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Monogenic susceptibility to infectious pathogens
Bloomfield, Markéta ; Šedivá, Anna (advisor) ; Koziar Vašáková, Martina (referee) ; Litzman, Jiří (referee)
(ENG) The modern approach to studies of monogenic inborn errors of immunity, driven by unprecedented advances of genetic tools, opens vast undiscovered areas of immune system components and functions. In particular, the diseases with striking clinical phenotypes with normal or near normal baseline immunophenotype, such as disorders of innate and intrinsic immunity with susceptibility to single pathogen, provide a unique window into the host-pathogen interactions. This thesis covers various novel aspects of immunopathology, genetics and clinical facets behind some such diseases, namely chronic mucocutaneous candidiasis due to hypermorphic (gain-of-function, GOF) STAT1 mutations, which hamper Th17-associated immune activities, and Mendelian susceptibility to mycobacterial diseases (MSMD) due to impairment of IL-12, IL-23/IFNγ signalling pathway. Moreover, it contributes to the mounting evidence that IL- 6 signalling is non-redundant in anti-staphylococcal immunity. Finally, it explores the novel Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS- TS) as a single pathogen-driven life-threatening immunopathology, which most likely develops due to individual, yet unknown, genetic predisposition. The findings presented in this thesis were in several cases translated...
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Adaptive immune system in patients with primary immunodeficiencies
Klocperk, Adam ; Šedivá, Anna (advisor) ; Filipp, Dominik (referee) ; Litzman, Jiří (referee)
(ENG) This thesis summarizes the results of a project dedicated to adaptive immune system of patients with partial DiGeorge syndrome caused by deletion of 22q11.2. The introduction sets the DiGeorge syndrome into a broader context of international pathophysio- clinical classification of primary immunodeficiencies and goes into detail describing its history, causes, clinical phenotype, therapeutic options and changes of the immune system. The attached manuscripts illustrate the premature aging of the T cell population, but also impaired development of B cells with low class-switched memory and high naïve subpopulations, along with high serum levels of BAFF, a B cell survival factor. The surprising lack of T independent marginal zone- like (MZ-like) B cells is reflected in decreased natural anti-α-Gal antibodies. The faulty B cell maturation and imperfect germinal center response is not caused by a deficit of follicular helper T cells, which are in fact increased in DiGeorge syndrome patients, and in most cases doesn't lead to hypogammaglobulinaemia. Despite the high incidence of autoimmune disease, in particular thyroiditis and thrombocytopenia, and a trend towards hypergammaglobulinaemia in adolescence and adulthood, we saw normal proportion of regulatory T cells (Tregs) and normal expression of...
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Adaptive immune system in patients with primary immunodeficiencies
Klocperk, Adam ; Šedivá, Anna (advisor) ; Filipp, Dominik (referee) ; Litzman, Jiří (referee)
(ENG) This thesis summarizes the results of a project dedicated to adaptive immune system of patients with partial DiGeorge syndrome caused by deletion of 22q11.2. The introduction sets the DiGeorge syndrome into a broader context of international pathophysio- clinical classification of primary immunodeficiencies and goes into detail describing its history, causes, clinical phenotype, therapeutic options and changes of the immune system. The attached manuscripts illustrate the premature aging of the T cell population, but also impaired development of B cells with low class-switched memory and high naïve subpopulations, along with high serum levels of BAFF, a B cell survival factor. The surprising lack of T independent marginal zone- like (MZ-like) B cells is reflected in decreased natural anti-α-Gal antibodies. The faulty B cell maturation and imperfect germinal center response is not caused by a deficit of follicular helper T cells, which are in fact increased in DiGeorge syndrome patients, and in most cases doesn't lead to hypogammaglobulinaemia. Despite the high incidence of autoimmune disease, in particular thyroiditis and thrombocytopenia, and a trend towards hypergammaglobulinaemia in adolescence and adulthood, we saw normal proportion of regulatory T cells (Tregs) and normal expression of...
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Laboratory parameters in the detection of the effect of anticancer therapy on immune system
Králíčková, Pavlína ; Melichar, Bohuslav (advisor) ; Tesařová, Petra (referee) ; Litzman, Jiří (referee)
Laboratory parameters in the detection of the effect of anticancer therapy on immune system Summary We can consider the immune response to cancer cells as the last barrier in carcinogenesis. Chemotherapeutics interfere directly or indirectly with tumour microenvironment. Our work was divided into two parts. The aim of our study was to describe the distribution of lymphocyte subsets in peripheral blood and urinary neopterin in breast cancer patients in relatation to the treatment in the part one, and elucidate the correlation between CD14+CD16+ monocytes, urinary neopterin and risk factors of atherosclerosis in the part two. We show that the changes of lymphocyte subpopulations are present even at the time of cancer diagnosis. The treatment could positively affect the anticancer response. The changes of these lymphocytes subsets during therapy in patients with metastatic stage of disease are less expressed. The restoration of the immune system is a long-term process. The systemic inflammatory response connected with tumour presence could contribute to the accented atherosclerosis, possible long-term complication in cancer patients.
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