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<p><strong>BACKGROUND</strong>.<strong> </strong>Classically, radiography (x-ray) has been used to visualize the destructive effects of uncontrolled rheumatoid arthritis (RA) on articular bones. Both x-ray and magnetic resonance imaging (MRI) may be used to visualize erosive disease. The multi-slice and multi-planar characteristics of MRI provide greater detail per anatomy imaged than x-ray.</p> <p><strong>OBJECTIVE</strong>. The objective of this dissertation was to compare the relative merits of x-ray and MRI erosion detection.</p> <p><strong>METHODS</strong>. In Chapters 1 through 3, RA, its clinical management, and the role of diagnostic imaging were introduced. In Chapter 4, the overall objective was first investigated by evaluating the current state of knowledge using a systematic review. In Chapter 5, inter-rater reliability across four participating radiologists was investigated. In Chapter 6, reliability-adjusted evaluations were used to directly compare paired x-ray and MR images.</p> <p><strong>RESULTS</strong>. The systematic review indicated that x-ray has low sensitivity and high specificity for MRI erosions. The associations were dependent on RA symptom duration. The findings from the prospective studies conducted were consistent with the literature. In a patient-centred analysis, the proportion of patients with erosive disease detected on either modality was dependent on the anatomy compared. Despite similar proportions of patients with erosive disease detected in comparable diagnostic imaging sittings, the proportions were comprised of markedly different patients.</p> <p><strong>CONCLUSIONS</strong>. The literature comparing x-ray and MRI erosion detection was systematically reviewed. The dependence of the relative diagnostic test accuracy on symptom duration was highlighted. At the patient level of analysis, the greater number of anatomical sites examined on x-ray overcomes the superiority of MRI to detect erosions at the unit of measurement. The two modalities are complementary insofar that they detect erosive disease in distinct patients. Further investigation into the merit of imaging varied anatomy on MR and optimally accounting for inter-rater reliability in such comparisons is warranted.</p> / Doctor of Philosophy (PhD)

Rates of immune-mediated diseases (IMDs) have rapidly increased. Although the exact etiology has not yet been fully elucidated, disruptions to the microbiome has been proposed as a potential mechanism. We conducted a retrospective, longitudinal, birth cohort study utilizing electronic health records (EHR) to investigate the association between early life antibiotic exposure and the risk of developing juvenile idiopathic arthritis (JIA), pediatric psoriasis, or type 1 diabetes. Incident rate ratios (IRR) were estimated using modified Poisson regression models and adjusted for significant confounders. Children exposed to two or more antibiotics prior to 12 months of age had a 69% increased risk of developing JIA (1.69 IRR, 95% CI [1.04-2.73]), which rose to 97% when exposed prior to 6 months (1.97 IRR, 95% CI [1.11-3.49]). Children exposed to a penicillin antibiotic had a 62% increase in risk for psoriasis (1.62 IRR, 95% CI [1.06-2.49]), which rose slightly to 64% when exposure occurred between 6 and 12 months of age [(1.64 IRR, 95% CI [1.04-2.59]). We found a moderate to strong association between early antibiotic exposure and risk for JIA and psoriasis when exposure was examined by age, frequency, and type of antibiotic, but not for type 1 diabetes. Potential interactions effects between infection and antibiotics with an increased susceptibility to early life infections among children with an IMD was also observed. Overall, children exposed to antibiotics at an early age have an increased probability of developing an IMD after 12 months of age. However, alternative explanations for this association should be considered. / Public Health

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that affects the feet in up to 90% of patients, and can result in bone erosions. Little is known about disease activity at the metatarsophalangeal joints (MTPJs). Magnetic resonance imaging is used to visualize erosions, but does not provide quantification. Quantitative computed tomography (QCT) allows for differentiation between bone layers and quantifies volumetric bone mineral density (vBMD). We used a peripheral QCT (pQCT) scanner in MTPJs 2-5 in RA patients to determine reliability of a pQCT protocol, and then we determined the variability in vBMD between RA patients and controls. Patients (n=25) diagnosed with RA (2010 ACR criteria) were recruited from an academic Rheumatology clinic. Controls (n=27) were also recruited and matched for sex, age and ethnicity. Baseline MR data demonstrated that 80%, 64%, 40% and 20% of patients had erosions at MTPJs 2-5, respectively. One year later, MTPJs 2-5 were scanned using pQCT (XCT 2000); 2 transaxial slices were acquired per joint. A trained pQCT operator acquired 2 scans per participant with repositioning. Test-retest, intra- and inter-rater reliability were assessed blindly for total and cortical subcortical densities (mg/cm3). Reliability was reported as root mean square coefficients of variation (%RMSCV) and RMS standard deviation (RMSSD). The mean (SD) age and disease duration were 57.8 (10.2) years and 5.0 (0.9) years, respectively. Test-retest reliability was better for MTPJs 2 and 3, than MTPJs 4 and 5. Inter- and intra-rater reliability demonstrated high reproducibility. Total and cortical subcortical vBMD appeared lower in RA patients than controls. We have reliably determined vBMD using pQCT in MTPJs 2 and 3 in RA patients. The lower vBMD in MTPJ 3 suggests that RA patients may have true erosions at this joint. This research is in the early phases, but we hope to explore the correspondence between pQCT and other RA assessment tools. / Thesis / Master of Science (MSc) / Rheumatoid arthritis (RA) affects joints in the hands and feet. The bones of these joints are affected by periarticular bone loss leading to bone erosions. Magnetic resonance imaging (MRI) and X-ray are used to visualize erosions. Since erosions are characterized by a decrease in bone mineral density (BMD) leading to holes in the bone, we tested the reliability of a peripheral quantitative computed tomography (pQCT) scanner, to measure volumetric BMD (vBMD) in 25 RA patients and compared vBMD to healthy controls. The vBMD measures appeared lower in RA patients than healthy individuals in some joints. As well, there was agreement between bone erosions detected by MRI and reduced vBMD measured by pQCT. Although we could not monitor the change over time, we are hopeful that this scanner will be able to better characterize RA disease activity, with vBMD as a surrogate marker for erosion presence.

Agriculture is the backbone of the Haitian economy and provides employment 80% employment to the Haitian population (Lundahl, 1992). Also 85% of people in rural areas generate money from agricultural activities (IFAD, 2008). In the rural areas, men and women participate in agricultural production. However, the women play a vital role in the whole process starting from land preparation to crop sale (Gaspard, 2013). The Haitian women, despite of their function in crop productions (Dor, 2016), face different health issues, which have influence over Haitian agricultural system. Therefore, the research purposed was to investigate the impact of women heath issues on agricultural production Fondwa. A qualitative case study was used to investigate ten women farmers in the community of Fondwa, which is a small farming area in southwest part of Haiti. An interview questionnaire was used for data collection. Findings of the study showed that the women's contribution to farming is vital for promoting agricultural production, and they face different health issues that are linked to the environment and water pollution. Lastly, the women health problems influence agricultural production in the Fondwa area by preventing them from doing their daily agricultural activities, which have a direct impact over family and country's income. / MSLFS

Die Methoden der Netzwerktheorie erfreuen sich wachsender Beliebtheit, da sie die Darstellung von komplexen Systemen durch Netzwerke erlauben. Diese werden nur mit einer Menge von Knoten erfasst, die durch Kanten verbunden werden. Derzeit verfügbare Methoden beschränken sich hauptsächlich auf die deskriptive Analyse der Netzwerkstruktur. In der hier vorliegenden Arbeit werden verschiedene Ansätze für die Inferenz über Prozessen in komplexen Netzwerken vorgestellt. Diese Prozesse beeinflussen messbare Größen in Netzwerkknoten und werden durch eine Menge von Zufallszahlen beschrieben. Alle vorgestellten Methoden sind durch praktische Anwendungen motiviert, wie die Übertragung von Lebensmittelinfektionen, die Verbreitung von Zugverspätungen, oder auch die Regulierung von genetischen Effekten. Zunächst wird ein allgemeines dynamisches Metapopulationsmodell für die Verbreitung von Lebensmittelinfektionen vorgestellt, welches die lokalen Infektionsdynamiken mit den netzwerkbasierten Transportwegen von kontaminierten Lebensmitteln zusammenführt. Dieses Modell ermöglicht die effiziente Simulationen verschiedener realistischer Lebensmittelinfektionsepidemien. Zweitens wird ein explorativer Ansatz zur Ursprungsbestimmung von Verbreitungsprozessen entwickelt. Auf Grundlage einer netzwerkbasierten Redefinition der geodätischen Distanz können komplexe Verbreitungsmuster in ein systematisches, kreisrundes Ausbreitungsschema projiziert werden. Dies gilt genau dann, wenn der Ursprungsnetzwerkknoten als Bezugspunkt gewählt wird. Die Methode wird erfolgreich auf den EHEC/HUS Epidemie 2011 in Deutschland angewandt. Die Ergebnisse legen nahe, dass die Methode die aufwändigen Standarduntersuchungen bei Lebensmittelinfektionsepidemien sinnvoll ergänzen kann. Zudem kann dieser explorative Ansatz zur Identifikation von Ursprungsverspätungen in Transportnetzwerken angewandt werden. Die Ergebnisse von umfangreichen Simulationsstudien mit verschiedenstensten Übertragungsmechanismen lassen auf eine allgemeine Anwendbarkeit des Ansatzes bei der Ursprungsbestimmung von Verbreitungsprozessen in vielfältigen Bereichen hoffen. Schließlich wird gezeigt, dass kernelbasierte Methoden eine Alternative für die statistische Analyse von Prozessen in Netzwerken darstellen können. Es wurde ein netzwerkbasierter Kern für den logistischen Kernel Machine Test entwickelt, welcher die nahtlose Integration von biologischem Wissen in die Analyse von Daten aus genomweiten Assoziationsstudien erlaubt. Die Methode wird erfolgreich bei der Analyse genetischer Ursachen für rheumatische Arthritis und Lungenkrebs getestet. Zusammenfassend machen die Ergebnisse der vorgestellten Methoden deutlich, dass die Netzwerk-theoretische Analyse von Verbreitungsprozessen einen wesentlichen Beitrag zur Beantwortung verschiedenster Fragestellungen in unterschiedlichen Anwendungen liefern kann.

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease causing inflammation of the synovium resulting in severe pain, joint disfigurement and disability as well as malaise, fatigue and a depressed immune system. Treatment consists of three broad phases; firstly, following diagnosis treatment is focussed on rapid reduction of pain and inflammation. Secondly, maintenance of quiescence is sought through medication. Finally, if disease activity remains high despite medication, escalation to anti-TNF α therapy is required to prevent permanent joint damage and disability. The primary course of treatment is prescription of disease modifying anti-rheumatic drugs (DMARDs) within 3 months of onset of symptoms. However, DMARDs can take 8-12 weeks to exhibit a noticeable benefit whereas unpleasant side effects can occur shortly after initiation. Also, DMARDs do not alleviate pain; therefore it is difficult for patients to attribute recovery to this medication. For these reasons, although it is imperative for future health and functioning to take DMARDs as prescribed, non-adherence is common at 30-50%. Non-adherence to treatment can be intentional, where a decision is made not to conform to the prescription, or unintentional which is often due to forgetting. To measure intentional non-adherence, a validated measure of adherence for rheumatoid arthritis was reduced through exploratory factor analysis from 19 items to 5 items by removing items that did not add to the explained variance of adherence. The CQR5 explained 53% of the variance in adherence and was shown to have a good fit to the data through confirmatory factor analysis. A discriminant function equation was generated that correctly identifies 88.5% of patients as high or low adherers and has high clinical utility due to the brevity for patients and unidimensionality for easy interpretation. The CQR5 was used throughout the programme of research to measure intentional non-adherence along with a separate measure of unintentional non-adherence. Four commonly used social cognition models of illness were measured in 227 RA patients to determine which had the best utility for predicting non-adherence to DMARDs. Patients were recruited to represent the three stages of illness including newly diagnosed, established on DMARD therapy and established with concurrent anti-TNF α therapy. Logistic regression analysis showed that the Self Regulatory Model best predicted intentional non-adherence as patients with perceptions of worse consequences of RA and longer disease duration were more likely to be highly adherent to DMARDs in cross-sectional analysis. In contrast, the Theory of Planned Behaviour better predicted patients who self-reported forgetting their DMARDs with patients with more confidence in being able to take their medications (Perceived Behavioural Control) being less likely to forget. 171 patients were successfully followed-up six months after baseline recruitment. The longitudinal results showed that the social cognition models differed for patients at different stages of the illness suggesting that their experience of living with rheumatoid arthritis influenced perceptions of their illness and medications. Newly diagnosed patients scored lower on factors measuring perceptions of disease chronicity and seriousness whereas patients that had escalated to anti-TNF α therapy scored higher on these factors. The newly diagnosed patients also showed more variability in the social cognition scores whereas the more established patients demonstrated stable models of illness. This supports Leventhal’s (1992) theory that illness representations will be regulated through integration of knowledge and experience of an illness. Structural equation modelling was used to establish the best predictors of intentional non-adherence at six month follow-up. In support of research in other chronic illnesses (Horne & Weinman, 2002; Niklas, Dunbar & Wild, 2010), the effect of perceptions of the consequences and chronicity of the illness on adherence are mediated by perceptions of the necessity of the medication. In addition, the impact of the emotional reaction to the illness on adherence to DMARDs is mediated by concerns about the medication. In addition, this study incorporated factors from the Theory of Planned Behaviour to explain medication adherence and found that the influence of friends and family impacts on the patient’s confidence to follow the prescription accurately which in turn as an effect on adherence to DMARDs. This large longitudinal study found that by combining factors from a number of social cognition models, it is possible to explain and predict intentional non-adherence and provides some evidence for best ways to intervene to improve adherence and prognosis. To provide a more comprehensive and clinically useful picture of non-adherence, a Cost of Illness study was carried which found that patients self-reporting low adherence to DMARDs also had significantly higher costs for this medication. This was caused by an increased incidence of Leflunamide prescribing for patients who often forget their medication and was maintained longitudinally. This association has not been previously reported in the literature and provides some evidence that non-adherence to DMARDs is having a concrete effect on the clinical management of patients. Finally, an SMS text message based reminder service designed to remind patients who self-report forgetting their medications was tested through a simulation study for the cost and likely benefit in health related quality of life using the health economic analysis of the longitudinal study and the results of a survey establishing the feasibility of implementing such a service in the rheumatology clinic. A sensitivity analysis testing the number of messages sent and the cost per message found that a reminder service for the sample of patients in this programme of research would cost between £1387.00 and £142.27 per year. This would equate to a cost per Quality Adjusted Life Year (QALY) gain of between £2889.58 and £296.40 by enabling patients to adhere more rigorously to their DMARD regimen. This programme of research is the first to test four commonly used social cognition models to predict adherence to DMARDs in a large, multi-centre longitudinal study of rheumatoid arthritis patients. Perceptions of the likely duration and consequences of the illness, as measured by the Illness Perceptions Questionnaire and the necessity of medications (measured by the Beliefs about Medications Questionnaire) along with self-efficacy (measured by the Theory of Planned Behaviour) explained 24% of the variance in intentional adherence over six months. The results show the importance of considering intentional and unintentional non-adherence separately as they appear to have different underlying mechanisms as well as patients in different phases of the illness as their experience influences their social cognition models of illness. A simple SMS based reminder service could act as a cue to action to reduce unintentional non-adherence whereas addressing issues surrounding maladaptive perceptions about the illness and the treatment could improve intentional non-adherence which has the potential to improve the prognosis and quality of life for patients as well as safe costs for the NHS.

Les récepteurs tyrosine kinases sont un groupe de molécules clés de signalisation, qui ont 2 fonctions: la détection des stimuli de l'environnement extérieur des cellules et la transmission de ces signaux à l’intérieur des cellules. Dans les 20 dernières années, notre laboratoire a choisi d'étudier la fonction d’Ephb6 kinase, un récepteur tyrosine kinase fortement exprimé dans les lymphocytes T.Comme Efnb1 et Efnb2 sont tous des ligands pour Ephb6, nous avons ensuite procédé à étudier leur rôle dans la fonction des cellules T in vitro et in vivo. Des cellules T spécifiques mutants (KO) dans les gènes Efnb1 ou Efnb2 ainsi que les doubles mutants Efnb1/b2 (double KO) ont été générés, mais il n’y avait que les souris double KO qui ont démontré de la déficience dans le développement des thymocytes, fonction de Th1 et Th17, la signalisation du récepteur d’IL-6, et les réponses antivirales. Des preuves solides indiquent que la reconnaissance d’auto-antigène par les cellules T est un événement précoce dans la pathogenèse de la PR. Donc, nous avons postulé que les cellules T spécifique Efnb1 / b2 double KO chez la souris peuvent protéger les souris de l’arthrite induite par collagène (CIA), un modèle de souris de la PR humaine. Nous avons trouvé que Efnb1et Efnb2 dans les cellules T étaient essentielles pour la production d'anticorps pathogéniques et de la migration des lymphocytes T vers les pattes enflammées chez les souris CIA. Notre étude clinique suggère que l'expression de EFNB1 dans les cellules T pourrait être un paramètre utile pour surveiller l'activité de la maladie de RA et la réponse de traitement. Pour élucider les événements dans le programme d'activation des lymphocytes T, nous avons exploré par l'analyse des micropuces d'ADN pour identifier des molécules qui ont été exprimées de manière différente dans le WT par rapport aux cellules T Ephb6 KO dans le stade précoce de l’activation des cellules T. Environ 30 molécules étaient sur ou sous exprimées plus de 3 fois dans les cellules T WT par rapport aux cellules T KO pendant les 16 premières heures après stimulation par l'anti-CD3. Stra6 (stimulée par le gène de l'acide rétinoïque 6) et Armc5 (Armadillo répéter contenant 5) ont été parmi ceux qui ont été validées pour leur expression altérée. STRA6 est un récepteur de haute affinité pour le plasma rétinol-binding protéine (RBP) et un médiateur pour absorption cellulaire de vitamine A. Cellules T KO et WT étaient similaires en termes de prolifération et les réponses immunitaires anti-virales de virus de la chorioméningite lymphocytaire (LCMV). Ainsi, la sur-régulation de Stra6 est soit un événement parallèle qui ne soit pas essentiel pour le programme d'activation des lymphocytes T, ou il est très essentiel que la redondance existe, et sa suppression ne montre aucun effet apparent sur l'activation des cellules T. ARMC5 est une protéine intracellulaire contenant sept répétitions en tandem d’armadillo et un domaine BTB. Les fonctions du ARMC5 dans le système immunitaire ne sont pas encore connues. Nos résultats d'hybridation in situ ont montré une expression élevée de Armc5 dans le thymus, et une expression modérée dans les ganglions lymphatiques et la rate. Nous avons généré des souris KO Armc5. Fait interessant, les cellules T Armc5 KO présentaient de la prolifération diminuée et de la différenciation compromise vers Th1 et Th17 in vitro. Les souris KO étaient résistantes à l'induction expérimentale d’encéphalite auto-immune, et ont été compromises dans les réponses immunitaires anti-LCMV. En utilisant de la levure 2-hybride test, nous avons identifié 8 protéines ARMC5-associantes, qui sont connues pour les rôles dans l'activation de la cellule, le cycle cellulaire et l'apoptose. Une étude mécanique est en cours. Nos résultats montrent que Armc5 est essentiel dans la programme d'activation/de prolifération/de différenciation des lymphocytes T. Nos études ont augmenté nos connaissances sur EFNB1, EFNB2, STRA6 et ARMC5 en biologie des lymphocytes T et leur pertinence à des troubles immunitaires dans des modèles animaux ainsi que chez l'être humaine. / Receptor tyrosine kinases are a group of key signaling molecules, which have dual functions: sensing the environmental stimuli outside the cells and transmitting them into the cells. 20 years ago, our laboratory started to study the function of Ephb6 kinase, a receptor tyrosine kinase highly expressed in T lymphocytes. As both Efnb1 and Efnb2 are the ligands for Ephb6, we then proceeded to study their roles in T cell function in vitro and in vivo. T cellspecific Efnb1, Efnb2 single gene knockout (KO), as well as Efnb1/b2 double KO mice were generated, but only the double KO mice showed compromised thymocyte development, Th1 and Th17 function, IL-6 receptor signaling, and anti-virus responses. Strong evidence indicates that T cells play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Thus, we postulated that T cell-specific Efnb1/b2 double KO in mice may protect mice from collagen-induced arthritis (CIA), a mouse model for human RA. We found that Efnb1 and Efnb2 in T cells were essential for pathogenic antibody production and T cell migration to the inflamed paws in mice with CIA. Our clinical study suggests that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses. Naïve T cells have the ability to expansion and differentiation into effector cells once they encounter foreign antigens, during which a large number of molecules are modulated. Some of these molecules play essential regulatory roles, while others exert house keeping functions and/or act as supporters to cope with increased or changed metabolic demands. To fully elucidate events in the T cell activation program, we undertook unbiased exploration with DNA microarray analysis to identify molecules that were differentially expressed in WT versus Ephb6 KO T cells in the early T-cell activation stage. About 30 molecules were up- or down-regulated more than three folds in WT T cells compared with KO T cells. Stra6 (stimulated by retinoic acid gene 6) and Armc5 (Armadillo repeat-containing 5) were among those that had been validated for their altered expression. We generated mice with these two genes deleted to study their roles in T cell function in vitro and in vivo. STRA6 is a high-affinity receptor for plasma retinol-binding protein (RBP) and mediates cellular vitamin A uptake. Stra6 KO mice manifest normal spleen and thymus in size, cellularity and lymphocyte subpopulations. KO and WT T cells were similar regarding proliferation, differentiation and anti-viral immune responses to lymphocytic choriomeningitis virus (LCMV). Thus, the up-regulation of Stra6 is either a parallel event which is not essential for the T cell activation program or it is so critical that heavy redundancy exists. ARMC5 is an intracellular protein containing seven tandem armadillo repeats and one BTB domain. Functions of ARMC5 in the immune system are not known previously. Our in situ hybridization results showed high expression of Armc5 in the thymus and moderate expression in the spleen and lymph nodes. A transient increase of Armc5 expression in T cells after TCR activation was found. To investigate its roles in T cell function, Armc5 KO mice were generated. The KO mice weighed 40% less than their WT counterparts. Lymphoid organs (the thymus, spleen and lymph nodes) of the KO mice appeared to be of normal size, weight, cellularity, and lymphocyte subpopulations. Intriguingly, Armc5 KO T cells presented decreased proliferation and compromised differentiation towards Th1 and Th17 in vitro. The KO mice were resistant to experimental autoimmune encephalitis induction and were compromised in anti-LCMV immune responses. Using yeast 2-hybrid assay, we have identified 8 ARMC5-assciating proteins, which have known functions in cell cycling and apoptosis. Further mechanistic study is underway. Our results reveal that Armc5 is vital in the T cell activation/proliferation /differentiation program. Our studies have augmented our knowledge about EFNB1, EFNB2, STRA6 and ARMC5 in T cell biology and their relevance to immune disorders in animal models as well as in humans.

La polyarthrite rhumatoïde (PR) est une maladie auto-immune chronique. Elle est caractérisée par une inflammation persistante touchant de multiples petites articulations, causant douleurs, rougeurs, gonflements et déformations. Des études menées auprès de patients et d’animaux ont démontré que certains auto-anticorps, cytokines et enzymes tissue-déstructives sont des médiateurs importants dans le développement de la PR. Au cours des deux dernières décennies, les traitements de fond (DMARDs en anglais) ont été démontrés très efficaces pour traiter la PR. D'autre part, des effets secondaires ont été rapportés pour ces traitements, par exemple l'augmentation du risque d'infections opportunistes. L’objectif de ce travail est d’acquérir des connaissances sur le rôle du TL1A (TNF-like molécule 1 A; TNFSF15) et son partenaire Nob1 (Pno1 ; YOR145c) dans la pathogenèse de la PR afin de découvrir de nouveaux médicaments contre ces molécules dans l'avenir. TL1A est un membre de la famille du TNF. Il déclenche des signaux co-stimulateurs via le récepteur de mort 3 (DR3) et induit la prolifération ainsi que la production des cytokines pro inflammatoires par les lymphocytes. Des données multiples suggèrent l'implication de la cascade TL1A-DR3 dans plusieurs maladies auto-immunes. Donc, nous avons proposé les hypothèses suivantes:1) la production locale de TL1A dans les articulations est un composant d’un cercle vicieux qui aggrave la PR; 2) dans la PR, la production de TL1A dans les organes lymphoïde augmente la production d’auto-anticorps pathogénique. Au cours de ce travail, nous avons démontré que la TL1A aggrave la maladie chez les souris où l’arthrite a été induite par le collagène (AIC). Par ailleurs, nous avons constaté que l’expression de TL1A est élevée dans les tissus atteints de PR ainsi que dans les ganglions lymphatiques drainant de la souris AIC. Mécaniquement, nous avons découvert que la TL1A est induite par le TNF-α et IL-17 produits par les cellules T in vitro. Ces résultats montrent directement que les TL1A-DR3 jouent un rôle essentiel dans la pathogenèse de la PR. De plus, afin de poursuivre notre étude, la TL1A a été génétiquement supprimée dans les souris (TL1A KO). Nous avons montré que les souris TL1A KO n’ont aucune anomalie apparente et aucun dysfonctionnement du système immunitaire dans des conditions normales. Cependant, ces souris manifestent des AIC améliorées et une réduction significative des niveaux d'anticorps, anti-collagène du type II i dans le sérum. Nous avons trouvé que les ganglions lymphatiques de drainage (dLNs) de souris KO étaient plus petites avec une cellularité inférieure comparativement aux souris WT de 14 jours après l’immunisation. De plus, nous avons découvert que le DR3 a été exprimé par les cellules plasmatiques dans l’étape de la différenciation terminale et ces cellules surviennent mieux en présence de TL1A. La conclusion de cette étude apporte des nouvelles connaissances sur le rôle de TL1A qui amplifie les réponses humorales d’AIC. Nous avons suggéré que TL1A pourrait augmenter la réponse d’initiation d'anticorps contre collagène II (CII) ainsi que prolonger la survie des cellules plasmatiques. Une autre molécule qui nous intéresse est Pno1. Des études antérieures menées chez la levure ont suggéré que Pno1 est essentielle pour la néogénèse du protéasome et du ribosome Le protéasome étant crucial pour la différenciation terminale des cellules plasmatiques pendant les réponses humorales chez les mammifères, nous avons donc supposé que Pno1 joue un rôle dans la production d'anticorps pathogenique dans la PR via la voie du protéasome. Nous avons donc généré des souris génétiquement modifiées pour Pno1 afin d’étudier la fonction de Pno1 in vivo. Cependant, une mutation non-sens dans le Pno1 provoque une létalité embryonnaire à un stade très précoce chez les souris. D'autre part, une réduction de 50% de Pno1 ou une surexpression de Pno1 n’ont aucun effet ni sur le fonctionnent des cellules T et B, ni sur les activités du protéasome ainsi que sur la réponse humorale dans l’AIC. Ces résultats suggèrent que Pno1 est une molécule essentielle sans redondance. Par conséquent, il n’est pas une cible appropriée pour le développement de médicaments thérapeutiques. En conclusion, nos études ont révélé que la TL1A n’est pas essentielle pour maintenir les fonctions du système immunitaire dans des conditions normales. En revanche, il joue un rôle critique dans la pathogenèse de la PR en favorisant l'inflammation locale et la réponse humorale contre des auto-antigènes. Par conséquent, une inhibition de la TL1A pourrait être une stratégie thérapeutique pour le traitement de la PR. Au contraire, Pno1 est essentiel pour la fonction normale des cellules. Une délétion totale pourrait entraîner des conséquences graves. Il n’est pas une cible appropriée pour développer des médicaments de la PR. / Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation of multiple small joints, which manifests pain, redness, swelling, and deformation. Studies with patients and animal models have found that autoantibodies, cytokines and tissue-destructive enzymes are important mediators of the pathogenesis of RA. In the past two decades, biologic disease-modifying antirheumatic drugs (DMARDs) have achieved great success in the treatment of RA. On the other hand, they are also associated with adverse effect like increasing the chance of opportunistic infections. The aim of present work was to investigate the roles of TNF-like molecule 1A (TL1A; TNFSF15) and partner of Nob1 (Pno1; YOR145c) in the pathogenesis of RA for developing novel drugs based on these molecules in the future. TL1A is a member of the TNF superfamily. It triggers costimulatory signals though death receptor 3 (DR3) and induces the proliferation and pro-inflammatory cytokine production in lymphocytes. Multiple lines of evidence suggest the implication of TL1A-DR3 signaling in several autoimmune diseases. Therefore, We hypothesized that 1) local TL1A production in the joints is a component of a vicious circle aggravating RA; 2) in RA, TL1A production in lymphoid organs enhances pathogenic autoantibody production. We demonstrated that the TL1A aggravates disease in murine collagen-induced arthritis (CIA). Moreover, we found elevated TL1A expression in RA-affected tissues, as well as in the draining lymph nodes (dLNs) of CIA mice. Mechanistically, we discovered that TL1A induces TNF-α and IL-17 production by T cells in vitro. These findings provided direct evidence that TL1A-DR3 signaling plays a critical role in the pathogenesis of RA. TL1A knockout (TL1A KO) mice were generated to further our study. We showed that TL1A KO mice have no visual anomaly, and no malfunction of immune system under a normal circumstance. However, they display ameliorated CIA and significantly reduced anti-Collagen II antibody levels in sera. We found that the draining lymph nodes (dLNs) from KO mice were smaller in size and lower in cellularity compared with their WT counterparts 14 days after immunization. Furthermore, we discovered that terminally differentiated plasma cells express DR3 and they survive better in the presence of TL1A. Our findings in this study present novel knowledge about the role of iii TL1A promoting the humoral responses in CIA; we suggest that TL1A could elevate the initial Ab response against Collagen II (CII), as well as prolong the survival of plasma cells producing such pathogenic Abs. Another molecule we were interested in present study is Pno1. Previous studies conducted in yeast suggest that Pno1 is essential to the proteasome and ribosome neogenesis. Since proteasome is crucial for the terminal differentiation of plasma cells during the humoral response in mammals, we hypothesized that Pno1 plays a role in the pathogenic Ab production in RA by affecting the proteasome assembly. For this purpose, we generated pno1 gene- modified mice to investigate the function of Pno1 in vivo. However, null-mutation in pno1 causes embryonic lethality in mice at a very early stage. On the other hand, a half amount reduction or overexpression of Pno1 is neither harmful nor useful to the T and B cell function, proteasome activities as well as humoral immune responses in CIA. These findings suggest that Pno1 is a vital molecule with no redundancy and is absolutely required for cell function, but animals can function normally with a small fraction of the normal Pno1 expression level. Thus, it might not be an appropriate target for developing therapeutic drugs. In conclusion, our studies suggest that TL1A seems not essential in maintaining the immune functions under normal circumstances, but plays critical roles in the pathogenesis of RA by promoting local inflammation and humoral immune responses against autoantigens. Therefore, inhibiting TL1A could be a propitious therapeutic strategy for treating RA. In contrast, Pno1 is vital to the normal cell function, and its disruption could cause disastrous consequences. Thus, it might not be a good drug target for treating RA.

La polyarthrite rhumatoïde (PR) est le rhumatisme inflammatoire chronique le plus fréquent. La PR est une maladie génétique où il existe plusieurs allèles de susceptibilité HLA-DRB1. Les auto-anticorps anti-protéines citrullinées sont les plus spécifiques de la PR. Ils sont détectés par les tests anti-peptides cycliques citrullinés (anti-CCP). 1/L’objectif de notre premier travail était de montrer l’influence des allèles susceptibilité HLA-DR sur la présence d’anti-CCP dans notre population marseillaise de PR. Nous avons montré que les allèles de susceptibilité HLA-DR ne sont pas nécessaires à la présence des anticorps anti-CCP. Nous avons mis en évidence une association entre l’allèle HLA-DRB1*04:04 et la présence des anti-CCP.2/Environ un tiers des patients présentant une PR n’ont pas d’anticorps anti-CCP. Nous avons donc recherché des nouveaux auto-anticorps pour le diagnostic de la maladie.Les auto-anticorps dirigés contre le domaine catalytique de la protéine B-Raf (v raf murine sarcoma viral oncogen homologue B1) ont été identifiés par la technique des puces à protéines chez les patients PR. B-Raf est une sérine-thréonine kinase qui est impliquée dans la voie des MAP-kinases. Nous avons montré que les auto-anticorps anti-B-Raf activent B-Raf. Nous avons montré que le peptide p25 de B-Raf est spécifiquement reconnu par les auto-anticorps des PR. Les auto-anticorps anti-p25 identifient 21% des patients PR sans anticorps anti-CCP.3/En utilisant des puces à protéines, nous avons identifié 24 nouveaux auto-antigènes associés aux PR débutantes. Quatre de ces auto-antigènes ont été validés par ELISA : GABA(A) receptor associated protein like, zinc finger protein 706, tropomyosin 2 et WIBG (within BGCN homolog (Drosophila)). Les auto-anticorps anti-WIBG identifient exclusivement les PR.Ces nouveaux auto-antigènes pourront être utilisés dans le diagnostic des PR débutantes et des PR sans anticorps anti-CCP. / Rheumatoid arthritis (RA) is a chronic inflammatory disease with a prevalence of 0.5% wordwilde. HLA-DR genes are the strongest genetic prevalence in RA. The sera of RA patients contain many auto-antibodies. The most characteristic are directed at citrullinated proteins (ACPA). ACPA can be detected by commercially available enzyme-linked immune-absorbent assays using synthetic cyclic citrullinated peptides (CCP).1/In the first work we tested whether the presence of RA associated HLA-DRB1 alleles individually influences anti-CCP production in a population of RA from Marseille. We showed RA associated HLA-DR alleles are not mandatory for the production of anti-CCP. HLA-DRB1*04:04 was the most strongly associated with the presence of anti-CCP in RA sera. 2/ Anti-CCP antibodies are detected in 65% of RA patients. We wanted to detect new auto-antibodies for the diagnosis of RA.By screening protein arrays we found that B-Raf (v raf murine sarcoma viral oncogen homologue B1) is a major non-citrullinated auto-antigen recognized by 35% of RA patients’sera. B-Raf encodes a serine threonine-kinase involved in the MAPK signaling pathway. We showed that anti-B-Raf auto-antibodies activate the in vitro phosphorylation of MEK1 mediated by B-Raf.We found that one peptide of B-Raf, p25, is specifically recognized by auto-antibodies from RA patients. Of interest, anti-p25 auto-antibodies are detected in 21% of anti-CCP negative RA patients.3/We identified 24 new auto-antigens associated with RA patients with disease duration less than one year using 8000 human protein arrays. We identified four auto-antigens recognized almost uniquely by sera of early RA patients: GABA(A) receptor associated protein like, zinc finger protein 706, tropomyosin 2 and WIBG (within BGCN homolog (Drosophila)). These reactivities were confirmed by ELISA on purified proteins. Auto-antibodies to anti-WIBG identify exclusively RA patients’sera. These new auto-antigens could be used for the diagnosis of anti-CCP negative RA patients and in early RA.