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The role of innate immunity cells in the pathogenesis of celiac disease
Dáňová, Klára ; Palová Jelínková, Lenka (advisor) ; Černý, Jan (referee)
Celiac disease is an autoimmune disease which occurs in susceptible individuals after ingestion of food containing gluten. Gluten and its monomeric fraction gliadin induce inflammatory damage of the small intestine by activating the immune cells that react strongly to gluten peptides. Gluten peptides have the ability to activate cells of adaptive as well as innate immune system. This work is focused on the production of interleukin (IL)-1 in antigen presenting cells stimulated with peptic gliadin digest. We found that monocytes and peripheral blood mononuclear cells (PBMC) isolated from blood of celiac patients secrete significantly more IL-1α and IL-1β than cells of healthy donors after stimulation with gliadin digest. The gliadin-induced IL-1β expression is controlled by a signaling cascade that includes MAPK kinase family molecules and transcription factor NF-κB. Moreover, we found that the adaptor proteins MyD88 and TRIF as well as Toll-like receptor (TLR) 2 and 4 play a role in the signaling cascade underlying gliadin-induced IL-1β expression by using murine bone marrow derived dendritic cells (BMDC). The precursor form of IL-1β in gliadin- stimulated PBMC and murine BMDC is maturated by caspase-1. In celiac PBMC the gliadin- induced maturation and secretion of IL-1β depends on the potassium...
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The role of the immune system in the immunopathogenesis of autoimmune diseases and the therapeutic modulation of autoimmune reaction by tolerogenic dendritic cells
Dáňová, Klára ; Palová Jelínková, Lenka (advisor) ; Prokešová, Ludmila (referee) ; Heneberg, Petr (referee)
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...
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The innate immunity and circulating monocytes - their significance and function in pathogenesis of coeliac disease.
Němečková, Iva ; Daňková, Pavlína (advisor) ; Palová Jelínková, Lenka (referee)
8 Abstract Introduction: Celiac disease is indentified as the loss of oral tolerance to gluten, it is an organ-specific autoimmune disease in which both, adaptive and innate immunity participate. Monocytes are important part of immune system; they have many functions and express very diverse membrane receptors including Toll-like receptors (TLRs). TLRs are involved in the innate immune response, specifically TLR2 and TLR4 are crucial for recognition of bacterial components and TLR7 recognizes virus's ssRNA. Monocytes also produce prolaktin (PRL), which acts as a cytokine that modulates immune responses. To clarify the role of innate immunity and circulating monocytes in pathogenesis of celiac disease, we focused on changes in expression of selected Toll-like receptors (TLR2, TLR4, TLR7), prolactin, some pro- a anti-inflammatory cytokines (TNF-α, IL-6, IL-12, IL-10). We monitored the influence of the SNP - 1149 G/T on the expression of PRL mRNA. Another objective of this work was the introduction and optimization of in vitro methods for cultivation and stimulation of peripheral monocytes. Material and Methods: This pilot study includes 21 patients with celiac disease and 40 healthy controls. For determination of mRNA levels of the studied genes we isolated RNA from monocytes that were isolated by...
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The role of innate immunity cells in the pathogenesis of celiac disease
Dáňová, Klára ; Palová Jelínková, Lenka (advisor) ; Černý, Jan (referee)
Celiac disease is an autoimmune disease which occurs in susceptible individuals after ingestion of food containing gluten. Gluten and its monomeric fraction gliadin induce inflammatory damage of the small intestine by activating the immune cells that react strongly to gluten peptides. Gluten peptides have the ability to activate cells of adaptive as well as innate immune system. This work is focused on the production of interleukin (IL)-1 in antigen presenting cells stimulated with peptic gliadin digest. We found that monocytes and peripheral blood mononuclear cells (PBMC) isolated from blood of celiac patients secrete significantly more IL-1α and IL-1β than cells of healthy donors after stimulation with gliadin digest. The gliadin-induced IL-1β expression is controlled by a signaling cascade that includes MAPK kinase family molecules and transcription factor NF-κB. Moreover, we found that the adaptor proteins MyD88 and TRIF as well as Toll-like receptor (TLR) 2 and 4 play a role in the signaling cascade underlying gliadin-induced IL-1β expression by using murine bone marrow derived dendritic cells (BMDC). The precursor form of IL-1β in gliadin- stimulated PBMC and murine BMDC is maturated by caspase-1. In celiac PBMC the gliadin- induced maturation and secretion of IL-1β depends on the potassium...
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Účast monocytů a dendritických buněk v patogenezi celiakie
Tučková, Ludmila ; Palová-Jelínková, Lenka ; Rožková, D. ; Černá, M. ; Pecharová, Barbara ; Smythies, L. ; Smith, P. ; Dvořák, M. ; Fruhauf, P. ; Tlaskalová, Helena
This work studies the involvement of monocytes and dendritic cells in coelias cisease pathogenesis
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Stimulace P3MoC izolovaných z krve celiakálních pacientů gliadinovými fragmenty
Cinová, Jana ; Palová-Jelínková, Lenka ; Smythies, L. ; Černá, M. ; Pecharová, Barbara ; Dvořák, M. ; Fruhauf, P. ; Tlaskalová, Helena ; Smith, P. ; Tučková, Ludmila
We documented that gliadin digest stimulate PBMoC (isolated from celiac patients and healthydonors) to IL-8 and TNF alfa production through the NF-kappa B pathway. Monocytes expressed increased levels of dendritic cell markers
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Gliadin fragments induce phenotypic and functional maturation of human dendritic cells
Palová-Jelínková, Lenka ; Rožková, D. ; Pecharová, Barbara ; Bártová, J. ; Šedivá, A. ; Tlaskalová, Helena ; Spíšek, R. ; Tučková, Ludmila
Gliadin treatment also resulted in increased NF- B/DNA binding activity of p50 and p65 subunits. Taken together, gliadin peptides can contribute to overcoming the stage of unresponsiveness of immature DC by inducing phenotypic and functional DC maturation, resulting in more efficient processing and presentation of gliadin peptides to specific T lymphocytes
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The response of peripheral blood monocytes from celiac patients to gliadin peptides
Cinová, Jana ; Palová-Jelínková, Lenka ; Smythies, L. ; Černá, M. ; Pecharová, Barbara ; Dvořák, M. ; Fruhauf, P. ; Tlaskalová, Helena ; Smith, P. ; Tučková, Ludmila
We documented that gliadin digest stimulate PBMoC (isolated from celiac patients and healthydonors) to IL-8 and TNF alfa production through the NF-kappa B pathway. Monocytes expressed increased levels of dendritic cell markers
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