema gerenciador de conteúdos Drupal. O objetivo do sistema é proporcionar um ambiente estruturado, no qual as informações clínicas e de expressão gênica de pacientes portadores de AR são cadastradas e categorizadas, para que, a partir destas informações, os algoritmos de aprendizado de máquinas possam ser treinados para selecionar características clínicas e genes relevantes para a predição da resposta dos pacientes ao tratamento com Drogas Anti-Reumáticas Modificadoras da Doença (DMARDs). Após o treinamento, os modelos gerados podem ser utilizados para a predição da resposta à DMARDs de novos pacientes. O sistema visa selecionar possíveis características que permitam identificar precocemente os pacientes que irão evoluir de forma mais agressiva e, assim, fornecer uma nova ferramenta para que os médicos possam indicar o melhor tratamento possível para cada paciente individualmente. O Sistema desenvolvido foi denominado ARIA e está disponível através do endereço http://gbi.fmrp.usp.br/artrite. Apenas médicos e colaboradores do projeto têm permissão para acessá-lo. Estão disponíveis os seguintes conteúdos: Cadastro de Pacientes, Ferramenta de Seleção de Atributos e Ferramenta de Predição da Resposta dos Pacientes à DMARDs. Além disso, o sistema disponibiliza diversas possibilidades de visualização e interação com tais conteúdos. Estão cadastrados, até o momento, 126 pacientes, sendo que 106 deles são utilizados para o treinamento da ferramenta de seleção de atributos e vinte deles para os testes da ferramenta de predição da resposta à DMARDs. / Rheumatoid Arthritis (RA) is a chronic, inflammatory, autoimmune disease, whose manifestations are observed, mainly in the joints. One point of extreme importance in this disease is the early diagnosis and the begging of the treatment as quickly as possible. These procedures try to avoid joints damage and bone erosions, since these damages are often irreversible. This project aimed to develop a computational system to aid diagnosis of rheumatoid arthritis patients. Artificial intelligence techniques, such as Artificial Neural Networks, Decision Trees and Genetic Algorithms, and the content management system Drupal were employed to the system development. The system goal is to provide a structured environment in which clinical and gene expression information about RA patients are registered and categorized. From the information stored in the system database, the machine learning algorithms can be trained to select clinical information or genes which are relevant to predicting the patients response to treatment with Disease Modifying Anti-Rheumatic Drugs (DMARDs). After the training, the generated models generated can be used for predicting the response to DMARDs of new RA patients. The system aims to select characteristics to early identify patients who might have more aggressively disease outcome and thus, it provides a new tool to physicians in the analysis of the best treatment for each patient individually. The system developed was called ARIA System and it is available at the web site http://gbi.fmrp.usp.br/artrite. Only doctors and collaborator researchers have permission to access it. The contents available in the system are the following: Patients Register, Feature Selection Tool and Prediction the Response to DMARDs Tool. Besides these contents, the system offers different kinds of displaying and interaction with the content. There are, until now, 126 patients registered in the ARIA System, 106 of them are used for training the features selection tool and twenty of them are used to test the tool for predicting patients response to DMARDs.

Orientador: Juliana Trindade Clemente Napimoga / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-24T16:30:34Z (GMT). No. of bitstreams: 1 Quinteiro_MarianadaSilva_D.pdf: 18806737 bytes, checksum: 28c4cd737128e1c9696fdffe0daafeac (MD5) Previous issue date: 2014 / Resumo: O processo inflamatório induzido pela Artrite Reumatoide (AR) na articulação temporomandibular (ATM) resulta em uma dor persistente causando estresse em muitos pacientes. ... Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital / Abstract: Inflammation of the temporomandibular joint (TMJ) induced by Rheumatoid Arthritis (RA) have often resulted in persistent pain and caused distress to many patients... Note: The complete abstract is available with the full electronic digital thesis or dissertations / Doutorado / Fisiologia Oral / Doutora em Odontologia

Orientador: Manoel Barros Bertolo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T16:46:42Z (GMT). No. of bitstreams: 1 Almeida_MariadoSocorroTeixeiraMoreira_D.pdf: 2149275 bytes, checksum: 99ea931f214943626d6352a600cd07e9 (MD5) Previous issue date: 2014 / Resumo: Objetivo: Determinar a frequência dos antígenos HLA-DR em pacientes piauienses com artrite reumatoide (AR) e envolvimento pulmonar. Pacientes e métodos: Foram avaliados 97 pacientes piauienses com AR. A genotipagem do HLA-DR foi realizada através da técnica de amplificação pela reação em cadeia da polimerase. Resultados: Oitenta e cinco pacientes (88,0%) eram do sexo feminino, 77,0% não caucasoides e tinham idade média de 47,3 anos. Cinquenta e quatro pacientes (56,0%) apresentavam manifestações extra-articulares, sendo nódulos subcutâneos a mais frequente (19,0%). Após a realização de avaliação pulmonar, constatou-se comprometimento pulmonar em 54 (56,0%) pacientes. HLA mais frequente foi o HLA DRB4*01, seguido por DRB1*04, DRB3 e DRB1*01 e nos pacientes com comprometimento pulmonar foram HLA-DRB4*01, HLA-DRB1*04 e HLA-DRB1*13. Conclusão: O HLA mais frequente foi o HLA-DRB4*01 em todos os pacientes do estudos e nos pacientes com envolvimento pulmonar também foi o HLA-DRB4*01, não havendo, no entanto, associação estatisticamente significativa / Abstract: Aims: To establish the frequency of HLA-DR antigens in individuals with rheumatoid arthritis (RA) from Piaui with and without lung affection. Participants and methods: The sample comprised 97 individuals. HLA-DR was genotyped by means of polymerase chain reaction amplification. Results: A total of 85 participants (88.0%) were female; 77.0% were non-white; and the average age of the sample was 47.3 years old. A total of 54 participants (56.0%) exhibited extra-articular manifestations, most frequently subcutaneous nodules (19.0%). Lung assessment detected affection in 54 (56.0%) participants. HLA-DRB4*01 was the most frequently found allele, followed by HLA-DRB1*04, HLA-DRB3 and HLA-DRB1*01, whereas the most frequent alleles were HLA-DRB4*01, HLA-DRB1*04 and HLA-DRB1*01 in the participants with lung affection. Conclusion: HLA-DRB4*01 was the allele most frequently found overall, and HLA-DRB4*01 was the most frequent allele among the participants with lung affection; however, the association was not statistically significant / Doutorado / Medicina Interna / Doutora em Ciências Médicas

Orientador: Manoel Barros Bertolo / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T00:50:53Z (GMT). No. of bitstreams: 1 Bernardes_CynaraFerreira_M.pdf: 2007451 bytes, checksum: e391b0c846a262e5780f400dd970089f (MD5) Previous issue date: 2013 / Resumo: Objetivos: Avaliar a eficácia do uso das palmilhas em pacientes com Artrite Reumatóide (AR) na redução da dor, melhora da função e redução da média dos picos de pressão plantar. Material e Métodos: Vinte e sete pacientes com AR e dor nos pés foram avaliados em relação à dor, presença de deformidade e calosidades, incapacidade (Heath Assessment Questionnaire - HAQ-DI) e atividade de doença (Clinical Disease Activity Index - CDAI). Palmilhas foram prescritas de acordo com a necessidade de cada sujeito com objetivo de suporte articular e redução de dor. Os pacientes foram submetidos à avaliação pelo Foot Function Index (FFI) e podobarometria (Sistema F-SCAN) com a avaliação da média dos picos de pressão plantar em consulta inicial e após duas semanas de intervenção. Resultados: Houve redução do FFI após a intervenção em todas sub escalas. Os escores iniciais mais elevados do FFI total e suas subescalas de incapacidade (FFI-inc) e limitação da atividade (FFI-la) foram significativamente relacionados aos maiores escores do CDAI e HAQ-DI (p < 0.05). A melhora do FFI foi independente da idade dos sujeitos, tempo de doença, CDAI e HAQ-DI. Não houve redução significativa na média dos picos de pressão plantar após a intervenção, mesmo quando foram avaliados separadamente os pacientes com dor predominante em ante pé e retro pé. As palmilhas foram usadas em média 7,08 horas por dia. Efeitos adversos menores foram observados em sete pacientes, nenhum resultando em interrupção do tratamento. Conclusão: Foi observado redução de dor e incapacidade em indivíduos com AR após o uso de palmilhas, sem redução significativa das médias dos picos de pressão plantar. Os benefícios do uso das órteses em pés reumatóides podem ser multifatoriais, não somente relacionado à melhor distribuição da pressão plantar, mas à melhor acomodação do pé e aumento do estímulo proprioceptivo / Abstract: Objective: To evaluate the efficacy of insoles in Rheumatoid Arthritis (AR) patients reducing pain, improving function and reducing the mean peak plantar pressure. Methods: Twenty-seven rheumatoid patients with foot pain were evaluated regarding foot deformity, disability (Health Assessment Questionnaire - HAQ-DI) and disease activity (Clinical Disease Activity Index - CDAI). Foot orthosis were prescribed according to each patient's needs aiming to provide a better joint support and to reduce pain. The Foot Function Index (FFI) and the mean peak plantar pressure (FSCAN system) were evaluated at baseline and after two weeks of intervention. Results: FFI values decreased in all subscales after intervention. Higher initial disability and activity limitation FFI subscales and FFI total scores were significantly related to higher CDAI and to higher HAQ-DI scores (p < 0.05). FFI improvement was independent from age, disease duration, CDAI and HAQ-DI. No significant reduction in the mean peak plantar pressure was noted, even if evaluating separately the patients with pain mainly on the forefoot or on the hindfoot. Orthosis were worn 7.08 hours-day on average. Minor adverse effects were noted in seven patients, none of them resulting in treatment interruption. Conclusion: Foot orthosis reduces patient's referred foot pain and foot disability with no significant reduction in the mean peak plantar pressure. The benefits of foot orthosis in RA may be multifactorial, not only related to plantar pressure distribution, but also to a better foot accommodation and increased proprioceptive stimulus / Mestrado / Clinica Medica / Mestra em Clínica Médica

L'autotaxine (ATX) est une protéine sécrétée par différents tissus y compris le foie, le tissu adipeux et l'os. L'ATX possède une activité lysophopholipase D responsable du clivage de la lysophosphatidyl-choline (LPC) en acide lysophosphatidique (LPA), facteur de croissance affectant la prolifération cellulaire, la différenciation et la migration. Il a été démontré que les effets biologiques du LPA pourraient être la conséquence de la production locale d'ATX dans un tissu ou une cellule donnée. Nous avons récemment démontré que le LPA contrôle l'ostéoclastogenèse et l'activité de résorption ostéoclastique. De plus, nous avons démontré que l'expression de Enpp2 (gène de l'ATX) augmente au cours de l'ostéoclastogenèse. Le but de notre étude était d'évaluer l'implication de l'ATX produite par les ostéoclastes au cours de l'ostéoclastogenèse et dans le contrôle de la masse osseuse, en particulier en conditions inflammatoires.La production et le rôle de l'ATX au cours de l'ostéoclastogenèse ont été analysés sur les ostéoclastes murins et humains. De plus, l'ATX a été spécifiquement ciblée dans les ostéoclastes avec l'utilisation des souris Enpp2fl/fl Ctsk-Cre et par le traitement pharmacologique des souris par un anti-ATX. La perte osseuse en conditions inflammatoires a été évaluée dans le modèle d'inflammation induite par le lipopolysaccharide (LPS) et dans les modèles de souris arthritiques par transfert de sérum K/BxN et avec la lignée transgénique surexprimant le TNF humain hTNF. La production de l'ATX par les ostéoclastes est cruciale pour l'activité de résorption osseuse ostéoclastique in vitro. Les souris Enpp2fl/fl Ctsk-Cre ne présentent pas de phénotype osseux en conditions physiologiques mais sont protégées de la perte osseuse systémique et des érosions osseuses observées en conditions arthritiques. De plus, l'ihibition pharmacologique de l'ATX protège les souris de la perte osseuse systémique et des érosions focales observées dans le modèle hTNF+/- .L'inhibition pharmacologique et génétique de l'ATX améliore la perte osseuse locale et systémique inflammatoire en inhibant la résorption osseuse. L'ATX semble être une cible thérapeutique prometteuse dans la prévention de la perte osseuse associée à l'inflammation / Autotaxin (ATX) is a secreted protein produced by various tissues including the liver, adipose tissue and bone. ATX exhibits a lysophospholipase D activity responsible for cleavage of lysophosphatidyl-choline (LPC) in lysophosphatidic acid (LPA) that in turn acts as a growth factor, affecting cell proliferation, differentiation, and migration. It has been shown that biological effects of LPA could be the direct consequence of local production of ATX in a given tissue or cell type. We showed that LPA controls osteoclastogenesis and osteoclast bone resorption activity. In addition, we observed that Enpp2 (ATX gene) was upregulated during osteoclastogenesis. The aim of the study was to evaluate if ATX produced by osteoclasts could play a role in osteoclastogenesis and bone mass control, especially in inflammatory conditions.The role of ATX on osteoclastogenesis and osteoclast activity were analysed by murine and human assays. ATX was targeted by conditional inactivation of Ennp2 (ATX gene) in osteoclasts (Enpp2fl/fl Ctsk-Cre) and by treatment with anti-ATX. Arthritic and erosive diseases were studied in arthritis models using human tumor necrosis factor transgenic (hTNF+/-) mice and K/BxN serum-treated mice. Systemic bone loss was analysed in the Lipopolysaccharide (LPS)-induced inflammation model. Joint inflammation and osteoclasts were assessed by histology and bone mass and bone erosion by micro-CT.ATX production by osteoclasts was observed and was revealed as a crucial factor controlling osteoclast activity. Inhibition of ATX led to reduced bone resorption in vitro. Then, we generated Enpp2fl/fl Ctsk-Cre+/- mice allowing ATX depletion specifically in mature osteoclasts. These mice showed no specific bone phenotype under physiological conditions but displayed significant protection against systemic bone loss and almost an absence of bone erosion formation after challenge with LPS and K/BxN serum transfer. Pharmacological inhibition of ATX significantly mitigated focal and systemic TNF-induced bone loss. Pharmacological and genetic inactivation of ATX ameliorates systemic and focal inflammatory bone loss by inhibiting bone resorption. ATX emerges as a new promising therapeutic target for the prevention of inflammatory associated bone loss

Durant ce travail de thèse j’ai étudié des mécanismes de contrôle de la réponse inflammatoire qui, lorsqu’ils sont dérégulés, peuvent mener à une pathologie autoimmune/autoinflammatoire sévère, la Polyarthrite Rhumatoïde (PR). J’ai essentiellement analysé deux aspects de ces mécanismes : en premier lieu, j’ai pu participer à la démonstration de l’importance de l’endonucléase DICER (impliquée dans la biogénèse des microARNs - miRs), dans le contexte de la PR, particulièrement au niveau des synoviocytes type fibroblastique (FLS), des cellules résidentes de la cavité synoviale. J’ai aussi initié une étude visant à identifier, in vivo, l’intégralité des transcrits dont l’expression est régulée par des miRs dans les FLS de patients atteints de PR. En plus de fournir une vision globale de la régulation miR-dépendante dans ces cellules, ce travail permettra aussi d’identifier des cibles de miRs d’intérêt dans la PR en s’affranchissant des prédictions bio-informatiques qui peuvent s’avérer incorrectes. Un second axe de mon projet de thèse avait pour objectif de fournir une meilleure description du dialogue intercellulaire dans la cavité articulaire. Pour cela, je me suis plus particulièrement intéressé au rôle des cellules dendritiques plasmacytoïdes (pDCs) dans la physiopathologie de la PR. Ainsi j’ai pu démontrer un rôle protecteur de ces cellules (initialement décrites pour leurs fonctions dans la défense antivirale), dans le contexte de l’arthrite inflammatoire dans plusieurs modèles murins. Ces travaux m’ont permis de proposer une stratégie thérapeutique innovante, basée sur le recrutement articulaire des pDCs. Cette approche, non invasive (par application topique de crème contenant 5% d’imiquimod), s’est montrée efficace aussi bien pour la réduction des symptômes cliniques de l’inflammation que pour l’amélioration des marqueurs biologiques comme l’érosion osseuse. / During my PhD, I studied the mechanisms that control inflammation which, when disturbed, can lead to a severe autoimmune/ auto inflammatory disease, rheumatoid arthritis (RA). My work was focused on the analysis of two aspects in these mechanisms: first, I participated to an analysis of the roles of the endonuclease DICER (involved in the biogenesis of microRNAs – miRs) in the pathogenesis of RA, specifically in fibroblast-like synoviocytes (FLS), which are resident cells of the synovial cavity. I also initiated a study aiming at the identification of the FLS transcriptome which is regulated by miRs in RA patients. This approach will provide an overview of the miR-dependent regulation in these cells and enable the identification of in vivo validated miR-targeted mRNAs in RA. A second axis of my thesis project aimed at providing a better description of the intercellular dialogue in the joint cavity. For this, I was particularly interested in the role of plasmacytoid dendritic cells (pDCs) in the pathophysiology of RA. I demonstrated a protective role of these cells (initially described for their functions in antiviral defense) in the context of inflammatory arthritis in several mouse models. During this work, I had the opportunity to try an innovative therapeutic strategy based on the recruitment and activation of pDCs in the joints. This noninvasive and painless approach (topical application of cream containing 5% imiquimod) was effective in reducing inflammatory clinical symptoms and also improved biological markers such as bone erosion.

Abstract The purpose of this study was to evaluate the value of 0.23T low-field magnetic resonance imaging (MRI) and nanocolloid (NC) scintigraphy in assessing joint pathology associated with rheumatoid arthritis (RA). Fat suppression methods combined with contrast media enhancement aid in distinguishing enhancing inflamed tissue from the surrounding fat, especially in the imaging of arthritic joints. The feasibility and image quality of a phase-shift water-fat MRI method for fat suppression at low-field 0.23T open configuration MR scanner was evaluated. The technique was combined with contrast-enhanced imaging to assess the conspicuity of synovial hypertrophy in the joints of 30 RA patients. Improved conspicuity and delineation of synovitis was detected with this method. However, because of a great amount of manual post processing, future development is needed to make this method more feasible. Contrast-enhanced MRI and NC scintigraphy may provide objective and quantitative information about the inflammatory activity in arthritic joints. The value of quantitative and semiquantitative measures of inflammation derived from NC scintigraphy and low-field MRI of the wrist joint of 28 early RA patients was evaluated. Furthermore, it was investigated whether these parameters have predictive value of further erosive development during two years of follow-up. Strong correlations were detected between the NC scintigraphy and MRI measures, and these parameters were associated with laboratory markers of inflammation. During the two-year follow-up, the initial MRI and NC scintigraphy measures were closely related with the progression of wrist joint erosions. Small erosive-like bone defects can occasionally be found in wrist MRI of patients without clinically overt arthritis. The prevalence of these lesions was studied in bilateral wrist MRI examinations of 31 healthy persons. Small lesions resembling erosions were detected in 14 out of 31 subjects. Altogether 24 of the 930 wrist bones evaluated showed such lesions (3%). Thus small changes resembling erosions can be found in the wrist MRI of healthy subjects; the significance of these findings must always be interpreted with reference to the clinical picture. In conclusion, early RA patients with high local inflammatory activity, as detected by NC scintigraphy and MRI are at risk of developing further bone damage. Furthermore, in the follow-up of early RA patients, if clinically sustained response is not achieved, these methods help to identify patients who need more intensive drug treatment.

Dysregulation between pro- and anti-inflammatory cytokines activity in rheumatoid arthritis (RA) contributes to immune dysregulation, chronic inflammation and subsequent joint destruction. Interleukin-37 (IL-37) has been described as an anti-inflammatory cytokine in several autoimmune diseases. The main aim of this work was to determine the levels of IL-37 in serum and synovial fluid (SF) of RA patients and to compare them with the levels in patients with osteoarthritis (OA) and further explore the association of IL-37 with disease activity and other clinical parameters. Subsequent goal was to study its anti-inflammatory function on RA synovial fibroblasts and describe other cells types of synovial tissue contributing to its production. IL-37 levels were detected using enzyme-linked immunosorbent assay (ELISA). Synovial fibroblasts were stimulated by lipopolysaccharide (LPS) and recombinant IL-37 (rIL-37). The levels of studied genes were detected by PCR. Synovial tissues and immune cells were visualized by immunohistochemical and by immunofluorescence staining. We found increased levels of IL-37 in SF of patients with RA in comparison to OA patients. There was a significant correlation between serum and SF levels of IL-37. RA as well as OA patients showed increased levels of IL-37 in serum than in...

Background: Age is an important risk factor for rheumatoid arthritis (RA), which often develops in middle age. However, how age-associated changes in immunity impact RA is poorly understood. Gut microbiota are known to be involved in the pathogenesis of RA, but the effects of microbiota in older subjects remain mostly unknown. Methods: We used segmented filamentous bacteria (SFB), a gut commensal species with immunomodulatory effects, and K/BxN mice, a T cell receptor (TCR) transgenic model, to study the effect of age and microbiota on autoimmune arthritis. Comparing young and middle-aged K/BxN T cells of the same TCR specificity allows us to study T cells with an age focus eliminating a key variable: TCR repertoire alteration with age. In addition to joints, we also studied pathological changes in the lung, an important extra-articular RA manifestation. We used flow cytometry to evaluate T follicular helper (Tfh) and T helper 17 (Th17) cells, as they both contribute to autoantibody production, a key disease index in both RA and K/BxN arthritis. Results: Middle-aged K/BxN mice had aggravated arthritis and pathological changes in the lung compared to young mice. Middle-aged mice displayed a strong accumulation of Tfh but not Th17 cells, and had defective Th17 differentiation and low expression of interleukin-23, a critical cytokine for Th17 maintenance. Although a soaring Tfh cell population accompanied by robust germinal center B cell responses were found in middle-aged mice, there was decreased cycling of Tfh cells, and SFB only induced the non-Tfh cells to upregulate Bcl-6, the Tfh master transcription factor, in the young but not the middle-aged group. Finally, the accumulated Tfh cells in middle-aged mice had an effector phenotype (CD62LloCD44hi). Conclusion: Age-dependent Tfh cell accumulation may play a crucial role in the increased autoimmune disease phenotype in middle-age. SFB, a potent stimulus for inducing Tfh differentiation, fails to promote Tfh differentiation in middle-aged K/BxN mice, suggesting that most of the middle-aged Tfh cells with an effector phenotype are Tfh effector memory cells induced at an earlier age. Our results also indicate that exposure to immunomodulatory commensals may allow the young host to develop an overactive immune system reminiscent of that found in the middle-aged host.

La Polyarthrite Rhumatoïde (PR) est une maladie auto-immune chronique qui détruit les articulations. Les auto-anticorps (AAc) les plus spécifiques sont dirigés contre des protéines citrullinées (ACPA). Environ 30% des patients ont des AAc dirigés contre la protéine B-Raf. Les ACPA sont des IgG produits sans réponse lymphocytaire T (LT) détectable contre les protéines citrullinées. Les enzymes PAD, responsables de la citrullination, sont la cible d’AAc dans la PR. Les LT pourrait être dirigés contre les PAD. Les LB produiraient des IgG contre les PAD et les protéines citrullinées, du fait qu’elles soient fixées aux PAD durant leur citrullination. Pour tester ce modèle, nous avons injecté des PAD à des souris et suivi les LT et les Ac anti-PAD ainsi que les ACPA. Nous avons montré que l’immunisation par PAD induit des LT anti-PAD, des Ac anti-PAD ainsi que des Ac anti-peptides de fibrinogène citrulliné.B-Raf est une ser/thr kinase de la voie des MAPK impliquée dans l’inflammation et l’activation des LT. Les LT de patients PR ont une sur-activation de la voie des MAPK, induisant une rupture de tolérance envers les auto-antigènes. Notre hypothèse est que des mutations du gène BRAF pourraient être à l’origine des AAc anti-B-Raf. Nous avons identifié la présence d’une mutation du gène BRAF entrainant la substitution de la valine en alanine en position 600 (V600A) qui est trouvée en plus grande quantité dans les cellules du sang périphérique et les LT des patients PR. V600A n’est pas corrélée à la présence d’AAc anti-B-Raf, mais augmente l’activité kinase de B-Raf qui pourrait activer la voie des MAPK dans les LT et une rupture de tolérance envers les auto-antigènes. / Rheumatoid Arthritis (RA) is a chronic inflammatory autoimmune joint disease. RA most specific autoantibodies (AAb) recognize citrulline proteins (ACPA). 30% of patients with RA have anti-B-Raf AAb. ACPA are IgG that arise in the absence of associated T cell responses. PAD enzymes, responsible for the citrullination, are also targets of AAb in RA. We thus propose a mechanism to explain the emergence of ACPA. We hypothesize that anti-citrullinated protein immunization arises because, at first, PAD is recognized by T cells, which, in turn help the production of AAb to neighbor proteins citrullinated by PAD. To test this model, we primed mice with PAD proteins and looked for immune response to PAD and citrullinated proteins. We found that PAD immunization leads to T cell response, Ab anti-PAD as well as anti-citrullinated fibrinogen peptides Ab production. Anti-PAD immunization could induce anti-citrullinated protein immunization.B-Raf, a ser-thr kinase of the MAPK signalling pathway, is involved in inflammation and in T cell activation. An overexpression of B-Raf is observed in T cells from RA patients increasing T cell activation to autoantigens. Our hypothesis is that BRAF gene mutations could trigger a rupture of tolerance and AAb production in RA. We have identified a BRAF mutation, a valine residue at position 600 is substituted by an alanine (V600A). V600A is found more often and at greater quantities in patients with RA, noteworthy in their T cells. This mutation does not correlate with Anti-B-Raf AAb presence but this is a strong enhancer of B-Raf kinase activity. This could lead to abnormal T cells activation and explain tolerance rupture in RA.