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Immunointerventional therapy of autoimmune diabetes with recent oncet in NOD mice.
Vargová, Lenka ; Saudek, František (advisor) ; Štechová, Kateřina (referee) ; Mráz, Miloš (referee)
Introduction: Type 1 diabetes mellitus is a chronic metabolic disease caused by autoimmune destruction of pancreatic beta cells. The theory of the disease onset is derived from study of a disease course in non-obese diabetic (NOD) mice, in which the diabetes occurs due to a dysregulation of the immune system. Experimental and clinical studies showed that the autoimmunity may be abrogated by immune intervention, which if initiated early enough may at least slow down the ongoing beta cells lost and preserve residual insulin secretion. But immune intervention alone is not sufficient to restore normoglycemia in the majority of cases. Several interventional studies showed that stimulation of proliferation and/or regeneration of beta cells are necessary to restore normoglycemia in animal models. Aim of the study: To find out, if the combination of a potent immunosuppression (murine anti-thymocyte globulin (mATG), gusperimus) together with stimulation of islet regeneration (sitagliptin) will be able to slow down or reverse the course of the disease. Another aim is to identify the mechanism by which the substances act. Material and methods: All experiments were performed in female NODShiLtJ (H2g7 ) mice. The following parameters were examined at day 0, 7, 14 and 28: blood glucose, subpopulations of...
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Autoantibodies against calreticulin in patients with dilated and hypertrophic cardiomyopathy
Sánchez, Daniel
Distinct cellular level of the Ca2+ binding chaperone calreticulin (CRT) is essential for cardiac development and postnatal function. However, CRT is also a potential autoantigen eliciting formation of antibodies (Ab), whose role is not yet clarified. Immunization with CRT leads to cardiac injury, and overexpression of CRT in cardiomyocytes induces dilated cardiomyopathy (DCM) in experimental animals. Hence, we analysed levels of anti-CRT Ab and calreticulin in the sera of patients with idiopatic DCM and hypertrophic cardiomyopathy (HCM). ELISA and immunoblot using human recombinant CRT and Pepscan with synthetic, overlapping decapeptides of CRT were used to detect anti-CRT Ab. Significantly increased levels of anti-CRT Ab of IgA (P<0.001) and IgG (P<0.05) isotypes were found in patients with both DCM (12/34 seropositive for IgA, 7/34 for IgG) and HCM (13/38 seropositive for IgA, 11/38 for IgG) when compared with controls (2/79 for IgA, 1/79 for IgG). Titration analysis in seropositive DCM and HCM patients documented anti-CRT Ab detected at 1/1600 dilution for IgG and 1/800 for IgA (and IgA1) and at least at 1/200 dilution for IgA2, IgG1, IgG2 and IgG3. Pepscan identified several immunogenic CRT epitopes: EVKIDNSQVESGSLED, IDDPTDSKPE, DKAPEHIPDPDA and RKEEEEAEDKEDDAEDKDEDEEDE recognised by IgA and...
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Rehabilitation issues for patient with acute disseminated encephalomyelitis
Tyburcová, Marie ; Zumrová, Alena (advisor) ; Málková, Michaela (referee)
Acute disseminated encephalomyelitis (ADEM) is a serious neurological disease with a variable progression, which can have permanent consequences for the patient, despite medical advances. An irreplaceable element of complex treatment is rehabilitation which has in recent years become a sophisticated preventative therapeutic method, mainly based on the study of plasticity and of the possibilities of brain regeneration. This work presents a comprehensive theoretical overview of our current knowledge of a relatively rare autoimmune disease of the central nervous system (CNS) as well as current options and procedures for affecting the course of the disease and its consequences through physiotherapy. It was written based on the collection of theoretical data, questioning and observation of the physiotherapy of a patient with ADEM, who was hospitalised for five months in various wards of 2nd Faculty of Medicine in Prague. Physiotherapeutic procedures are divided and applied in both the theoretical and practical parts of the work according to the phase model. Theoretical knowledge, drawn from published case studies, as well as the course of the observed patient's disease and his following convalescence clearly illustrate that provided the timely commencement of intensive treatment and the continuation...
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Snižují regulační T lymfocyty riziko autoimmunity indukované CD8+ T lymfocyty?
Chadimová, Tereza ; Štěpánek, Ondřej (advisor) ; Šenolt, Ladislav (referee)
5 Regulatory T cells (Tregs) are essential for the maintenance of peripheral self-tolerance and prevention of autoimmunity by suppressing the response of self-reactive CD8+ and CD4+ T cells. However, while interactions of Tregs with CD4+ T cells have been extensively studied, their effect on the self-tolerance of CD8+ T cells has not been explored in detail. The main aim of this diploma project was to provide evidence whether and how Tregs prevent autoimmunity induced by CD8+ T cells. We used an experimental mouse model of autoimmune diabetes allowing us to acutely deplete Tregs and titrate the number of self-reactive T cells, self- antigen affinity, and self-antigen doses. We found out that Tregs play an important role in the prevention of CD8+ T-cell mediated autoimmunity. Moreover, we revealed that Tregs suppress both high-affinity T cells that escape negative selection and relatively weakly self-reactive, but numerous, positively selected T cells. Tregs do so by increasing requirement for the number of self-reactive CD8+ T cells required for the autoimmunity induction. Intriguingly, presence of Tregs does not impact threshold for self-antigen. Moreover, for the first time, we showed that Tregs can suppress CD8+ T-cell-mediated autoimmunity in the absence of conventional CD4+ T cells. This means that...
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Glaucoma - family-based genetic analysis in relation to autoimmunity
Buchtelová, Aneta ; Daňková, Pavlína (advisor) ; Ďuďáková, Ľubica (referee)
Introduction: Recent findings about the pathogenesis of glaucoma have already demonstrated the presence of some specific autoimmune mechanisms. It has also been shown that autoimmune diseases often manifest in co-occurrence, such as celiac disease and type 1 diabetes mellitus or psoriasis. This association can be explained by sharing some of the risk variants of HLA molecules class II. Considering glaucoma an autoimmune disease, the question raises how the glaucoma genetic risk factors affect the phenotype of another autoimmune disease or vice versa, whether genetic risk variants associated for example with celiac disease can affect the glaucoma phenotype. Aims: The aims of this study were to i) identify possible genetic risk markers associated with the development of glaucoma, based on the available literature, and to map their occurrence among members of a three-generation family suffering from glaucoma and multiple autoimmune diseases, ii) find carriers of HLA-DQ2/DQ8 among the members of the same family, iii) verify whether an individual's genotype correlates with his/her phenotype, and iv) determine the potential effect of specific HLA alleles on the glaucoma phenotype. Material and methods: This study used DNA samples derived from 34 members of a three-generation family, in which coeliac...
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Immunological causes of female infertility
Bajerová, Kateřina ; Brynychová, Iva (advisor) ; Novák, Jan (referee)
Currently, up to 15 % of reproductive age couples struggle with infertility. Female infertility is the cause of conception issues in nearly 40 % of these cases. The origin of female infertility consists of wide range of causes and other factors. Immunological causes are certainly one of the most significant ones. In pathological conditions, defense mechanisms of female immune system can target alloantigens presented on sperm surface. Moreover, autoimmune response and antibody production can occur as well. Antibodies can target various parts of ovarian follicles and oocytes, phospholipids, nuclear antigens, enzymes etc. These antibodies can inhibit fertilization, maturation of oocytes and embryo, embryo implantation, and also recurrent miscarriages. The aim of this thesis is to summarize various causes of female infertility focusing on immunological pathologies. The thesis also describes functioning of immune mechanisms in the female reproductive tract and briefly touches on oogenesis and female hormonal cycle.
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Highly multiplexed virus detection in research of multifactorial diseases
Kunteová, Kateřina ; Cinek, Ondřej (advisor) ; Saláková, Martina (referee)
Next generation sequencing, which allows concurrent parallel sequencing of many samples and makes it possible to distinguish the infection from multiple viral types in the sample, is well suited as a detection format for such assays described below. The aim of the thesis was to develop a method that could detect all known types of human adenoviruses, human enteroviruses, and bacteriophages selected for their presence in the intestine. Using the next- generation sequencing. The first step was to design primers capable of detecting all known types of viruses, covering the area that is capable of distinguishing these viruses. This method was tested on a set of 47 human adenovirus samples and 30 human enterovirus samples of known serotype. Samples with two serotypes in different proportions were also created. After amplification of the target genome, the samples were purified and sequenced on MiSeq, Illumina. The method was further used in the typing of adenoviruses, enteroviruses and bacteriophages in pre-diabetic cohorts of DIPP, MIDIA, and a cohort of diabetics from African and Asian countries. The tested sample was RNA / DNA isolated from the stool specimen. We have demonstrated that the method is capable to detect all tested virus types, including infections with two different types, even if the...
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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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Immunological causes of male infertility
Stiborová, Martina ; Brynychová, Iva (advisor) ; Dostálová, Pavla (referee)
Infertility is defined as the inability to persuade a child after one year of regular unprotected contact, occurs in about 15% of partner couples. In addition to genetic, anatomical, hormonal and infectious causes, the importance of immunopathological mechanisms that contribute to infertility is 15%. The immune system is designed to protect the body's intrinsic stability and respond to so-called "dangerous" signals that can be induced by sperm as autoantigens for men and alloantigens for woman. A healthy individual has protective mechanisms in place to protect sperm from possible attack of the immune system. Failure of protective mechanisms and the natural immune system can result in antibodies against sperm. Antibodies against sperm proteins negatively affect sperm fertilization and are one of the main causes of infertility. This paper describes the possible occurrence of anti-sperm antibodies in both sexes. It also describes the development of sperm, immunological properties of the male and female sexual tract, and briefly summarizes the properties of anti-sperm antibodies and the treatment of immunological infertility. Key words: Reproduction, infertility, sperm cells, antisperm antibodies, autoimmunity
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