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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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Pathogenetic mechanisms of immune dysregulation and hematopoietic disorders
Svatoň, Michael ; Froňková, Eva (advisor) ; Filipp, Dominik (referee) ; Čermák, Jaroslav (referee)
Pathogenetic mechanisms of immune dysregulation and hematopoietic disorders Abstract The aim of my work was to introduce whole exome sequencing (WES) and a routine algorithm for data analysis in pediatric patients with suspected inborn error of immunity (IEI) or hematopoiesis. A clear molecular diagnosis based on genetic testingwas achieved in 25% of patients. Additionally, novel mutations not previously described in the pathogenesis of IEI or hematopoietic failure were revealed in 9% of the patients. Validation experiments were designed to confirm the causality of the identified mutations in the pathogenesis of the disease, based on literature review and known mechanisms of immune system development and regulation in these patients. Thanks to WES, we were able to elucidate the cause of two new congenital diseases - megaloblastic anemia due to a homozygous mutation of the SLC19A1 gene and immune dysregulation syndrome with autoimmune and autoinflammatory manifestations due to an X-linked mutation of the TLR8 gene in monozygotic twins with chronic autoimmune hemolytic anemia (AIHA). In five additional patients, novel mutations in the STAT3, SPTA1, SAMD9 and XIAP genes were identified and their causality in the pathogenesis of hematopoietic failure or IEI was demonstrated. In one patient with an atypical...
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