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Acute myeloid leukemia makes up for 18 % of all leukemias among pediatric and young adult patients. The complete remission rate (80-90 %) and the overall survival (70 %) of the patients is relatively high, nevertheless, the relapse rate is still almost at 50 % and the prognosis remains extremely bad. The relapse treatment is rather challenging because the persisting leukemic clones might in fact start to be refractory to chemotherapy. Lately, NK cells are being perceived as an attractive therapeutical tool for treatment of the relapses. NK cells are a subpopulation of innate lymphoid cells, possessing the ability to eliminate dysfunctional cells through cytotoxic activities and further perpetuate the immune response. One of the advantages of NK cells is their functional independency of specific antigens. In the light of growing evidence about the role of leukemic stem cells in context of acute myeloid leukemia, NK cells seem to offer a new perspective in therapeutical efforts to eliminate them via several cytotoxic mechanisms. Yet despite optimistic preliminary results, treating this disease has proved to be rather challenging and the NK cell-based immunotherapy is still facing several limitations. Transforming growth factor β is partially responsible for maintenance of leukemic stem cell...

 T lymphocytes are a unique type of T lymphocytes which, because of their innate-like qualities, belong to the so-called innate lymphocytes. Although they are a relatively rare population of T lymphocytes in peripheral blood, they are enriched in many peripheral tissues where they participate in immune responses to infectious pathogens and cell transformation. In addition, they play a role in the development of several autoimmune disorders. Recently, non- immune functions of  T lymphocytes in tissue repair and tissue homeostasis have also been emphasized. This work focuses on the characterization of  T lymphocytes, especially those residing in adipose tissue.  T lymphocytes regulate adipose tissue homeostasis and overall energy metabolism. The roles of  T lymphocytes under physiological and non-physiological conditions are described, including their impact on the development of obesity and metabolic syndrome. The possible applications of these lymphocytes in the treatment of these diseases are also briefly mentioned.

Mitochondrial transfer represents a form of intercellular communication. In this process, mitochondria are delivered from the donor cell to the recipient cell through several structures. The transfer of mitochondria is observed under pathological and physiological conditions and is accompanied by specific signaling. Mitochondria uptake by injured cells promotes tissue regeneration. This bachelor thesis discusses general knowledge of mitochondrial transfer focusing on mesenchymal stem cells (MSCs) as a donor cell type. Furthermore, the regenerative effect of MSC-derived mitochondria transfer to cells damaged by various pathologies is summarized. In this regard, MSCs have significant therapeutic potential that could be used in future clinical strategies for a number of diseases. Keywords: mitochondria, transfer, mesenchymal stem cells, regeneration

The ability to sense painful stimuli is essential to protect the body. Up to date, the underlying molecular mechanisms are still not completely understood; therefore, the treatment of chronic inflammatory pain remains challenging. The TRPV1 channel is one of the known nociceptors mediating the sensation of burning stimuli. Its agonist is capsaicin, the pungent compound of chilli peppers. This channel has been extensively studied in neurones; however, its function in immune cells is not well understood. Especially in macrophages, data regarding the role of TRPV1 in macrophage polarisation are often contradictory. Thus, further research in this area is desired to clarify the function of TRPV1 in immune cells. This diploma thesis aims to investigate the role of TRPV1 in macrophage polarisation during the inflammatory response. In this work, macrophages were stimulated with capsaicin prior to, after or concurrently with the application of LPS to determine the effect of TRPV1 activation on the inflammatory response. The involvement of MAP kinases in signalling after TRPV1 activation by capsaicin was addressed confirming that ERK 1/2 is part of the signalling cascade. Furthermore, this work proposes that activation of TRPV1 in the context of the LPS-induced inflammatory response could lead to the switch...

Identification of new regulators of proinflammatory signaling pathways Helena Dráberová Protein 4.1R has been described in immune system as regulator of migration and cell adhesion, but was also shown to play a role in activation of T lymphocytes. Polymorphism in gene ORMDL-3 is associated with asthma risk in children and correlates with increased ORMDL-3 expression. This disertation thesis describes the function of proteins 4.1R and ORMDL-3 in activation of mast cells after stimulation of FcεRI receptor. IL-17 is a proinflammatory cytokine that plays a role in immune response against fungal and yeast infections. IL-17 however also plays a role in the pathology of autoimmune diseases such as reumatoid arthritis, psoriasis and multiple sclerosis. IL-17 signaling is tightly regulated, however the exact mechanism has not been described. This disertation thesis describes the IL-17R complex by mass spectrometry and analyze the function of its known and newly discovered components in cells deficient in individual proteins by method CRISPR-Cas9. Last part focuses on the discovery of new subunit of IL-17RC protein CMTM4, which role in IL-17 signaling has not been described so far. CMTM4 stabilizes IL-17RC and is required for its surface expression. In vitro data are supported by data from autoimmune model of...

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...

Statins are widely used for their eminent hypolipidemic effect as anti-atherosclerotic drugs from the 90's of the 20th century. Even though there are new approaches, statins are still the first choice in the prevention of cardiovascular diseases. At the beginning of the 21st century, the anti- inflammatory effect independent of lipid-lowering properties was discovered. This diploma thesis deals with the effect of statin treatment on macrophage polarisation in vitro. Macrophages differentiated from blood monocytes were used in this thesis. The effect of statin treatment on the expression of surface markers (CD16, CD15, CD36, CD163, CD206, ABCA-1 and Trem-2) was evaluated by flow cytometry. The qPCR method was used to quantify the effect of statin treatment on the gene expression of inflammatory genes (NFκB, IL-1β, IL-6, TNFα and iNOS), anti- inflammatory genes (Arg-1, TGFβ) and genes which play a role in the adhesion and migration of monocytes and macrophages to vessel intima (VCAM-1 and MCP-1). Griess method was used to evaluate the effect of statin treatment on the inducible NO-synthase activity. Last, but not least, the effect of statin treatment on proteosynthesis of inflammatory cytokines (IL-1β, IL-6 a TNFα) and anti-inflammatory cytokine IL-10 was measured. Flow cytometry results show that...

Leishmaniasis, a disease caused by Leishmania parasites, ranks as the leading neglected tropical disease in terms of morbidity and mortality. Genotype of the infected organism is an important factor that influences susceptibility to and manifestations of this disease. To study human disease using mouse models, several strains are required, which could collectively exhibit different human pathophysiology. In the current thesis, we investigated the genetic influence on resting levels of immune cells in mice, because these resting levels could influence susceptibility to many of clinical disorders, including infectious diseases; and we performed a systematic review of the role of host genetics and cytokines in Leishmania infections. Moreover, we employed systems genetics to map genes causing susceptibility to leishmaniasis, and to identify additional mechanisms controlling response to Leishmania parasites. Also, we fine mapped the locus Leishmania major response 15 (Lmr15) in order to functionally characterize its role and to identify novel potential candidate genes regulating the response to L. major. Finally, we show a novel role of guanylate binding proteins 2b and 5 in the resistance to L. major. Strain B10.O20 carrying 3.6% of O20-derived genes on the C57BL/10 genetic background, on chromosomes...

Mesenchymal stem cells (MSCs) are classified as multipotent stem cells. They possess the ability to differentiate into many cell types, promote angiogenesis, increase cell survival in damaged tissue and modulate the immune response. These functions of MSCs are used in the treatment of various injuries and some diseases. This work characterizes MSCs, with a focus on their energy metabolism, specifically on the switch in their metabolic phenotype between glycolysis and oxidative phosphorylation in different states of MSCs, during cell culture and after transplantation. Finally, two modulations of MSC metabolism are presented, including cultivation in a hypoxic environment and quiescence induced by serum deprivation, which increase cell survival under the ischemic conditions that MSCs enter after transplantation. Key words: mesenchymal stem cells, metabolism, glycolysis, oxidative phosphorylation

Acute myeloid leukemia (AML) is a cancerous disease of hematopoiesis characterised by accumulation of immature cells (blasts) of the myeloid lineage. AML blasts utilise a range of mechanisms to escape the immune system including alteration of their metabolism or expression of inhibitory molecules. Activation of these mechanisms is not yet fully understood. One of the pathways used to regulate a great number of cellular processes is the mammalian target of rapamycin (mTOR) pathway. mTOR kinase forms two complexes, mTORC1 and mTORC2, each regulating different substrates and cellular functions. The aim of this thesis was to analyze the influence of inhibition of each of the mTOR complexes on the metabolism (oxidative phosphorylation and glycolysis) and expression of immune escape markers (HLA-I, HLA-DR, CLIP, PD-L1, TIM-3) was analysed. The inhibitor JR-AB2-011 (an mTORC2 inhibitor) reduced the mitochondrial respiration rate in the majority of the cell lines, but its impact on the cell immunophenotype was only weak. Importantly, we found that the effect on the cell metabolism did not stem from the inhibition of mTORC2. Rapamycin (an mTORC1 inhibitor) decreased both metabolic rates, as well as glucose uptake. At the same time, CLIP, PD-L1, and TIM-3 expression was reduced in all the studied cell lines,...

Immunotherapy experienced ups and downs before being recognized as a paramount therapy for cancer. Evidence from the latest studies revealed that the tumour microenvironment (TME) plays a decisive role in the outcome of immunotherapeutic treatment. In addition, one of the mechanisms used by cancer cells to evade immunosurveillance is reduction of the expression of major histocompatibility complex class I (MHC-I), by which cancer cells become invisible to cytotoxic T lymphocytes (CTLs). Therefore, cancer immunotherapy should involve combined strategies to target both tumour cells and TME from different sites by activating other immune cells in addition to CTLs, such as tumour-associated macrophages (TAMs). This Ph.D. thesis aimed to investigate combined immunotherapy, composed of DNA immunization, immunostimulatory compounds, and an immune checkpoint inhibitor to activate adaptive and innate immunity and inhibit immunosuppression, respectively. For this purpose, murine models related to HPV-16-induced tumours with either reversibly (TC-1/A9 cell line) or irreversibly (TC-1/dB2m) reduced MHC-I expression were used. The development of the TC-1/dB2m clone was a part of this project and this clone was obtained by deactivating the B2m gene. An important focus of the research was the analysis of TAMs isolated from...

Although the relationship between the effects of cold and infection has been studied for a long time, the mechanisms contributing to this phenomenon have not yet been discovered. While short-term exposure to cold triggers a stress response and the production of proinflammatory cytokines, long-term cold exposure induces adaptation and anti- inflammatory shift. The role of cold adaptation in the development and the process of the organism's response to infection remains an unresolved issue. In this diploma thesis, we focused on determining the effect of cold stress or cold adaptation on the immune system of rats which was stimulated by ligands of Toll-like receptors (TLRs). The obtained results showed the importance of γδT lymphocytes and their cytokine production in the process of cold adaptation. To determine how cold adaptation affects the response to infectious agents, we studied changes in the proportion of different immune cell populations in rats treated with the TLR2/6 ligand Pam2CSK4. We determined significant changes in the activation of myeloid cells and B lymphocytes, but also in the population of γδT lymphocytes. Our obtained results suggested the importance of γδT lymphocytes and the protective effect of cold adaptation. Key words: immune system, cold stress, cold adaptation, infection,...

Many studies show the ability of gut microbes to modulate the anti-tumour immune response by direct triggering the immune cells or by bacterial metabolites. Interestingly bacteria may even migrate to the tumour tissue and orchestrate the immune response on site. These anti-tumour effects can be improved by the administration of immune checkpoint inhibitors (ICI). Notably, some microbial effects occur only in the presence of ICI. On the contrary, microbiota may also promote tumour growth and negatively impact the effects of ICI therapy. We have disrupted the gut microbiota homeostasis by antibiotics (ATB) to study the effects of gut microbiota on the ICI. This disturbance led surprisingly to reduced tumour growth and enhanced pro-inflammatory immune response not only in the gut but also within the tumour tissue, where especially IFN-γ orchestrated the anti-tumour immune response. Importantly the anti-tumour immune response could be transferred through colonisation of germ-free mice by ATB-changed gut microbiota if concomitantly anti- programmed cell death protein 1 (αPD-1) monoclonal antibody was administrated. These mice had elevated levels of segmented filamentous bacteria (SFB), which induced systemic immune response with increased expression of IL-17 and elevated amounts of Th 17 cells,...

The application of nanoparticles in the field of theranostics requires knowledge of the specific interaction of nanoparticles with the immune system. One of the first cells with which nanoparticles interact when given to the body are cells of the mononuclear phagocytic system. The aim of this diploma thesis is to prepare an in vitro study that describes the effect of two types of gold and three types of silicon ultra-small nanoparticles on immune cells. Immune cells are presented in the form of primary PBMCs isolated from whole blood , and cells of monocytic cell line THP-1 in the form of monocytes and differentiated macrophages. During the experiments with primary cells, emphasis is placed on maintaining the concept of personalized protein corona. After characterization of the immune cells used, cells are subsequently stimulated with ultra-small nanoparticles and the influence of these nanoparticles on cell metabolism, viability, degree of differentiation and secretion of pro- and antiinflammatory cytokines is monitored. The outcome takes into account further use of the tested nanoparticles in the field of biomedicine. Key words: primary monocytes, cell lines, differentiation, macrophages, cytokines, cytotoxicity

Early postnatal period is characterised by generally immature phenotype of the newborn's immune system. The maturation of the immune system including setting appropriate regulatory responses is occurring during this period and encountering pioneering bacteria colonizing neonate plays an important role. In the early days after birth, the immune system of a newborn is very limited, and the adaptive part is mostly represented by antibodies transferred from the mother by cord blood (CB) in the womb and then by colostrum and mother's milk after labour. Therefore, innate immunity plays a key role in defence (against pathogens) in neonates and is largely represented by neutrophils. This study aims to better understand neutrophil biology and phenotype in umbilical CB, compared to neutrophils from peripheral blood (PB) of mothers and healthy non pregnant women (referred to as HC). The assessment of neutrophil phenotype based on surface markers was performed using flow cytometry. Expression of genes linked to antimicrobial function was measured using quantitative PCR. Functional properties of neutrophils, metabolic activity during activation and phagocytosis, and suppressive properties were assessed using the SeaHorse machine and flow cytometry, respectively. Here we confirm the presence of immature CD16low...

The role of microorganisms and other factors in the process of autoimmune uveitis Abstract The aim of this work was to gain new knowledge about the influence and the mechanisms of the effect of microorganisms in the process of autoimmune uveitis. A mouse model of experimental autoimmune uveitis (EAU) was used and the influence of oral broad-spectrum antibiotic, i.e. metronidazole, as well as probiotic bacteria Escherichia coli O83:K24:H31 (EcO) nad Escherichia coli Nissle 1917 (EcN) were tested in preventive and therapeutic regimens. The grade of inflammation was assessed clinically in vivo and histologically post mortem. Immunological analysis of lymph nodes and Peyer's patches were performed. Evaluation of the effect of metronidazole proved significant reduction of inflammatory activity in both regimes - intitiation 1 week or 2 weeks before the EAU induction. In case of probiotics, protective effect was proved only in case of live EcN administered 2 weeks before or from the time of EAU induction. Its protective effect was accompanied with decreased interphotoreceptor retinoid-binding protein (IRBP)-specific T-lymphocyte response in the sentinel lymph nodes of the site of immunization 7 days after the induction of EAU and cervical lymph nodes as soon as there were apparent clinical signs of intraocular...

Circadian clock in the suprachiasmatic nucleus of the hypothalamus (SCN) regulates daily rhythms in behavior and physiology and is an important part of the mechanisms regulating mammalian homeostasis. SCN are synchronized with a 24hour cycle mainly by light, but they can also be regulated by a variety of nonphotic signals, such as growth factors, opioids, cytokines, or lipopolysaccharide (LPS), which act by inducing the JAK/STAT signaling pathway. STAT family proteins (i.e. signal transducers and activator of transcription) regulate many aspects of cellular physiology, from growth and differentiation to immune response. However, the JAK/STAT signaling pathway has not yet been studied in the SCN and the function of STAT proteins in the SCN has not yet been clarified. In the first part of the thesis, we focused on localization of STAT3 and STAT5 proteins in the rat SCN and determination of rhythm in proteins and mRNA. Our experiments showed the daily rhythm in the levels of STAT3 protein in SCN astrocytes of rat with low but significant amplitude and with maximum in the morning. In addition, we revealed strong but nonrhythmic expression of STAT5A protein in astrocytes and STAT5B protein in nonastrocytic cells of SCN. It was also found that Stat3 mRNA show, similarly to protein, circadian rhythm in...

Cutaneous melanoma is a very aggressive cancer with increasing incidence. It originates from transformed pigmented skin cells (melanocytes). The main risk factor for melanoma development is exposure to UV light and repeated sunburns. In approximately 10 % of cases, melanoma occurs on hereditary basis. Patients with cutaneous melanoma diagnosed in early stages have very good prognosis, with surgical resection of the primary tumour being mostly sufficient for treatment. In contrast, the advanced melanoma stages with metastases are often progressive and refractory to conventional therapies. Cutaneous melanoma is referred to as an immunogenic tumour that is frequently infiltrated by cells of the immune system. Tumours with immune cell infiltration show better prognosis. Spontaneous regression may occur. Over the last few years, progress has been made in the treatment of melanoma using checkpoints molecules (anti-CTLA-4 and anti-PD-1) to activate patients own immune system to recognize tumour lesions. In the tumour microenvironment, cytokines play an important role, enabling communication between cells and regulation of cell proliferation and migration and thus the tumour development. Cytokines (IL-2, IFNα) can be used in adjuvant therapy of melanoma. This work analysed levels of expressed cytokines in...

Dermal fibroblasts participate actively in the regulation of wound healing process. They migrate and proliferate during the proliferative phase into the wound site and respond to signals from damaged tissue by secretion of a various pro-inflammatory molecules (e.g. interleukins IL6 and IL8) and extracellular matrix components (e.g. collagen type I, hyaluronan, fibronectin). The disruption of the balance and timing of synthesis and degradation of these molecules can lead to the transition of normal to abnormal non-healing process. Several stress factors act simultaneously in this type of wounds - impaired nutrition supply, inflammation, bacterial contamination, oxidative stress etc. However, the latest in vitro research of dermal fibroblasts in wound healing apply most often only one stress factor. This thesis deals with the response of dermal fibroblasts to the wound conditions. For the first time, a comprehensive study of the functional response of the cells to the two key wound stress factors is described in 2D culture and 3D self-made collagen hydrogel culture. In the first part of the thesis response of dermal fibroblasts to the wound conditions applying two stress factors - low nutrition (2% FBS) and inflammation simulated by bacterial lipopolysaccharide (LPS) - is characterized. The...

Maintaining of homeostasis is essential for the survival of the organism. Stress disturbs the homeostasis and prepares the organism for mental or physical stress. During the stress situation, the endogenous stress factors are released. Through these factors stress affects tissue regeneration, the immune system and other metabolic processes. Chronic stress impacts many parts of body and mind and has a negative effect on these processes. Acute stress has the opposite effect. Mesenchymal stem cells (MSCs) participate in regenerative processes and modulate the immune system. Therefore, it can be assumed that stress will affect on MSCs. The aim of this study was to investigate the effect of stress factors, norepinephrine and corticosterone on the properties and function of MSCs in acute and chronic stress model. In our study, stress factors did not affect the morphology, vitality and differentiation of MSCs. However, the metabolic activity of MSCs was reduced regardless of the duration of their action. The action of stress factors also affected the production of some immunologically relevant molecules and proteins. Unfortunately, the results did not show a clear effect of stress factors on the lymphocyte modulation by MSCs. Key words: mesenchymal stem cells, catecholamines, adrenergic receptors,...

Type 1 diabetes (T1D) is an autoimmune disease leading to destruction of insulin-secreting pancreatic -cells. Environmental factors e.g. exposures to infections, dietary components play a substantial role in etiopathogenesis of T1D and are responsible for rapid increase of T1D incidence in past decades, preferentially in developed countries. Despite long record of T1D research no causative cure or efficient prevention exists. While gluten displays proinflammatory properties, gluten-free diet (GFD) has been documented by several studies as a strong diabetes- preventive environmental factor in spontaneous animal models of T1D, mostly in NOD mouse. The aim of this thesis is to better characterize effects of GFD on the immune system of NOD mouse. Using flow cytometry, we compared effects of GFD vs standard (STD) Altromin diets on NK cell subsets, Tregs, as well as other regulatory cell subsets and their cytokine profile in prediabetic SPF NOD females that were exposed to the diets since "in utero". A reference diabetes incidence in NOD females in our SPF facility kept on STD and GFD was recorded. Diabetes-preventive capacity of GFD were tested by using the NOD-SCID model of diabetes transfer, in which splenocytes from at-onset NOD females kept on GFD or STD were transferred to NOD-SCID recipients....

Autophagy is an essential mechanism of recycling, which represents a path leading to utilization and reorganization of intracellular components (nutrients, organelles, etc). Recent studies on adipose tissue have shown, that autophagy plays crucial role in differentiation of the adipocytes precursors and in phenotypic tissue transformations. The aim of this thesis is to summarize the characteristics of autophagy in terms of various adipose tissues as well as to present the regulation of autophagy as a potentially useful in therapy focused on obesity treatment. However, with the regulation of autophagy, there are risks that will also be considered in the present thesis. Keywords: autophagy, adipose tissue, therapy

Maintaining energy homeostasis at reduced temperatures is essential for the survival of the organisms. In this diploma thesis, we determined the impact of cold stress and cold adaptation on the rat immune system. A number of different factors participate at the process of thermoregulation, but the adrenergic signalling plays a crucial role. The binding of norepinephrine to β-adrenergic receptors leads to the formation of brown adipose tissue, which is necessary for non-shivering thermogenesis, as well as for energy balance. Bioactive products of adipocytes subsequently modulate the immune system, this process is significantly influenced by signalling of nerve cells. In order to understand neuro-immune interaction during the cold adaptation, we monitored changes in immune cell populations and the production of soluble products in rats treated with specific inhibitors of β-adrenergic receptors. Relationship between the immune and nervous system seems to be very important in many biological processes. Deciphering basic mechanisms of the influence of cold adaptation on immune cells can therefore explain other clinically relevant topics, such as treatment of obesity. Key words: immune system, cold adaptation, norepinephrine, adrenergic receptor, cytokines, brown adipose tissue, non-shivering thermogenesis

In recent years there has been a focus on cancer therapies that use patient's immune system instead of invasive traditional methods. One such method of immunotherapy is using checkpoint inhibitors. Blockade of PD-1/PD-L1 signaling pathway is one of main immunotherapy approaches utilizing patient's immune cells to combat cancer cells. Despite of positives that come along with this blockade, many patients do not respond to treatment. Therefore, better understanding of immune mechanisms and factors that affect the efficacy is needed. Finding and summarizing predictive biomarkers play an important role in selection of patients with highest chances of positive outcome and it could result in higher percentage of positively responding patients. It could also prevent patients from experiencing adverse events and unnecessary discomfort. Key words: immune checkpoints, immunotherapy, inhibitors, PD-1, PD-L1, biomarkers

Thyroid hormones are essential mainly for prenatal development and they maintain the homeostasis of many organs and body processes in adulthood. Therefore, the correct function of the regulatory axis between the hypothalamus, pituitary gland and thyroid gland is very important. Lack of these hormones is manifested, for example, by the formation of goiter, cretenism and bradycardia, excess in weight loss, ophthalmopathy, excessive sweating, tachycardia and also goiter formation. A serious problem is also the mutation of thyroid hormone receptors in target tissues. It causes nervous system disorders, hearing, vision, digestive system, incorrect cardiac function, delayed growth and mental development. Thyroid hormones are essential for the formation and activation of brown adipose tissue. This, together with the shivering thermogenesis of skeletal muscle, is involved in facultative thermogenesis, helping homoeothermic mammals to maintain a constant body core temperature. In addition, brown adipose tissue is an important endocrine organ that secretes active substances called batokines upon cold activation. Batokines have beneficial effects in the treatment of obesity, diabetes and cardiovascular disease. So we can assume that cold adaptation could effectively help in the treatment of civilization...

Human intestine represents an essential immune organ that creates the largest interface between our immune system and microbiota from the environment. Considerable parts of the intestine are often severely damaged during Crohn's disease (CD), chronic inflammatory condition with a rising incidence in the western countries. Outbreak of intestinal inflammation is associated with the loss of intestinal homeostasis, co-manifested as a microbial dysbiosis. It is yet unknown whether this bacterial dysbiosis is the cause of intestinal inflammation, or rather it's consequence. In healthy individuals, the homeostatic relationship is greatly influenced by Paneth cells (PC). These cells produce and secrete a wide variety of antimicrobial proteins and peptides, such as enteric α-defensins, that constantly shape the composition of intestinal microbiota. Unsurprisingly, defects in PC's functioning have been linked to the development of CD. Here, we build on our previously published data which showed that a defect in immune central tolerance is the cause of PC depletion. Due to phenotypic and functional resemblance, we hypothesized that such depletion of PCs could constitute a trigger for the development of CD in at least a subset of these patients. This thesis represents a case control study of newly diagnosed...