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The impact of maternal-fetal microchimerism on the development of the offspring's immune system
Malinská, Nikola ; Černý, Jan (advisor) ; Balounová, Jana (referee)
Maternal-fetal microchimerism is a phenomenon in which maternal cells migrate to the offspring's tissue during both pregnancy and breastfeeding. These cells are mainly leukocytes and stem cells. These maternal cells have functional potential in the offspring and influence, among other things, the development of their immune system. The main cell population detectable in various tissues of the offspring are T lymphocytes. These maternal T lymphocytes not only have effector function, but also influence the development of the offspring's T lymphocytes in the thymus or maturation of offspring's B lymphocytes in the lymph nodes. Migration of maternal leukocyte also leads to transfer of immune memory through generations. Maternal microchimerism is also capable of balancing immunodeficiencies of the offspring. Maternal cells expressing IL-2 were detected in mice deficient in IL-2 and maternal IgG secreting plasma cells were found in offsprings deficient in B cell. This work is focused on the influence of maternal cells transported within maternal microchimerism on the development of the offspring's immune system as well as the effector functions of maternal cells migrating through the placenta and breast milk to the offspring.
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Identification and characterization of novel regulators of hematopoietic stem cell function
Grušanović, Srđan ; Alberich Jorda, Meritxell (advisor) ; Balounová, Jana (referee) ; Froňková, Eva (referee)
Hematopoietic stem cells (HSCs) are sitting atop a carefully orchestrated system, called the hematopoietic system. HSCs maintain the constant production of mature blood cells throughout our life, and dysregulated HSC function may lead to severe health problems including bone marrow aplasia and leukemia. Thus, HSC activity needs to be tightly controlled by a complex network of cell intrinsic and cell extrinsic factors. In this thesis, we focus on two previously uncharacterized extrinsic mechanisms that might be involved in the regulation of HSC function. A common aspect of these mechanisms is the production of pro-inflammatory cytokines. First, we investigated the impact of donor NK cells on donor HSC function upon bone marrow transplantation, a frequent clinical intervention. We observed that NK cells negatively affect HSC engraftment and reconstitution during transplantation. To address the potential mechanism, we employed Cebpg knockout mice, which produce non-functional NK cells, and determined that NK cells affect HSC activity through the production of IFNγ. Remarkably, IFNγ-blocking antibodies improved murine and human HSC activity upon bone marrow transplantation. Altogether, we concluded that suppression of inflammatory signals generated by donor innate immune cells can have a significant...
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Phenotypic and functional characterization of leukocytes in patients with immune system dysregulation
Fejtková, Martina ; Kanderová, Veronika (advisor) ; Vlková, Marcela (referee) ; Balounová, Jana (referee)
Inborn errors of immunity (IEI) are a heterogenic group of diseases of the immune system causing dysregulations of both innate and adaptive immunity. New altered immune-related genes are discovered every year, nowadays reaching over 400. (Tangye et al., 2020) Here three new autoinflammatory disorders of IEI patients are described. Toll-like receptors (TLR) 7 and 8 are endosomal receptors in the innate immune response against external pathogens and endogenous autoantigens. A dysregulation in TLR7 and TLR8 in mice causes autoimmunity and inflammation, however, in humans, the immunopathology of TLR8 and TLR7 remains unclear. We identified a novel X-linked c.1715G>T mutation in TLR8 that leads to autoimmune haemolytic anaemia and autoinflammation in male twins caused by dysregulation in TLR8 and TLR7 response especially in myeloid cells (low TLR8 protein expression, cross-reactivity of TLR8 for TLR7 ligands and enhanced TLR7 response). Hematopoietic cell kinase (HCK) belongs to the Src family of kinases and is involved in myeloid cell migration, adhesion and degranulation. Kinase activity in the immune response must be strictly regulated. In HCK, this regulation is based on C-terminal inhibitory tyrosine, which when phosphorylated, HCK kinase activity is switched off. We identified a heterozygous...
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Mitochondrial transfer-mediated modulatory action of stem cells on immune cells
Somova, Veronika ; Krulová, Magdaléna (advisor) ; Balounová, Jana (referee)
Stem cells use different mechanisms of intercellular communication to modulate an immune response. Mitochondrial transfer is one of the mechanisms which induce metabolic changes, support cell survival, and change the phenotype of immune cells. Nevertheless, little is known about the mechanism used for transfer of mitochondria between different cell populations and the faith of mitochondria inside the acceptor cell. This thesis aims to describe the mechanism of transfer and the provided modulation. Factors that could affect mitochondrial transfer including reactive oxygen species production, apoptosis and mitochondria function were analyzed. And the impact of mitochondrial transfer on cell survival and mitophagy was described. The next aim was to compare the ability of mesenchymal stem cells (MSC) and Sertoli cells (SC) to transfer mitochondria, with MSC being more productive in the transfer of mitochondria than SC. Significant differences in the presence of mitochondria from donor MSC or SC in individual populations of immune cells were also detected. To explain these findings, the impact of reactive oxygen species on the transfer of mitochondria was analyzed in detail, although it wasn't confirmed. However, it needs to be highlighted that mitophagy plays an important role before and after...
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Public use of natural goods
Nováková, Katarína ; Svoboda, Petr (advisor) ; Balounová, Jana (referee)
Public use of natural goods Abstract The diploma thesis deals with the legal regulation of public use, as the right to free use of public affairs by an unlimited range of subjects, namely natural goods, namely air, water, forest, and landscape, as components of the environment. Jurisprudence distinguishes between general and special public use. General use can be considered a basic type of public use, which is usually established by law. For some farms, such the atmosphere arises from their natural nature and the emergence of general use by the owner's de facto dedication to the farm cannot be ruled out. The special use is realized based on the act of application of the law always issued by name to a specific entity, which can be both a natural and a legal person. Permits for special uses are issued by administrative authorities, whose jurisdiction is defined by the individual laws under which the permit is issued. Ownership of a public matter is limited by public law but is not completely withdrawn. Within the framework of public use, relations arise between users and owners of public affairs. The content of these relationships is mutual rights and obligations. It is the user's right to use the natural property within the set limits and at the same time, it is the user's duty to refrain from actions that...
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Regulatory mechanisms in normal and malignant granulopoiesis
Kardošová, Miroslava ; Alberich Jorda, Meritxell (advisor) ; Stopka, Tomáš (referee) ; Balounová, Jana (referee)
Neutrophils, known primarily as key players in defense against invading pathogens, represent an essential component of both the innate and adaptive immunity. Continuous production of large quantities of neutrophils is ensured by a complex process termed granulopoiesis. In order to maintain a stable neutrophilic population, granulopoiesis requires to be tightly regulated. Moreover, impaired granulopoiesis may lead to aberrant bone marrow function and, ultimately, give rise to acute myeloid leukemia (AML). Despite decades of research, the mechanisms regulating granulopoiesis are still unclear. In particular, the CCAAT/enhancer binding protein (C/EBP) family of transcription factors plays a critical role in this process. C/EBPα acts as a master regulator of granulopoiesis mainly by orchestrating expression of its target genes, which will mediate granulocytic differentiation. Thus, characterization of novel C/EBPα target genes is critical for a better understanding of the molecular mechanisms that regulate granulopoiesis. Previously, we showed that another C/EBP member, CEBPG, is a direct target of C/EBPα. In the first part of the present work, we addressed the unknown role of C/EBPγ in granulopoiesis. We observed that Cebpg conditional knockout (KO) mice, which have the Cebpg gene ablated specifically...
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Toll like receptors and myeloid cells in development and disease
Balounová, Jana ; Filipp, Dominik (advisor) ; Špíšek, Radek (referee) ; Vannucci, Luca Ernesto (referee)
Toll like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to pathogens. Primarily they are responsible for induction and regulation of the innate and adaptive immune responses whereby the effector function is executed chiefly by differentiated myeloid cells. Somewhat unexpectedly, TLRs have been also shown to be involved in direct pathogen sensing by bone marrow-derived hematopoietic stem cells (HSCs) and hematopoietic progenitors when, under inflammatory conditions, the rapid generation of innate immune effector cells that effectively combat the infection is of utmost priority. While it has been recognized that the release of inflammatory cytokines from inflamed tissues along with the changes in proportions of differentiating cells in the bone marrow (BM) as well as the BM niche can nudge the differentiation of adult BM-derived cells towards myeloid cells and granulocytes, a direct role of TLRs expressed by HSCs in this process has been demonstrated only recently. However, whether a similar mechanism operates also during embryonic hematopoiesis is unknown. Here we show that TLRs and their adaptor proteins are functionally expressed during early stages of embryogenesis by short-lived maternally-transferred...
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