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Role of microbiota and gut inflammation in the pathogenesis of experimental colorectal cancer
Klimešová, Klára ; Tlaskalová - Hogenová, Helena (advisor) ; Vítek, Libor (referee) ; Reiniš, Milan (referee)
Mucosal surface of the gut is in continuous contact with foreign compounds derived from diet as well as from commensal or pathogenic microorganisms. Thousands of years of symbiosis resulted in tight cooperation between the host and its microbiota. Microbiota composition and metabolism actively influence host's physiological as well as pathological processes. Chronic inflammation is characterized by prolonged active inflammatory response associated with tissue damage. This status results from accumulation of defects in various factors including gut barrier functions as well as mechanisms of innate and adaptive immunity. It's commonly accepted that chronic inflammatory diseases of the gastrointestinal tract like IBD, are associated with an increased risk of CAC development. Two publications related to this thesis deal with modulatory effects of peroral administration of components of commensal bacteria or probiotics on intestinal inflammation. Using acute or chronic model of DSS-induced colitis, we demonstrated that oral treatment of BALB/c mice with membranous fraction of the commensal, Parabacteroides distasonis, as well as with lysate of probiotic bacterium Lactobacillus casei DN-114 001 significantly reduces the severity of intestinal inflammation. Moreover, the treatment was associated with reduction of...
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Inflammation and cancer in germ-free vs. conventionally reared animals
Čaja, Fabián ; Vannucci, Luca Ernesto (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Smrž, Daniel (referee)
Inflammation is considered as one of the main defence mechanisms of the immune system against threats that occur in the body. When present in its acute form, minimal or no detectable subsequent damage of original affected tissue exists. The more pathological form, chronic inflammation, is associated with permanent damage of the tissue and typically a hallmark of various diseases such as ulcerative colitis or colon carcinogenesis. These two pathologies are evolving in the unique colon microenvironment, where intensive interaction between the host cells and bacteria is present. The aim of our study was to investigate the immunological (ELISA, FACS, RT-PCR) and structural (histology, confocal microscopy) changes in the colon mucosa of Wistar-AVN rats induced by dextran sodium sulphate (DSS) to produce colon colitis and by azoxymethane (AOM) to produce colon carcinogenesis. Conventional (CV) and also germ-free (GF) reared animals were used to investigate the effects of the mucosal inflammation activated by the administered inducers as well as the role of colon microbiota - as promoters of a continuous immune activation - in the modulation of immunity and collagen scaffold remodelling. Our results showed that even in the early period after the induction, both inducers produced a smouldering...
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Bacterial components in experimental intestinal inflammation prevention and therapy
Kverka, Miloslav ; Tlaskalová - Hogenová, Helena (advisor) ; Šedivá, Anna (referee) ; Stříž, Ilja (referee)
Although strong protective immune response is essential for preventing invasion by pathogens, equivalent responses against antigens originating from commensal bacteria can lead to chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Manipulating the mucosal immune responses with microbial antigens might be an excellent tool to IBD therapy or prevention. Our aim was to gain some insight into the regulation of the intestinal inflammation and to isolate bacterial immunomodulatory components that could be used in intestinal inflammation therapy and prevention. One particular mechanism of how healthy colon tissue regulates the inflammation during acute experimental colitis is through modulation of bioavailability of glucocorticoids (GCs) in gut mucosa. Here, we show that intestinal inflammation changes the local GC metabolism, which ultimately leads to decrease in inflammatory readiness of cells in the gut mucosa and in mesenteric lymph nodes. This pre-receptor regulation of GC function could represent an important homeostatic function of the gut mucosa. The actual triggers of intestinal inflammation in IBD seem to be either microbial dysbiosis or microbes with special "pathogenic" abilities, which both could be rectified by feeding with probiotics. Here, we report that oral feeding with live...
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Mucosal immunity in upper respiratory tract diseases and autoimmunity diseases
Fundová, Petra ; Tlaskalová - Hogenová, Helena (advisor) ; Prokešová, Ludmila (referee) ; Bártová, Jiřina (referee)
Mucosal immune system comprises not only the major compartment of the immune system but also important interface with the outer environment. It is responsible in maintaining an intricate balance with the danger and non-danger stimuli of the outer world by employing specific anatomical features and unique functional mechanisms. Mucosal immune system has been long understudied, perhaps due to the limited accessibility, and its biological importance is thus still underevaluated. However, it has become evident that it is important to study mucosal immune system not only in local mucosal affections but also when uncovering pathogenic mechanisms and novel prevention strategies of organ specific autoimmune diseases such as type 1 diabetes. Thus, the first, more clinically oriented part of this thesis is focused on mucosal immune system of the upper respiratory tract in disease conditions - in nasal polyposis (NP). Because there is a substantial accumulation of eosinophils and neutrophils in the most frequent type of NP, we investigated and described increased expression of chemokine receptors CCR1 and CCR3 in NP versus nasal mucosa. Both innate immune mechanisms as well as homeostasis of epithelial cells may participate in NP. We have documented increased numbers of iNOS-positive and insulin-like growth...
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Anti-cytoskeletal antibodies in patients with multiple sclerosis and other neurological diseases
Švarcová, Jana ; Matouš-Malbohan, Ivan (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Průša, Richard (referee)
This thesis focuses on the role of anti-cytoskeletal antibodies in various neurodegenerative diseases. Autoantibodies against different axonal cytoskeletal proteins, such as the light (NF-L) and medium (NF-M) subunits of neurofilament and tubulin (TU), in serum and cerebrospinal fluid may be generated in response to the release of cytoskeleton from damaged neurons. The aim of this study was to assess autoimmune involvement in amyotrophic lateral sclerosis (ALS) as well as to evaluate antibody light and medium neurofilament subunit in serum and cerebrospinal fluid (CSF) of patients with ALS. Furthermore, we were interested in the relationships among these antibodies in the serum and in the CSF as well as between the two anti-NF antibody subtypes. Secondly, the aim was to compare the levels of anti-tubulin antibodies (anti-TU) in cerebrospinal fluid and serum in multiple sclerosis (MS) disease, using bovine tubulin as the antigen in one enzyme-linked immunosorbent assay (ELISA) method (anti-TUb antibodies) and a synthetic neuron-specific octapeptide of tubulin in a second ELISA method (anti-TUs antibodies). In the observed groups of ALS patients, serum levels of anti-NF-L antibodies were higher in ALS patients than in controls and serum anti-NF-L antibodies and intrathecal anti- NF-M antibodies were...
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Immunologic Characteristics of Cord Blood in Children with Increased Risk of Allergy Development Preventive Use of Probiotics
Hrdý, Jiří ; Prokešová, Ludmila (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Ulčová-Gallová, Zdeňka (referee)
Allergy is one of the most common diseases. Identification of early prognostic markers pointing to an increased risk of allergy development is therefore of increasing importance. Cord blood represents an easily attainable clinical material for searching for prognostic markers signalizing future allergy development. Proportions of Th1 cytokines, Th2 cytokines and regulatory cytokines were tested in cord blood of children of allergic mothers (children in relatively high risk of allergy development) in comparison with cord blood of children of healthy mothers (low risk children). Also the activities of lymphocytes, dendritic cells (DC) and regulatory cells (Tregs) were compared in children of healthy and allergic mothers. The generally increased activity of both in vitro stimulated and non-stimulated mononuclear cord blood leukocytes was proved in children of allergic mothers in comparison with low risk children. The increased activity of DC of high risk children was detectable only after polyclonal stimulation. Significantly less pronounced functional properties of cord blood Tregs were found in children of allergic mothers when compared with children of healthy mothers. The increased reactivity of lymphocytes and DC together with the decreased activity of Tregs can support an easier...
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Immunoregulatory characteristics of immune cells of children of allergic and non-allergic mothers and the possibility of their modulation with probiotic E. coli strain O83:K24:H31
Černý, Viktor ; Hrdý, Jiří (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Černá, Marie (referee)
Due to high incidence, medical and socioeconomic burden and impact on individual quality of life and productivity, allergic disorders are a crucial issue for 21st century immunology. Much still remains to be elucidated, particularly regarding the very early processes in allergy development. In order to introduce timely, effective preventive measures, novel, more reliable predictive factors of allergy risk also need to be established. Dysregulation of proper balance between the branches of immune response, particularly unwarranted dominance of Th2, is the underlying cause of allergy. After birth, new immune balance needs to be established to prepare the neonate for adequate reactivity towards newly encountered environmental stimuli. Regulatory T cells (Treg) play a central role in finely setting this balance and inducing tolerance towards harmless environmental antigens, including allergens. Interactions with external factors, most importantly microbiota, modulate this process during the early postnatal "window of opportunity." Analysis of cord blood Treg of children of allergic mothers uncovered decreased presence of function-associated surface markers and lower production of IL-10. Furthermore, decreased proportion of Helios- induced Treg was observed in children with higher risk of allergy....
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Composition of skin microbiome in psoriatic patients
Stehlíková, Zuzana ; Jůzlová, P. ; Rob, F. ; Herzogová, J. ; Koren, O. ; Uzan, A. ; Tlaskalová-Hogenová, Helena ; Jirásková Zákostelská, Zuzana
Psoriasis is a chronic noninfectious and inflammatory skin disease, whose pathogenesis involves environmental triggers, including microbiota. In our study we compared bacterial composition between healthy controls and psoriatic patients using V1V2 hypervariable region of 16S rRNA. We found higher species diversity in psoriatic lesions than in contralateral psoriatic healthy site or in healthy control skin. Genus Propionibacterium was more abundant in contralateral healthy sites (57.77%) than in affected psoriatic sites of psoriatic patients (47.12%). On the other hand, we found higher abundance of genus Staphylococcus in psoriatic lesions (18.78%), while lower abundance in contralateral healthy sites (9.52%). Since Propionibacterium are commensal bacteria, the shift in their abundance from healthy to psoriatic skin could be due to disturbation of natural skin habitat. Interpretation of higher presence of Staphylococcus in psoriatic lesions comparing to contralateral healthy sites requires further species characterization. To complete the picture about psoriatic microbiome we will further investigate skin fungal composition in identical samples.
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Role of microbiota in mouse experimental model of psoriasis
Jirásková Zákostelská, Zuzana ; Stehlíková, Zuzana ; Klimešová, Klára ; Rossmann, Pavel ; Dvořák, Jiří ; Novosádová, Iva ; Kostovčík, Martin ; Coufal, Štěpán ; Šrůtková, Dagmar ; Hudcovic, Tomáš ; Štěpánková, Renata ; Rob, F. ; Jůzlová, P. ; Herzogová, J. ; Tlaskalová-Hogenová, Helena ; Kverka, Miloslav
Anotace v anglickém jazyce\n\nMouse model of human psoriasis and gnotobiotic are important tools in understanding the role of gut and skin microbiota in pathogenesis of psoriasis. In our experiments we showed that gnotobiotic mice, as well as conventional mice treated with antibiotics, have milder skin inflammation in comparison with control conventional mice. Treatment with broad spectrum antibiotics led to dramatic shift in gut microbial composition, in particular, we observed extensive increase of order Lactobacillales. To analyze the potential effect of Lactobacillales on skin inflammation, we further monocolonized mice with L. plantarum WCFS1. Also monocolonized mice showed lower skin inflammation in comparison with conventional mice. To understand whether microbial dysbiosis is cause or effect of psoriasis needs to be further investigated.\n\n
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BAFF (B-cell Activating Factor of the TNF Family) in patients with idiopathic inflammatory myopathieswith respect to autoantibody profile.
Kryštůfková, Olga ; Vencovský, Jiří (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Blažíčková, Stanislava (referee)
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of chronic muscle diseases with frequent extramuscular organ involvement that contributes to serious prognosis. The presence of autoantibodies and composition of muscle infiltrates both support autoimmune nature of the disease and pathogenic role of B lymphocytes. Besides the traditional diagnostic subgroups, autoantibody characterised phenotype subsets have been identified with presumed similar pathogenic mechanisms. The best known is the antisynthetase syndrome which is characterised by presence of myositis, antisynthetase autoantibodies (with anti-Jo-1 being the most frequent), interstitial lung disease and other extramuscular manifestations. BAFF (B cell-Activating Factor of the TNF Family) is a key factor in B cell homeostasis modulation. In high levels, it allows survival of autoreactive B cell clones and thus participates in the pathogenesis of autoimmune diseases. Its expression is induced by type I interferons (IFN-1). The aim of the PhD thesis was to explore the role of BAFF in pathogenesis of IIMs by analysis of its serum levels, the receptors for BAFF in muscle tissue, their associations to IFN-1 and expression of BAFF gene mRNA transcription variants in peripheral blood cells. Further aspect was to study a possible...
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