A Hepatite Autoimune (HAI) é uma doença inflamatória crônica oriunda de autoimunidade, ocasionando fibrose hepática. O objetivo desse estudo foi verificar possíveis inter-relações entre HLA-G, BAMBI e processos inflamatórios/fibrogênicos hepáticos na Hepatite Autoimune, tanto em biópsias de pacientes pré quanto póstratamento com imunossupressores. Foram selecionadas noventa e cinco biópsias de pacientes do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto diagnosticados com HAI, associados ou não a depósitos de ferro no fígado. As biópsias foram submetidas à imuno-histoquímica para marcação das proteínas HLAG e BAMBI. As estatísticas foram determinadas pelos testes Mann-Whitney e correlação de Spearman. A expressão de HLA-G e de BAMBI se apresentou aumentados conforme o agravamento da inflamação e fibrose em pacientes pré- tratamento com boa ou má resposta ao tratamento. No entanto, a expressão de HLAG e de BAMBI foi reduzida nas biópsias pós-tratamento apenas nos pacientes bom respondedores (diminuição da fibrose). Não houve quaisquer relações entre as quantificações de HLA-G e BAMBI com o número de plasmócitos ou com depósitos de ferro no fígado tanto em pacientes pré quanto pós-tratamento. Os resultados sugerem que tanto HLA-G quanto BAMBI são imunorreguladores sensíveis à intensidade do processo inflamatório no fígado, tendo suas expressões aumentadas ou diminuídas de acordo com a demanda por substâncias que regulem compostos e células imunológicas na HAI. Sugerem também que o infiltrado plasmocitário não é regulado diretamente pelo HLA-G ou BAMBI, e que os depósitos de ferro no fígado não são capazes de influenciar nem o grau inflamatório, nem as expressões de HLAG e BAMBI. / Autoimmune Hepatitis (HAI) is a chronic inflammatory disease originating from autoimmunity, causing liver fibrosis. The objective of this study was to verify possible interrelations between HLA-G, BAMBI and inflammatory / fibrogenic hepatic processes in Autoimmune Hepatitis, both in pre and post-treatment immunosuppressive biopsies. Ninety-five biopsies of patients from the Clinical Hospital of the Medical School of Ribeirão Preto diagnosed with HAI, associated or not with iron deposits in the liver, were selected. Biopsies were submitted to immunohistochemistry for the labeling of HLA-G and BAMBI proteins. The statistics were determined by the Mann-Whitney tests and Spearman\'s correlation. The expression of HLA-G and BAMBI was increased as worsening of inflammation and fibrosis in pre-treatment patients with good or poor response to treatment. However, the expression of HLA-G and BAMBI was reduced in post-treatment biopsies only in patients with good responders (decreased fibrosis). There were no relationships between the quantifications of HLA-G and BAMBI with the number of plasma cells or with liver iron deposits in both pre and post-treatment patients. The results suggest that both HLA-G and BAMBI are immunoregulators sensitive to the intensity of the inflammatory process in the liver, their expressions being increased or decreased according to the demand for substances that regulate immune cells and compounds in HAI. They also suggest that plasmacytic infiltrate is not directly regulated by HLA-G or BAMBI, and that the liver iron deposits are not capable of influencing either the inflammatory grade or the expressions of HLA-G and BAMBI.

La population actuelle de l'archipel des Comores est considérée comme étant le résultat de contacts entre des populations d'origine Africaine Bantoue, Arabe et Austronésienne. Le but de cette étude est de décrire sa structure génétique, au travers de l'analyse de six groupes sanguins érythrocytaires, du polymorphisme du locus HLA-DR-B1 et des gènes KIR. 164 individus, non apparentés, d'origine Comorienne résidant à Marseille ont été étudiés. Les résultats révèlent que la contribution génétique des populations originaires de l'Afrique Bantoue est la plus importante (50 à 60%) et est en accord avec la forte influence culturelle encore présente. La contribution des populations en provenance de la Péninsule Arabique est plus faible (30%) et semble à la hauteur de leur influence religieuse et linguistique. Enfin, comme au niveau linguistique, l'impact du Sud Est Asiatique sur le pool génétique Comorien paraît quasiment absent. De plus, cette étude génétique, en révélant les écarts phénotypiques qui existent entre une population migrante et celle des donneurs de sang du pays d'accueil, souligne la nécessité d'actions spécifiques de sensibilisation au don de sang.

Type 1 diabetes (T1D) is a chronic disease caused by destruction of the insulin producing beta-cells in the pancreas. The incidence of T1D has increased rapidly, especially in the Western world and among young children. The pathogenesis of T1D is not fully understood, but the beta-cells are believed to be destroyed by an autoimmune process initiated years before the onset of T1D. During this pre-clinical period, autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the tyrosine phosphatase-like protein IA-2 (IA-2A) can be detected and are used to identify individuals at risk of T1D. The major genetic determinant for T1D is the HLA class II genes, but also polymorphism in the insulin gene and CTLA-4 gene are associated with T1D. The risk genes cannot explain the rapid increase in incidence of T1D, therefore a role for different environmental factors has been suggested. The aim was to study the prevalence of beta-cell autoantibodies in children from the general population in relation to known genetic and environmental risk factors, and in young patients with T1D in high and low incidence areas. Short duration of breast-feeding was associated with an increased risk of developing beta-cell autoantibodies in children from the general population at 5-6 years of age. We found an association between positivity for GADA and/or IAA at the age of 5-6 years and a short duration of total breastfeeding, and also between positivity for GADA, IA-2A and/or IAA and a short duration of exclusive breast-feeding. Our findings suggest that breast-feeding has a long term protective effect on the risk of beta-cell autoimmunity in children from the general population. The T1D related risk genes were not associated with beta-cell autoantibodies other than GADA in children from the general population at 5-6 years of age. Children with the DR4-DQ8 haplotype were more often positive for GADA than children without this haplotype. We found no association of GADA with DR3-DQ2 haplotype or between these two haplotypes and any of the other autoantibodies. Our results suggest that beta-cell autoimmunity in children from the general population is not strongly associated with any risk genes of T1D other than DR4-DQ8. In the non-diabetic children with allergic heredity GADA was detectable in almost all children, IA-2A in about half and IAA in 10% of the children. The levels low of these autoantibodies fluctuated with age and different patterns of fluctuations were seen for GADA and IA-2A, which may reflect differences in the immune response to the autoantigens. In patients with newly diagnosed T1D, we found some differences between patients from a high incidence country (Sweden) and a country with a lower incidence (Lithuania). Among the Swedish patients, the prevalence of IAA and GADA or multiple autoantibodies was higher than in Lithuanian patients. The risk genes DR4-DQ8 and the heterozygous high risk combination DR4-DQ8/DR3-DQ2 was more common among the Swedish patients than Lithuanian patients. Patients with low levels of IAA had higher levels of HbA1c and ketones, indicating that patients without IAA or with low levels of IAA have a more severe onset of T1D. Our findings indicate that beta-cell autoimmunity is more pronounced in a high incidence area compared to an area with a lower incidence. In conclusion, short duration of breast-feeding is a risk factor for beta-cell autoantibodies in children from the general population, and the beta-cell autoantibodies in these children are not associated with specific risk genes. Children with newly diagnosed T1D in a high incidence area carry risk genes and have autoantibodies more often than newly diagnosed children from an area with a lower incidence, perhaps indicating different disease phenotypes.

Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. PsA has a heterogeneous pattern, expressed by different manifestations such as mild mono-oligoarthritis or very severe, erosive and destructive polyarthritis. Measurable inflammatory activity is not always prominent. The aetiology is unknown but genetic factors are believed to be of importance. The pattern of inheritance is proposed to be polygenic. The aim of this study was to estimate the prevalence of joint and axial manifestations, characterise the disease in relation to inflammatory and genetic markers, and to identify disease susceptibility gene(s) for PsA in patients from northern Sweden. All patients from the city of Umeå (n=276), selected from a community and hospital based psoriasis register (n=1737) at the Dept of Dermatology, were invited to a prevalence study. Two hundred-two patients were examined and 97 (48%) had inflammatory manifestations such as peripheral arthritis, axial disease, undifferentiated spondylarthropathy (uSpA) and enthesopathies. Of the 67 patients (33 %) with peripheral arthritis and/or axial disease, 30 were not previously diagnosed. The association of clinical manifestations and potential markers of aggressive joint disease with HLA associations were analysed in 88 patients with PsA. We were not able to confirm findings of other groups reporting strong association with several HLA-antigens. The prevalence of HLA-B17, B37 and B62 was increased compared with controls, but the strongest predictive factors among our patients for an aggressive disease, in a multiple logistic analysis, were polyarthritic disease and distal interphalangeal engagement. In order to investigate for disease susceptibility genes, five genetic loci were analysed with microsatellites and single nucleotide polymorphisms in an association study of 120 patients with PsA. There was a significant association with the TNFB locus on chromosome 6p but not with any other loci examined; 1q21 (PSORS4), 3q21 (PSORS5), 8q24 and CTLA4. When stratifying for the TNFB alleles the association was confined to allele 123. In a subgroup of patients who were HLA-typed (n=83), we were not able to verify linkage disequilibrium with the TNFB allele 123 and the HLA antigens; B17, B27, B37, B62 or Cw*0602. The presence of renal abnormalities was evaluated as a manifestation of systemic inflammation in 73 patients with PsA. Renal abnormalities defined as decreased creatinine-clearance (≤ mean - 2SD) and/or urinary albumin >25 mg/24 h was found in 23% of the patients. The predictive factors for renal abnormalities was inflammatory activity (ESR > 25 mm/h and/or CRP >15 mg/L) indicating a systemic effect in some of the patients. In conclusion, we found high prevalence of inflammatory manifestations in patients with psoriasis. There was no strong association between PsA and HLA antigens and predictive factors for aggressive disease were polyarthritic disease and DIP joint engagement. The TNFB locus was associated with PsA and there were no linkage disequilibrium with the HLA antigens B17, B27, B62 or Cw*0602. There were evidence for systemic effects as renal abnormalities in patients with PsA and measurable inflammatory activity.

In nearly allmodern tracking systems, signal processing is an important part with state estimation as the fundamental component. To evaluate and to reassess different tracking systems in an affordable way, simulations that are in accordance with reality are largely used. Simulation software that is composed of many different simulating modules, such as high level architecture (HLA) standardized software, is capable of simulating very realistic data and scenarios. A modular and general-purpose state estimation functionality for filtering provides a profound basis for simulating most modern tracking systems, which in this thesis work is precisely what is created and implemented in an HLA-framework. Some of the most widely used estimators, the iterated Schmidt extended Kalman filter, the scaled unscented Kalman filter, and the particle filter, are chosen to form a toolbox of such functionality. An indeed expandable toolbox that offers both unique and general features of each respective filter is designed and implemented, which can be utilized in not only tracking applications but in any application that is in need of fundamental state estimation. In order to prepare the user to make full use of this toolbox, the filters’ methods are described thoroughly, some of which are modified with adjustments that have been discovered in the process. Furthermore, to utilize these filters easily for the sake of user-friendliness, a linear algebraic shell is created, which has very straight-forward matrix handling and uses BOOST UBLAS as the underlying numerical library. It is used for the implementation of the filters in C++, which provides a very independent and portable code.

Logical time management is used to synchronize the executions of distributed simulation elements. In existing time management systems, such as High Level Architecture (HLA), logical times of the simulation elements are synchronized. However, in some cases synchronization can unnecessarily decrease the performance of the system. In the proposed HLA based time management mechanism, federates are clustered into logically related groups. The relevance of federates is taken to be a function of proximity which is defined as the distance between them in the virtual space. Thus, each federate cluster is composed of relatively close federates according to calculated distances. When federate clusters are sufficiently far from each other, there is no need to synchronize them, as they do not relate each other. So in PATiM mechanism, inter-cluster logical times are not synchronized when clusters are sufficiently distant. However, if the distant federate clusters get close to each other, they will need to resynchronize their logical times. This temporal partitioning is aimed at reducing network traffic and time management calculations and also increasing the concurrency between federates. The results obtained based on case applications have verified that clustering improves local performance as soon as federates become unrelated.

<p>In nearly allmodern tracking systems, signal processing is an important part with state estimation as the fundamental component. To evaluate and to reassess different tracking systems in an affordable way, simulations that are in accordance with reality are largely used. Simulation software that is composed of many different simulating modules, such as high level architecture (HLA) standardized software, is capable of simulating very realistic data and scenarios.</p><p>A modular and general-purpose state estimation functionality for filtering provides a profound basis for simulating most modern tracking systems, which in this thesis work is precisely what is created and implemented in an HLA-framework. Some of the most widely used estimators, the iterated Schmidt extended Kalman filter, the scaled unscented Kalman filter, and the particle filter, are chosen to form a toolbox of such functionality. An indeed expandable toolbox that offers both unique and general features of each respective filter is designed and implemented, which can be utilized in not only tracking applications but in any application that is in need of fundamental state estimation. In order to prepare the user to make full use of this toolbox, the filters’ methods are described thoroughly, some of which are modified with adjustments that have been discovered in the process.</p><p>Furthermore, to utilize these filters easily for the sake of user-friendliness, a linear algebraic shell is created, which has very straight-forward matrix handling and uses BOOST UBLAS as the underlying numerical library. It is used for the implementation of the filters in C++, which provides a very independent and portable code.</p>

Les pemphigus sont des maladies auto-immunes spécifiques d'organe qui affectent la peau et les muqueuses. Ils sont caractérisés par la production d'autoanticorps pathogènes dirigés contre des protéines du desmosome, plus particulièrement, les desmogléines qui permettent l'adhésion entre eux des kératinocytes de l'épiderme. Au cours des pemphigus superficiels (PS), la réponse auto-immune est dirigée contre la desmogléine 1 (Dsg1). Chez les malades atteints de PS, des lymphocytes T autoréactifs vis à vis de la Dsg1 sont présents et interviennent dans la production d'autoanticorps anti-Dsg1. Cet autoantigène est aussi la cible de la réponse auto-immune au cours d'autres formes de pemphigus tels que les pemphigus vulgaire et paranéoplasique et par conséquent, semble jouer un rôle clé dans ces maladies. Depuis plus d'une décennie, le rôle de l'autoantigène lui-même dans l'initiation, la propagation et la pérennisation de la réponse auto-immune a été conforté par de nombreux arguments expérimentaux. En nous appuyant sur ce concept, nous avons entrepris d'étudier l'intervention de la Dsg1 dans les mécanismes physiopathologiques qui concourent au développement des pemphigus. Dans un premier temps, nous avons démontré l'expression dans l'épiderme humain, d'une isoforme tronquée de la Dsg1 générée par épissage alternatif des transcrits DSG1. Cette Dsg1 soluble est porteuse d'une séquence peptidique spécifique qui se fixe avec une forte affinité à certaines molécules HLA de classe II de susceptibilité au PS en particulier, à la molécule DRB1*0102. Ce peptide est par ailleurs capable d'induire la prolifération de cellules mononuclées du sang périphérique chez 50% des malades atteints de la forme sporadique de PS. Ces patients expriment des allèles HLA de classe II associés à la maladie et deux d'entre eux sont porteurs de la molécule DRB1*0102. Ainsi, la modification de la Dsg1 par épissage alternatif pourrait-elle intervenir dans la rupture de la tolérance au niveau du compartiment T chez les individus prédisposés génétiquement par l'expression de certains allèles HLA de classe II et in fine, conduire à l'initiation d'une réponse auto-immune B dirigée contre la Dsg1. En second lieu, nous avons observé une diversification de la réponse anticorps chez des souris normales immunisées avec la région extracellulaire recombinante de la Dsg1. Les animaux immunisés produisent non seulement des IgG dirigées contre la Dsg1 mais aussi, contre d'autres protéines de l'épiderme. Nous avons dérivé cinq anticorps monoclonaux à partir des splénocytes isolés de ces souris et montré que trois d'entre eux sont dirigés spécifiquement contre la Dsg1. Les deux autres, 10A1 et CK1, ne réagissent pas avec la Dsg1 mais reconnaissent des protéines épidermiques de plus haut poids moléculaire, compatible avec ceux des autoantigènes de la famille des plakines spécifiquement reconnus par les anticorps au cours du pemphigus paranéoplasique, e.g. l'envoplakine et la périplakine. Grâce à une analyse protéomique ciblée combinant l'immunocriblage d'une carte protéique 2D d'épiderme humain et la spectrométrie de masse MALDI-ToF, nous avons montré que la protéine cible du 10A1 est l'envoplakine, et que le CK1 reconnaît à la fois l'envoplakine et la périplakine. Ainsi, en accord ce modèle expérimental murin, la réponse B anti-Dsg1 pourrait-elle gouverner la réponse vis à vis d'autres protéines du desmosome en particulier, les plakines, mimant de ce fait la diversité de la réponse auto-immune B observée au cours du pemphigus paranéoplasique. Enfin, nous démontrons par des analyses en PCR que l'ARNm de la Dsg1 est exprimé dans le thymus humain normal, que son expression augmente avec l'âge et de ce fait, que l'absence de l'expression thymique de cette autoantigène ne constitue pas l'origine de la rupture de la tolérance qui concoure au développement des PS. Nos résultats mettent en exergue le rôle la Dsg1 dans le processus auto-immun au cours des pemphigus, d'une part, à la phase d'initiation, avec l'intervention de cet autoantigène modifié par épissage alternatif dans la réponse lymphocytaire T et d'autre part, à la phase de propagation, avec la diversification de la réponse anticorps vis à vis d'autres antigènes desmosomiaux induite chez des souris normales immunisées avec cet autoantigène.

Lipoprotein(a) (Lp(a)) consists of an LDL-like particle and the specific protein apo(a), which is very similar to plasminogen. Apo(a) contains repeated kringle structures and a serine protease domain, which cannot be activated by t-PA. Lp(a) is considered to be a predictor for atherosclerotic disease. It has been found incorporated in atherosclerotic plaques and inhibits in vitro fibrinolysis. Lp(a) was determined in 1527 randomly selected individuals participating in the Northern Sweden WHO-MONICA project. A weak but significant relation between Lp(a) and increasing age was found. Menopausal status was the strongest independent predictor of Lp(a) level in women. Fibrinogen was independently related to Lp(a) in both sexes. Only a minor fraction of Lp(a) variance could be explained for in a multiple regression model, which is in agreement with the contention that Lp(a) is highly genetically determined. Lp(a) was determined in 1571 patients investigated with coronary angiography because of suspected severe coronary artery disease (CAD). Patients with proven CAD at elective angiography had significantly higher Lp(a) than patients without significant CAD or healthy controls. Lp(a) was found to be an independent discriminator of CAD in both sexes. HLA-DR genotype 13 or 17 was found more frequently in 30 male patients with angiographic CAD at young age (&lt; 50 years) than in 30 age matched controls. These genotypes were common in patients with high Lp(a) levels, which indicates that Lp(a) may be related to immunological processes. The reaction of Lp(a) was investigated in 32 patients with acute myocardial infarction (AMI). Lp(a) increased during the first week, but the response was comparatively weak. Individual Lp(a) responses were heterogeneous and no correlations to infarct size or changes in the acute phase proteins were found. In a randomized cross-over study on 36 hypercholesterolaemic patients treated with simvastatin/placebo during 12+12 weeks Lp(a) did not change significantly, but patients with high Lp(a) levels at baseline tended to develop further increased Lp(a). To conclude, Lp(a) was found to be an independent predictor of angiographic CAD in both men and women. Lp(a) levels are primarily genetically determined and only a small fraction of Lp(a) variance could be explained by other factors in this study. Lp(a) may be related to HLA DR types and immunological processes involved in atherosclerotic disease. Lp(a) increased slightly during the first week of AMI, but was not related to changes in the acute-phase proteins. The effective LDL-lowering agent simvastatin did not influence Lp(a) significantly. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 5 uppsatser.</p> / digitalisering@umu

Les travaux décrits dans cette thèse s'articulent autour des architectures de communication en réseaux locaux et réseaux distants pour les applications de simul! ation distribuée interactive, particulièrement dans le cadre d! u projet Platsim. Nous avons traité dans un premier temps, les aspects gestion de la QoS pour les simulations distribuées basées sur les middlewares HLA et DDS en réseaux locaux, et ensuite nous avons étendu cette contribution avec DDS sur des réseaux grandes distances. La première contribution consiste à enrichir PlatSim par un modèle formel pour la gestion de la QoS que nous avons implémentée sur HLA pour combler les manques de QoS dont souffre ce middleware. Ensuite, nous avons proposé une architecture pour l'interconnexion des simulateurs distribués avec le middleware DDS. L'utilisation de DDS est intéressante pour la simplicité de son implémentation et ses performances de communication déjà prouvées sur des systèmes complexes. Dans la deuxième contribution, nous avons développé un algorithme de navigation à l'estime (dead-reckoning) pour l'anticipation du comportement des entités simulées. Cette approche permet d'émuler leur comportement lors de la déterm! ination de l'erreur maximale admissible satisfaisant les contraintes de la QoS requise, ce qui, en cas de défaillance du système de communication, permet d'estimer le comportement des objets simulés. Ensuite, nous avons présenté une proposition pour l'interconnexion des simulations distribuées DDS et cette approche de dead-reckoning, par deux mécanismes différents: dans un premier temps, nous avons montré qu'il est possible d'utiliser le service de routage DDS pour mettre en place un "pont-fédéré" DDS permettant d'interconnecter des domaines DDS différents dans un même domaine IP, et ensuite nous avons proposé un "Proxy DDS" qui permet d'interconnecter des simulations DDS situées dans des domaines DDS différents et des domaines IP hétérogènes. Enfin, nos deux dernières contributions con cernent l'étude et la mise en place d'une architecture de communication à grande distance à QoS garantie pour les simulations distribuées sur DDS. Tout d'abord, nous avons présenté! une architecture de signalisation de la QoS pour en se basant! sur l'u tilisation conjointe du protocole COPS et de la signalisation SIP. Ensuite, nous avons étendu des travaux réalisés au LAAS-CNRS dans le cadre du projet européen EuQoS. Nous avons alors utilisé des composants de cette architecture que nous avons adaptés pour fournir, à l'utilisateur final ou à l'administrateur de l'application, des interfaces simples lui permettant de demander le type de service requis pour son application sans avoir besoin de changer le protocole de signalisation.