Academic literature on the topic 'Autoimunitní'

This diploma thesis is about the illness called multiple sclerosis. The theoretic part describes this illness, its history, types of multiple sclerosis and refers to economic costs. The practical part detected the position of patients and evaluates their quality of life. The most important in this part are economic costs of patient and economic costs of insurance companies.

In this study, we demonstrated that membrane immunofluorescence (MIF) with canine erythrocytes is a much more sensitive diagnostic technique compared with the Coombs test to detect auto-antibodies on RBC. We also demonstrate how the evaluation of the MIF test can be made more precisely which results in a more clear interpretation. Till nowadays the Evans syndrome (combined thrombocytopenia and anemia) is not very well diagnosed in dogs. Only a few studies with low animal numbers tested auto-antibodies on RBC and thrombocytes. Here we describe the frequency of Evans syndrome based on the evaluation of a large data set with 557 dogs. The novelty of the thesis also lies in making a research of the amount of CICs in sera of AIHA/AITP patients is described as well as the cytotoxic potential of patient’s sera for canine leucocytes. These new aspects of diagnosis (AIHA) and pathogenesis (AIHA/AITP) are not only relevant for dogs but also for humans and can be used for better differential diagnosis in medicine. The new findings with respect to circulating immune complexes and cytotoxicity are also offer new therapeutic concepts. Besides, the study has resulted in the characterization of monoclonal antibodies which allow for the detection of so far undetectable canine differentiation antigens (CD molecules) on canine erythrocytes (CD235) and thrombocytes (CD42a). The identified mAbs are useful in the identification of relevant target structures for autoantibodies on these cells.

Les lymphocytes T régulateurs exprimant le facteur de transcription Foxp3 (Treg) jouent un rôle majeur dans le contrôle des différents types des réponses immunitaires. Leur rôle est crucial puisqu'une absence totale de Treg chez la souris ou chez l'humain entraîne des pathologies auto-immunes létales, respectivement Scurfy and IPEX. Les Tregs sont également impliqués dans d'autres processus tels que la réparation tissulaire, le contrôle des inflammations chroniques et la tolérance fœto-maternelle et présentent de ce fait une hétérogénéité fonctionnelle. Certaines de ces spécifications fonctionnelles sont acquises en périphérie mais des données de la littérature suggèrent qu'une hétérogénéité des Tregs apparaît dès leur développement dans le thymus. Durant celui-ci, les précurseurs des Tregs interagissent avec des cellules stromales thymiques. Celles-ci expriment des complexes CMH:peptide reconnus par les précurseurs des Tregs grâce à leur récepteur à l'antigène, le TCR, et délivrent d'autres signaux, par exemple cytokiniques, nécessaires au développement des Tregs. Mon projet de thèse a visé à étudier les effets respectifs de deux interleukines, l'IL-2 et de l'IL-15, sur le développement des différentes sous-populations de Tregs. Après avoir confirmé l'importance quantitative de ces cytokines pour le développement des Tregs, nous nous sommes intéressés à l'aspect qualitatif de celui-ci. J'ai effectué des analyses de cytométrie et transcriptomiques (CITEseq) sur les Tregs en développement les plus matures afin de dresser l'inventaire détaillé des différentes sous-populations des Tregs thymiques. Mes résultats montrent une diversité fonctionnelle des Tregs en développement bien plus importante que celle rapportée dans la littérature. De plus, mes données suggèrent un besoin différent en IL-2 et IL-15 pour le développement des sous-populations de Tregs identifiées. Nos analyses par séquençage à haut débit du répertoire des TCR exprimé par les Tregs qui se développent en absence d'IL-2 ou d'IL-15, ont montré des répertoires partiellement différents des Tregs. Différentes sous-populations de Treg, avec des répertoires TCR et des besoins en cytokines distincts, se développent donc dans le thymus. A terme, la compréhension des implications exactes de ces sous-populations dans les différentes fonctions exercées par les Tregs permettra de les cibler dans le cadre du traitement de pathologies dans lesquelles le système immunitaire joue un rôle central, telles que les pathologies auto-immunes, l'inflammation chronique, le rejet des allogreffes et le cancer
Regulatory T cells that express the transcription factor Foxp3 (Treg) play a major role in controlling different types of immune responses. Their role is crucial since a total absence of Treg in mice or humans leads to lethal autoimmune pathologies, respectively Scurfy and IPEX. Tregs are also involved in other processes such as tissue repair, chronic inflammation control and maternal fetal tolerance and thus present a functional heterogeneity. Some of these functional specifications are acquired in the periphery but some data from the literature suggest that this Treg heterogeneity appears as soon as they develop in the thymus. During their development, the Treg precursors interact with thymic stromal cells which express MHC:peptide complexes recognized by Treg precursors trough their antigen receptor, TCR, and deliver other signals, for example cytokines, necessary for the development of Tregs. My thesis project aimed to study the effects of two interleukins, IL-2 and IL-15, on the development of different Treg subpopulations. After having confirmed the quantitative importance of these cytokines for the development of Tregs, we were interested in the qualitative aspect of this one. I performed cytometry and transcriptomic analyzes (CITEseq) on the most mature developing Tregs in order to draw up a detailed inventory of the different subpopulations of thymic Tregs. My results show a functional diversity of developing Tregs, much larger than the one reported in the literature. In addition, my data suggest a different need for IL-2 and IL-15 for the development of the identified Treg subpopulations. Our high throughput sequencing analyzes of the TCR repertoire expressed by Tregs that develop in the absence of IL-2 or IL-15, showed partially different Treg repertoires. Therefore, we showed that different Treg subpopulations, with different TCR repertoires and cytokine requirements, develop in the thymus. In the long term, understanding the exact implications of these subpopulations in the various functions exercised by the Tregs will help to target them in order to treat diseases in which the immune system plays a central role, such as autoimmune diseases, chronic inflammation, allograft rejection, and cancer

A Doença Reumática Cardíaca (DRC) é uma séria complicação de orofaringite causada por determinados sorotipos de Streptococcus pyogenes não tratada adequadamente em indivíduos suscetíveis. É um grande problema de saúde pública, principalmente nos países não desenvolvidos e em desenvolvimento, como Brasil, Índia, países da África, regiões de população aborígine da Austrália, e Egito. É altamente debilitante e com alta taxa de mortalidade devido ao comprometimento cardíaco. As lesões miocárdicas iniciais regridem, mas as lesões valvares, principalmente a mitral e a aórtica, são irreversíveis e progressivas. Muitos estudos já caracterizaram a resposta imune celular (linfócitos T) e humoral nos indivíduos acometidos pela doença. Mimetismo molecular e espalhamento de epítopo são os principais mecanismos que se pensa estar envolvidos na patogênese da DRC. Avaliamos, nesta pesquisa, o perfil de expressão proteica em valvas mitrais de indivíduos acometidos por DRC. Para detectar alterações específicas desta doença, comparamos as expressões de proteínas nos grupos portadores de DRC com insuficiência (DRC-INS) e com estenose (DRC-EST) a um grupo de indivíduos com degeneração mixomatosa de valva mitral (DMX) e outro sem valvulopatias (CTL). Alterações especificamente observadas em tecido mitral na DRC-INS ou DRC-EST em fases avançadas da doença podem explicar o mecanismo de desenvolvimento desses dois tipos de lesão. Foram encontradas 25 \"spots\", correpondendo a 29 proteínas diferencialmente expressas nos grupos com valvulopatias, refletindo principalmente alterações na matriz extracelular. Encontramos importante clivagem diferencial da vimentina, cuja proteína íntegra possui 54 kDa, formando fragmentos com ~40 e ~45 kDa, aumentados na DRC, principalmente na DRC-INS. O colágeno do tipo VI, com aproximadamente 95 kDa, encontrou-se com expressão diminuída exclusivamente no grupo DRC-INS. A Vitronectina foi encontrou-se aumentada em na DMX e na DRC-EST, em relação ao grupo controle, principalmente na DRC-EST. Lumican, por sua vez, teve expressão diminuída na DMX e na DRC-EST, apesar de possuir um único \"spot\" com expressão aumentada na DRC. Utilizando métodos de análise de padrões de expressão protéica in silico foram identificados conjuntos de proteínas capazes de discriminar as amostras de valva mitral por etiologia da doença. O presente trabalho pode auxiliar na elucidação dos mecanismos de desenvolvimento da doença e de alterações estruturais do tecido mitral em resposta às lesões autoimunes, bem como no diagnósticoda DRC.
Rheumatic Heart Disease (RHD) is a serious complication of oropharingitis caused by some serotypes of Streptococcus pyogenes not properly treated in susceptible individuals. It is a public health concern, mainly for undeveloped and developing countries, such as Brazil, India, some countries in Africa, aboriginal regions in Australia, and Egypt. It is highly debilitating with a high mortality rate due to cardiac commitment. Initial myocardial lesions disappear, but valvar lesions, mainly mitral and aortic, are irreversible and progressive. Many studies have characterized cellular (T lymphocytes) and humoral responses in individuals affected by the disease. Molecular mimicry and epitope spreading are the main mechanisms thought to be involved in the pathogenesis of RHD. We evaluated, in this research, the profile of protein expression in mitral valves from individuals affected by RHD. To detect alterations specific of this disease, we compared protein expression in the group of RHD with regurgitation (RHD-RGT) and stenosis (RHD-STN) to a group of individuals with mitral valve myxomatous degeneration (MXD) and another group without valvulopathies (CTL). Alterations specifically observed in the mitral tissue of RHD-RGT and RHD-STN in advanced stages of the disease can explain the mechanism of development for these two kinds of lesions. Twenty-five spots, corresponding to 29 proteins were found to be differentially expressed in the valvulopathy groups, reflecting mainly alterations in extracellular matrix. We found important differential cleavage of vimentin, the whole protein having 54 kDa, in fragments with ~40 and ~45 kDa, increased in RHD, mainly in RHD-RGT. Collagen type-VI, with approximatelly 95 kDa, was found to have decreased expression exclusivelly in the RHD-RGT group. Increased expression of Vitronectin was detected in DMX and RHD-EST groups, compared to the CTL group, mainly in the RHD-STN. Lumican, in turn, had decreased expression in the MXD and RHD-STN groups. By using in silico methods for analysis of patterns of protein expression, we identified sets of proteins capable of discriminating mitral valve samples by disease etiology. The present study might help elucidating the mechanisms of disease development and structural alterations in the mitral tissue in response to the autoimmune lesions, as well as in the diagnosis of RHD.

5 Anglický abstrakt Experimental autoimmune encephalomyelitis (EAE) is widely accepted as a murine model of human multiple sclerosis autoimmune disease. Murine EAE is usually actively induced by immunization with a suitable myelin antigen. Following immunization, CD4+ T helper lymphocytes Th1 and Th17 accumulate in the nervous tissue and via the production of cytokines, they mediate an inflammatory reaction and the subsequent destruction of myelin. The main goal of this study was the induction of EAE with clinically observable symptoms and the observation of changes in the counts and phenotypes of cells, mainly NK and T cells. NK cells express a wide range of inhibitory and activation receptors from the C-lectin-like receptor superfamily. The specific ligand of the activating NKR-P1C isoform is still unknown and thus this receptor's involvement in EAE was also observed. Another goal was the use of medication with regard to the disease progress improvement. For the purposes of this study, two inbred murine strains with distinct NKR-P1 surface expression were used - the SJL/J strain (expressing inhibitory NKR-P1B) and C57BL/6 (expression activating NKR-P1C). SJL mice elicited a relapse-remitting of EAE, while C57BL/6 had chronic EAE. Both mouse strains exerted changes in the counts of NK...

Immunotherapy based on dendritic cells (DCs) was first tested in clinical trials for the treatment of cancer in the 1990s. Currently, the ability of DCs to modulate immune responses is also being tested in several clinical studies focusing on autoimmune disease treatment with the aim of suppressing the overactivated immune system and restoring immune tolerance. For this purpose, so-called tolerogenic DCs with considerable suppressive potential are used. Tolerogenic DCs can be generated ex vivo from monocytes using pharmacological agents, which in DCs induce a regulatory phenotype with low expression of activation markers, high expression of inhibitory markers and secretion of suppressive cytokines. In the first part of this study, we show that cultivation of human blood monocytes in the presence of glucocorticoid dexamethasone and 19- nor-1,25-dihydroxyvitamin D2 (paricalcitol) enables ex vivo generation of tolerogenic DCs with a highly stable suppressive phenotype characterized by upregulated IL-10 production, inhibitory IL- T3 and PD-L1 molecule expression, the low stimulatory capacity and the ability to induce regulatory T cell development. Moreover, we show that metabolic changes and signaling through NF-κB, p38 MAPK, ERK1/2 molecules and the mTOR/STAT3 pathway play an important role in the...

Rheumatoid arthritis (RA) is a worldwide problem representing one of the most prevalent autoimmune diseases in the world. Despite the commonness of the disea- se, its pathogenesis has not been fully described. Immune cells ranging from antigen- presenting cells to T, B and NK cells playing various roles participate in the rheumatic process. In this work we concentrated on NK cells expressing a repertoire of activating and inhibitory receptors which influence their function in health and disease. We focused on the analysis of NK cell function and described its possible modulation by rheumatic autoantigens and multivalent glycodendrimers bearing 4 (GN4C) or 8 (GN8P) N-acetyl glucosamine moieties. The effect on NK cells and the glycosylation pathways was further studied in vitro. Finally, an in vivo study was performed on an animal model of RA - col- lagen-induced arthritis (CIA) to assess the effect of the compounds on clinical develop- ment of the disease and selected immune parameters. Comparison of NK cell cytotoxicity in patients suffering from RA, other inflam- matory diseases and healthy donors showed its impairment particularly in RA patients. Peripheral blood NK cells reacted to GN8P glycoconjugate by inhibition of their effector function in CD161 high-expressing samples. The MGAT5...

The pathology of immune system can lead to immune disorders. Immunodeficencies are caused by insufficient or missing immune response. On the other hand, allergies and autoimmune disorders represent a consequence of wrong control of the immune reaction and breakdown of an immune tolerance. Immunopathogenesis of allergic and autoimmune diseases are to some extent common to both immunopathologies; both represent harmful hypersensitive reaction to autoantigen or allergen and lead to the destruction of tissues and organs or to their dysfunction. Allergy and autoimmunity result from the combination of internal, mainly genetic, and external factors, such as infection. In this thesis, we focused on the mechanisms that lead to the disorders of regulation of immune reaction. We studied cohorts of patients with allergy or autoimmunity and we concentrated first on the genetic omponents that underlie both immun opathologies, furtheron mechanisms of innate immunity, particularly dendritic cells and finally on the adaptive immunity, mainly B cells and antibodies. One of our projects presented our experience with the therapy influencing B lymphocytes using monoclonal antibody against CD20 (rituximab). In summary, our studies present a complex view on immune reactions that contribute to allergic and autoimmune diseases. Our...

Introduction:Uveitis in an ocular inflammation affecting mostly people of working age. Uveitis is responsible for severe visual impairment despite of expanding new therapeutics. The animal models of uveitis were established, because the wide clinical variability of uveitis limits the studies in human medicine. The goal our project was to establish a reproducible model of experimental autoimmune uveitis in Czech Republic, and further on this model to observe the frequency of CD3+ and F4/80+ cells in retina, to assess the influence of microbial environment on intensity of intraocular inflammation and to test the therapeutical possibilities. Material and methods: The C57BL/6J mice were immunized by retinal antigen (IRBP 1-20, interphotoreceptor retinoid binding protein), enhanced by complete Freund's adjuvant and pertussis toxin and mild posterior autoimmune uveitis was induced. The mice were bred in conventional and germ-free (gnotobiotic) conditions. The uveitis intensity was evaluated in vivo biomicroscopically and post mortem histologically on hematoxylin eosin stained sections according to the standard protocol. The histological eye specimen were analyzed also by imunohistochemisty and by flow cytometry. Each experiment was performed for 35 days. The conventional mice with uveitis were treated...