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Novel mechanisms of T cell-mediated intestinal autoimmunity to Paneth cells
Brabec, Tomáš ; Filipp, Dominik (advisor) ; Janečková, Lucie (referee)
(En) Paneth cells are one of the major player in the maintenance of the homeostatic relationship between intestinal microbiota and the immune system. This function is largely achieved by their production of bactericidal enteric α-defensins (ED) and other antimicrobials. Disruption of Paneth cell functions is associated with severe human disorders such as Crohn's disease (CD) and Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED). However, there is only a very limited information regarding the interactions and regulatory circuits operating between Paneth cells and intestinal immune system in either health or under pathological conditions. The previous study conducted in our laboratory described a new mechanism for the initiation and maintenance of Paneth cells targeted autoimmunity. The suggested model was that ED-specific T cells escape the selection in the thymus, infiltrate the intestine and diminish Paneth cell numbers through autoimmune destruction. This process also lead to the accumulation of inflammation- inducing bacteria, which were implied to exacerbate the inflammatory autoimmunity. Since this model of intestinal autoimmunity is of correlative nature, its intrinsic mechanism and functional relationships between immune system, Paneth cells and microbiota are largely...
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AIRE-expressing cells in immune tolerance in health and disease
Vobořil, Matouš ; Filipp, Dominik (advisor) ; Černý, Jan (referee) ; Ehrlich, Lauren Ilyse Richie (referee)
The process of self-nonself discrimination by the immune system is a fundamental attribute of healthy organisms. Since T-cell receptors (TCRs) are generated by the random process of somatic recombination without regard to its targets, the newly developed T-cell clones could recognize either self or nonself antigens. The mechanisms of central tolerance robustly limit the self-reactive repertoire within the T-cell population via deletion of clones that express self-reactive TCRs or their deviation into the regulatory T-cells (Tregs). These processes occur mainly in the thymic medulla where the TCR reactivity to self-antigens is tested by various types of antigen-presenting cells, mainly medullary thymic epithelial cells (mTECs), dendritic cells (DCs), and B-cells. The cooperation between these cell-types has been shown to be essential for the establishment of thymic tolerance. A key molecule regulating the production of self-antigens is the autoimmune regulator (AIRE), which is thought to be expressed primarily by mTECs and its mutations are associated with the development of severe autoimmune disorders. In this context, the presented thesis describes the novel regulatory pathways important for the development of a functional and "harmless" repertoire of T-cells and for enforcement of tolerance....
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Novel mechanisms of T cell-mediated intestinal autoimmunity to Paneth cells
Brabec, Tomáš ; Filipp, Dominik (advisor) ; Janečková, Lucie (referee)
(En) Paneth cells are one of the major player in the maintenance of the homeostatic relationship between intestinal microbiota and the immune system. This function is largely achieved by their production of bactericidal enteric α-defensins (ED) and other antimicrobials. Disruption of Paneth cell functions is associated with severe human disorders such as Crohn's disease (CD) and Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED). However, there is only a very limited information regarding the interactions and regulatory circuits operating between Paneth cells and intestinal immune system in either health or under pathological conditions. The previous study conducted in our laboratory described a new mechanism for the initiation and maintenance of Paneth cells targeted autoimmunity. The suggested model was that ED-specific T cells escape the selection in the thymus, infiltrate the intestine and diminish Paneth cell numbers through autoimmune destruction. This process also lead to the accumulation of inflammation- inducing bacteria, which were implied to exacerbate the inflammatory autoimmunity. Since this model of intestinal autoimmunity is of correlative nature, its intrinsic mechanism and functional relationships between immune system, Paneth cells and microbiota are largely...
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The role of NF-kappa B signaling in establishment of central tolerance
Březina, Jiří ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Ce trál í tolera e, která je usta ove a v th u, výz a ě redukuje repertoár reaktiv í h T l fo tů a tí u ožňuje před házet rozvoji autoi u it í h o e o ě í. ez t ý Autoi u it í regulá Aire , který je e pri ova ý ikát í i edulár í i epiteliál í i uňka i řídí pro iskuit í ge ovou e presi tisí ů tkáňově spe ifi ký h a tige ů, která je zásad í pro úči ou egativ í selek reaktiv í h T l fo tů regulač í h l fo tů. Výzku posled í h dvou dekád sta ove í e trál í tolera e. této prá i předkládá ejdůležitější poz atk dokládají í její klíčovou roli ve vývoji u ěk pří é regula i ge ové e které hovoří ve prospě h edo e ě é skuteč ost , že hlav í regulátore pro esů podílejí í h se a vý , udržová í a fu k i e trál í tolera e Klíčová slova: Centrální tolerance, NF
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Emerging role of Toll-like receptors in central tolerance
Súkeníková, Lenka ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
Medullary thymic epithelial cells (mTECs) provide a specific thymic microenvironment for the processes associated with T cell development. Their irreplaceable function is the expression of specific set of antigens which are expressed only in peripheral tissues, called tissue restricted antigens (TRAs). Such expression, often referred to as promiscuous, was originally described with the discovery of transcriptional regulator Aire. Aire, which has a potential to interact with many other transcription factors, also binds to DNA, and thus can alter the general pattern of cellular gene expression. T cells exhibiting a strong affinity to TRAs expressed on mTECs are removed from the thymus by negative selection or their development is deviated to regulatory T cell (Treg) lineage. Studies on mice and humans confirmed the critical role of Aire protein in the establishment of the central tolerance. Inactivating mutations in Aire gene cause deficiency in TRA expression, failure to remove and the escape of self-specific T cells from the thymus to periphery, and in turn, autoimmunity. Experimental evidence points to the key role of NF-κB signaling pathway in mTECs development. The very same pathway is regulated also by Toll-like receptors (TLRs), which recognize evolutionary conserved structures derived from...
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Aire-expressing cells in immune peripheral tissues
Vobořil, Matouš ; Filipp, Dominik (advisor) ; Černý, Jan (referee)
5 Abstract Tolerance to "self" is the fundamental property of the immune system and its breakdown can lead to autoimmune diseases. In order to eliminate self-reactive T- cells during their development in thymus (central tolerance), Aire promotes the expression of peripheral self-antigens in medullary thymic epithelial cells (mTECs). Recently, Aire was suggested to fulfil a similar function in rare lymph node and spleen cells (peripheral tolerance). However, the detection, characterization and function of these extrathymic Aire-expressing cells is still obscure. The main objective of presented thesis was to investigate if Aire positive cells are also present in other lymphoid as well as non-lymphoid tissues. Using two independent mouse transgenic models we identified the Aire-reporter expressing cells in several lymphoid tissues such as Peyer's patches, spleen and bone marrow as well as in one non-lymphoid organ, the lungs. We show here that based on the expression of B220, EpCAM and CD11c markers these heterogenic cells consist of at least five phenotypically distinct subpopulations, and with the exception of those from lungs, all of them are strictly of hematopoietic origin. This study also demonstrates that Aire on protein level is predominantly expressed by one of these subpopulations with CD45+ MHCII+...
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Autoimmune and lymphoproliferative diseases: associations and common mechanisms
Dobiášová, Alena ; Daňková, Pavlína (advisor) ; Hušáková, Markéta (referee)
Autoimmune and lymphoproliferative diseases share some etiologic mechanisms. The origin of the diseases is complicated process that involves an accumulation of hereditary and somatic mutations in a hematopoetic cell, which thanks to changed activity overcomes different growth and survival control checkpoints. Such mutations are for example those located in genes coding for transcription factors, apoptotic signaling molecules, costimulatory molecules and secreted exctracellular molecules. All these molecules influence the balance between survival and programmed cell death. Their dysregulated expression enables the cell to overcome defensive mechanisms of the immune system. Therefore, autoimmune and malignant cells are able to survive though, under usual circumstances, they would be selected. The main aim of this work is to shed the light on the influence of the dysregulated expression of the particular molecules on the origin of autoimmune and lymphoproliferative diseases. Key words: autoimmune ilnesess, lymphoproliferative diseases, etiology, AIRE, c-MYC, TP53, FOXP3, Fas, PTEN, Bim, CTLA-4, CD5, CD30, CD40/CD40L, BAFF, α-taxilin, IL- 10.
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