Background. Rheumatoid arthritis (RA) is an autoimmune disease mainly affecting the joints but has also extra articular manifestations and an increased cardiovascular (CV) co-morbidity. Rheumatoid factor (RF) and antibodies against citrullinated proteins/peptides (ACPA) are diagnostically important and are related to a more severe disease. The aetiology is unknown but RA is considered a complex disease caused by both genetic and environmental factors. The heritability is estimated to be 60% with the main contribution from the HLA region. The relative homogeneity of the population in northern Sweden due to low immigration and founder effects has shown to be suitable for genetic studies. Objectives. The aim of this thesis has been to identify genes contributing to the susceptibility of RA and the CV co-morbidity in particular. To achieve this, multi-case families from the four northern most counties of Sweden were collected for linkage studies to identify susceptibility genes. Association studies with genetic polymorphisms in genes, involved in inflammation or being of importance for atherothrombotic manifestations (ATM) in the general population, were performed in RA-patients concerning ATM e.g. myocardial infarction, angina pectoris with intervention, stroke/TIA, deep vein thrombosis/pulmonary embolism (DVT/PE) at follow-up. Methods & Results. 47 families with 134 affected and 216 unaffected relatives were included in a genome-wide linkage study (GWL) performed with microsatellite markers at an average of 10cM resolution analysed using ABI PRISM 3730 DNA sequencer and non-parametric multipoint linkage in the Merlin program. Eight linked loci were identified with HLA as the most significant and a novel region on chromosome 14. In a follow-up analysis on a custom Illumina chip, with 13 additional families, yielding a total of 198 affected and 197 unaffected relatives. The majority of the 1536 single nucleotide polymorphisms (SNPs) used in the Illumina follow-up analyses was focused on chromosome 14. Statistical analyses with linkage and transmission disequilibrium test narrowed the region to 4 cM, a region containing multiple plausible RA candidate genes (Paper I). In Paper II  serum samples from 163 affected and 157 first degree relatives were analysed with EliA ACPA assay on ImmunoCAP250 for ACPA (IgA, IgG, IgM) and RF (IgA, IgM) isotypes. Both concentrations and frequencies were increased among the relatives compared with controls but lower compared with RA-patients and with a different relative distribution of the isotypes. The genetic contribution to ATM was studied in Paper III and IV using selected SNPs analysed using ABI PRISM 7900HT sequence detector system. In Paper III, RA-patients (n=467) were compared with age and sex matched controls (n=696) with respect to SNPs in tumor necrosis factor receptor II (TNFRII)(M196R), ß-fibrinogen -455 (G-455A), plasminogen activator inhibitor type-1 (PAI-1) (4G/5G) and Factor XIIIA (Val34Leu). Hypertension was predicted by TNFRII R allele and to a higher extent in combination with the A-allele in ß-fibrinogen. The 4G allele in PAI-1 was more frequent in patients with ischemic heart disease (IHD) and the FXIIIA Leu34 variant in patients with DVT/PE. In Paper IV, the minor allele of the polymorphism in growth differentiation factor 15 (GDF15) was found to be associated with RA (n=696) per se but also to ATM, a SNP in the 9p21.3 locus was also associated with ATM. A significant association to stroke was found in female patients homozygote for the minor allele of GDF15. Stoke among male patients was significantly associated with carrying the major allele of two SNPs in the CD40 gene. DVT/PE was associated with the minor allele of GDF15. Conclusion. A novel locus on chromosome 14 of importance for RA susceptibility in northern Sweden was found. The minor allele of TNFRII separately and together with the minor allele of ß-fibrinogen -455 was associated with hypertension and the 4G allele in PAI-1 was associated with IHD and  the Leu34 variant was associated with DVT/PE in RA patients. The GDF15 minor allele was associated with RA per se, ATM and DVT/PE in RA patients and a genotype in the SNP on 9p21.3 was associated with ATM. Stroke among females was associated with GDF15 and stroke among males with two SNPs in CD40.

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.

Background: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterised by autoantibody production and variable clinical features, ranging from mild to severe disease. Patients with SLE are at increased risk of developing accelerated atherosclerosis. Biomarkers have potential utility in SLE as markers of disease or predictors of future clinical events and mortality. Objective The aim of this thesis was to identify serological biomarkers predictive for erosive arthritis (EA), cardiovascular events (CVEs), mortality and subclinical atherosclerosis in SLE. Methods: In chapters 2 to 4, study subjects were SLE patients from Bath. Anti-cyclic citrullinated peptide antibodies (ACPA) and HLA-DR and -DQ were studied for markers of EA, and anticardiolipin (aCL) and lipoprotein profiles for markers of CVEs and mortality. In chapters 5 and 6, study subjects were women with SLE from Manchester. B-mode ultrasound scans of subjects' carotid arteries were performed at baseline and follow-up time-points to detect atherosclerotic plaque. Baseline IgG and IgM antiphospholipid (aPL) antibodies and CV risk factors were studied for markers of subclinical atherosclerosis. Clinical data collected for all studies included SLE features and auto-antibody profiles. Results: ACPA was identified as a marker of a SLE phenotype with EA - "rhupus". Patients with major erosive arthritis were HLA-DQB1*0302 carriers. Increased aCL GPL levels and total cholesterol : high density lipoprotein-C (TC : HDL-C) ratio were markers for future CVEs, and increased TC : HDL ratio, aCL GPL and lipoprotein(a) concentrations were markers for increased mortality. Lower HDL-C concentrations and anti-annexin A5 (anti-AnxA5) GPL were markers of carotid plaque progression. Conclusion: This thesis identified new markers for EA, subclinical atherosclerosis and future CVE and mortality risk in SLE. Strategies to incorporate these new CV markers into clinical CV risk assessments may assist in distinguishing the subset of SLE patients most at risk of developing accelerated atherosclerosis.

Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2015-04-08T22:07:57Z No. of bitstreams: 1 Isabella Vargas de Souza Lima.pdf: 9375405 bytes, checksum: a3d913a7254631a76ea5f2fc0da63ddc (MD5) / Made available in DSpace on 2015-04-08T22:07:57Z (GMT). No. of bitstreams: 1 Isabella Vargas de Souza Lima.pdf: 9375405 bytes, checksum: a3d913a7254631a76ea5f2fc0da63ddc (MD5) Previous issue date: 2012 / É reconhecida a interface entre a reumatologia, particularmente no que diz respeito às doenças autoimunes, e a infectologia, seja pela hipótese de agentes infecciosos atuando como gatilho das disfunções imunológicas, seja pelo risco infeccioso atribuído aos tratamentos imunossupressores. Adicionalmente, tem sido observada a produção de alguns autoanticorpos no curso de infecções. Por exemplo: em pacientes com tuberculose (TB), foi demonstrada a produção de anticorpos descritos como de alta especificidade para artrite reumatóide (AR) como os anticorpos antipeptídeos citrulinados (ACPAs) e, do mesmo modo, foi demonstrada a presença de anticorpos anticitoplasma de neutrófilos (ANCA) dentre os quais antiproteinase 3 (anti-PR3) e antimieloperoxidase (anti-MPO), que são marcadores de vasculites sistêmicas. Objetivos: a) revisar as publicações sobre positividade dos ACPAs em doenças infecciosas, b) pesquisar a prevalência destes anticorpos assim como do ANCA em uma população de portadores de tuberculose. Métodos: a) inicialmente foi realizada uma revisão sistemática sobre os estudos avaliando a presença de ACPAs em doenças infecciosas; b) posteriormente, um grupo de 50 pacientes com TB pulmonar não tratada ou com até 30 dias do início do tratamento foi avaliado quanto à presença de sintomas reumatológicos e, principalmente, quanto à positividade de anticorpos ACPAs, incluindo antipeptídeo citrulinado cíclico (anti-CCP) e antivimentina citrulinada modificada (anti-MCV) e quanto à positividade de ANCA por imunofluorescência indireta (IFI) e anticorpos anti-PR3 e anti-MPO por enzimaimunoensaio (ELISA). Resultados: a) a revisão sistemática foi publicada e encontra-se apresentada “Revisão de literatura” com o título Antibodies against cyclic citrullinated peptides in infectious diseases – a systematic review. Clin Rheumatol 2010, Dec 29(12): 1345-51. b) encontrou-se positividade de ACPAs em apenas dois (4%) dos 50 pacientes com TB e não houve positividade de ANCA por IFI ou a presença de anticorpos anti-PR3 ou anti-MPO por ELISA no soro desses pacientes. Estes resultados estão apresentados em dois artigos que foram submetidos para a revista Clinical Rheumatology (Canadá, fator de impacto 2011: 1,996), aguardando o parecer do corpo editorial. As versões submetidas encontram-se na sessão “Artigos”. Conclusões: embora estudos prévios tenham relatado a presença de ACPAs e ANCA em pacientes com TB, no presente estudo a positividade dos ACPAs foi baixa e não foi observada positividade para ANCA, anti-PR3 e anti-MPO, confirmando a alta especificidade destes testes para AR e vasculites sistêmicas, respectivamente.

La polyarthrite rhumatoïde est une pathologie auto-immune qui affecte près de 1% de la population mondiale et se caractérise par une inflammation articulaire, des altérations cartilagineuses et osseuses notamment associées à des douleurs chroniques articulaires, souvent résistantes aux thérapeutiques actuelles. Que ce soit à un stade préclinique, où l’on parle d’arthralgie, ou à un stade établi de la pathologie, ces douleurs constituent un réel handicap pour les patients atteints avec plus de 60% d’entre eux insatisfaits de sa prise en charge. La présence d’une synovite étant nécessaire au diagnostic de la PR, aucune stratégie thérapeutique n’est mise en place à un stade préclinique. En outre, à un stade établi, la stratégie actuelle vise en premier lieu à diminuer l’activité de la pathologie sans prise en charge de la douleur en tant que telle. Parmi les acteurs de la synovite dans la PR, un rôle essentiel est attribué au facteur de croissance des nerfs ou Nerve Growth Factor dans la mise en place et le maintien des symptômes douloureux. Les anti-NGF sont connus comme des molécules antalgiques prometteuses. Néanmoins, de par son action pléiotropique, cibler cette neurotrophine conduit à des effets indésirables potentiellement importants. Dans la première partie de ce travail, nous avons cherché à mieux caractériser l’implication spécifique des voies de signalisation intracellulaires au récepteur tyrosine kinase de type A (TrkA) de haute affinité au NGF, dans un contexte de douleur articulaire inflammatoire (arthrite) mais aussi de douleurs somatique et viscérale. Un modèle de knock-out total pour le récepteur TrkA n’étant pas viable, nous avons réalisé une étude multimodale chez des souris knock-in TrkA/C, exprimant un récepteur chimérique composé de la partie extracellulaire native du récepteur TrkA et des parties transmembranaire et intracellulaire fonctionnelles du récepteur à la neurotrophine 3 : le récepteur TrkC. Ce dernier n’étant que peu ou pas impliqué dans la douleur inflammatoire. Ainsi, le NGF pourra se lier normalement au récepteur TrkA/C mais activera les voies de signalisation intracellulaires du récepteur TrkC. Les résultats de nos études ont mis en évidence qu’une absence d’activation de certaines voies en aval de TrkA (i.e. c-Jun et p38 MAPK) au niveau des DRGs chez les souris TrkA/C, impacte significativement la mise en place des symptômes douloureux, en particulier l’hypersensibilité mécanique, que ce soit dans un contexte de douleur articulaire, somatique ou viscérale, sans affecter l’hyperalgie thermique au chaud. Ces résultats résultent d’une part de la diminution de la néo-innervation CGRP+ mais aussi de changements transcriptionnels de certains neurotransmetteurs et mécanotransducteurs dont le canal ionique sensible aux protons : ASIC3. De plus, un lien entre NGF/TrkA et le remodelage osseux, en particulier, l’activation ostéoclastique, a été démontré mettant en avant un rôle doublement bénéfique de l’inhibition de certaines voies associées à TrkA, à la fois dans certains symptômes douloureux et l’érosion osseuse retrouvée dans la PR. Dans un deuxième temps, nous nous sommes intéressés aux mécanismes impliqués dans l’arthralgie induite par l’injection d’autoanticorps anti-peptides citrullinées (ACPA). La majorité des patients PR sont positifs pour les ACPA qui peuvent être produits des mois voire des années, avant son diagnostic et semblent être directement associés au développement des symptômes douloureux. Cette arthralgie constitue l’un des premiers signes d’une PR émergente et peu persister, même suite à la prise en charge thérapeutique des patients PR. Tout d’abord, nous avons confirmé que les sous-types monoclonaux IgG1 ACPA diffèrent par leurs propriétés pronociceptives et érosives de l’os, certainement liées à leurs différentes réactivités vis-à-vis des épitopes citrullinés. (...) / Rheumatoid arthritis is an autoimmune disease that affects nearly 1% people worldwide and is characterized by joint inflammation, cartilage and bone damages, associated with chronic joint pain, often resistant to current therapies. Whether at a preclinical stage, where we talk about arthralgia, or at an established stage of the pathology, pain constitutes a real burden for the patients with more than 60% rating their pain management has unsatisfactory. The presence of synovitis is necessary for the diagnosis of established RA, therefore, no real therapeutic strategy is used at a preclinical stage. In addition, at an established stage, the current strategy aimed primarily at reducing the activity of the pathology without an actual management of the pain as such. Among the actors of synovitis in RA, Nerve Growth Factor plays a critical role in the establishment and maintenance of painful symptoms. Anti-NGF are known as promising analgesic drugs. Nevertheless, due to pleiotropic effects of NGF, targeting this neurotrophin leads to significant adverse effects. In the first part of this work, we sought to better characterize the specific involvement of intracellular signaling pathways of the high affinity tyrosine kinase A (TrkA) receptor of NGF in a context of inflammatory joint pain (arthritis), but also of somatic and visceral pain. Since a total knockout of TrkA receptor in mice is not viable, we performed a multimodal study in TrkA/C knock-in mice, expressing a chimeric receptor composed of the native extracellular part of TrkA receptor and, the transmembrane and intracellular functional parts of the neurotrophin 3 receptor: TrkC receptor, which is not really involved in inflammatory pain. Thus, NGF can bind normally to the TrkA/C receptor but activates the intracellular signaling pathways downstream of TrkC receptor. Our results have shown that a lack of activation of certain TrkA pathways (i.e. c-Jun and p38 MAPK) in the DRGs of TrkA/C mice, has a significant impact on the development of painful symptoms, especially mechanical hypersensitivity in a context of articular, somatic, or visceral pain, without affecting heat thermal hyperalgesia. These effects result, on one hand, from the decrease of CGRP+ nerve sprouting and in another hand, from the transcriptional changes of some neurotransmitters and mechanotransducers including the proton-sensitive ion channel: ASIC3. In addition, our studies highlight a direct link between NGF/TrkA and bone remodeling, in particular, osteoclastic activity, suggesting a beneficial role of the inhibition of some specific TrkA-associated pathways, in both mechanical hypersensitivity and bone erosion found in RA.In a second part of our work, we investigated the mechanisms involved in arthralgia induced by the injection of autoantibodies against citrullinated peptides (ACPA). The majority of RA patients is positive for ACPA that can be produced months to years before RA diagnosis and appear to be directly associated with the development of pain. Arthralgia is one of the first signs of an emerging RA and can persist even following RA treatment. First, we confirmed that monoclonal ACPA IgG1 subtypes differ in their pronociceptive and bone erosive properties certainly link to their reactivity patterns against citrullinated epitopes on different targets especially those engaging osteoclast activity. Thus, the combination of B02/B09 ACPA clones induced pain like behaviour without any inflammation, but is associated with an alteration of bone homeostasis in injected mice. We suggest that as a result of ACPA-induced osteoclast activation, certain factors (e.g. protons and/or lipids) are released, which sensitize ASIC3, ultimately leading to pain.

Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated. Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (<58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed. Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years. Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

Ces travaux de thèse concernent le développement de nouvelles méthodes de séparation aveugle de mélanges linéaires instantanés pour des applications à des données hyperspectrales en astrophysique. Nous avons proposé trois approches pour effectuer la séparation des données. Une première contribution est fondée sur l'hybridation de deux méthodes existantes de séparation aveugle de source (SAS) : la méthode SpaceCORR nécessitant une hypothèse de parcimonie et une méthode de factorisation en matrices non négatives (NMF). Nous montrons que l'utilisation des résultats de SpaceCORR pour initialiser la NMF permet d'améliorer les performances des méthodes utilisées seules. Nous avons ensuite proposé une première méthode originale permettant de relâcher la contrainte de parcimonie de SpaceCORR. La méthode MASS (pour \textit{Maximum Angle Source Separation}) est une méthode géométrique basée sur l'extraction de pixels mono-sources pour réaliser la séparation des données. Nous avons également étudié l'hybridation de MASS avec la NMF. Enfin, nous avons proposé une seconde approche permettant de relâcher la contrainte de parcimonie de SpaceCORR. La méthode originale SIBIS (pour \textit{Subspace-Intersection Blind Identification and Separation}) est une méthode géométrique basée sur l'identification de l'intersection de sous-espaces engendrés par des régions de l'image hyperspectrale. Ces intersections permettent, sous une hypothèse faible de parcimonie, de réaliser la séparation des données. L'ensemble des approches proposées dans ces travaux ont été validées par des tests sur données simulées puis appliquées sur données réelles. Les résultats obtenus sur ces données sont très encourageants et sont comparés à ceux obtenus par des méthodes de la littérature. / This thesis deals with the development of new blind separation methods for linear instantaneous mixtures applicable to astrophysical hyperspectral data sets. We propose three approaches to perform data separation. A first contribution is based on hybridization of two existing blind source separation (BSS) methods: the SpaceCORR method, requiring a sparsity assumption, and a non-negative matrix factorization (NMF) method. We show that using SpaceCORR results to initialize the NMF improves the performance of the methods used alone. We then proposed a first original method to relax the sparsity constraint of SpaceCORR. The method called MASS (Maximum Angle Source Separation) is a geometric method based on the extraction of single-source pixels to achieve the separation of data. We also studied the hybridization of MASS with the NMF. Finally, we proposed an approach to relax the sparsity constraint of SpaceCORR. The original method called SIBIS (Subspace-Intersection Blind Identification and Separation) is a geometric method based on the identification of intersections of subspaces generated by regions of the hyperspectral image. Under a sparsity assumption, these intersections allow one to achieve the separation of the data. The approaches proposed in this manuscript have been validated by experimentations on simulated data and then applied to real data. The results obtained on our data are very encouraging and are compared with those obtained by methods from the literature.

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