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The role of S100 proteins in the pathogenesis of rheumatic diseases
Andrés Cerezo, Lucie ; Šenolt, Ladislav (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Recent findings and better understanding to the pathogenesis of rheumatic diseases contributed to the development of biological therapies targeting cytokines and immune cells. Several S100 proteins exert cytokine-like effects and participate in the regulation of the inflammatory process. The aim of this work was to study the role of selected S100 proteins in the activity and in the pathogenesis of the rheumatic diseases. Results: Our data show for the first time an association of S100A4 proteinwith RA disease activity and decrease of the bioactive form, but not the total amount of S100A4, after aplication of tumour necrosis factor (TNF) blocking biologic therapy in patients with RA. We demonstrated that in vitro S100A4 acts as a potent pro-inflammatory mediator inducing production of TNFα, interleukin (IL)-1β and IL-6 in PBMCs via Toll-like receptor 4 (TLR-4), transcription factor NFκB and tyrosine kinases erk1/2 and p38. Moreover, S100A4 can play an important role in the pathogenesis of inflammatory myopathies. S100A4 is present in the inflammatory infiltrate of the affected muscles and in the regenerating muscles and may act as a cytokine-like factor indirectly promoting muscle fiber damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines. We...
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Molecular aspects of musculoskeletal diseases and the role of small regulatory RNAs
Pleštilová, Lenka ; Vencovský, Jiří (advisor) ; Šedivá, Anna (referee) ; Hrnčíř, Zbyněk (referee)
Rheumatic diseases are common, usually chronic, painful and to some extent invalidating medical conditions. Understanding of the disease pathogenesis is still very fragmentary. Hyperreactivity of the immune system and defect of autotolerance are probably contributed by local factors, which helps to explain, why some joints/muscles are more affected than others. All this results from a complex net of interactions between immune cells, synovial fibroblasts, chondrocytes, osteocytes, myocytes and other cells. In the submitted PhD thesis I have focused on three groups of molecules: regulatory RNAs, S100 proteins and autoantibodies. In the theoretical part, I sum up the current knowledge on their biogenesis, function and the role in rheumatology. In the investigative part, I present six original publications and one review on the role of those molecules in development of rheumatoid arthritis (RA) and idiopathic inflammatory myositis (IIM). One of the main studies was focused on expression of PIWI-interacting RNAs (piRNAs) in RA synovial fibroblasts (SF). piRNAs are small regulatory RNAs which in complex with PIWIL proteins regulate gene expression and silence transpozoms. piRNA expression was considered to be limited to germline and cancer cells. We have found 267 PIWI-interacting RNAs to be expressed...
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Molecular aspects of musculoskeletal diseases and the role of small regulatory RNAs
Pleštilová, Lenka ; Vencovský, Jiří (advisor) ; Šedivá, Anna (referee) ; Hrnčíř, Zbyněk (referee)
Rheumatic diseases are common, usually chronic, painful and to some extent invalidating medical conditions. Understanding of the disease pathogenesis is still very fragmentary. Hyperreactivity of the immune system and defect of autotolerance are probably contributed by local factors, which helps to explain, why some joints/muscles are more affected than others. All this results from a complex net of interactions between immune cells, synovial fibroblasts, chondrocytes, osteocytes, myocytes and other cells. In the submitted PhD thesis I have focused on three groups of molecules: regulatory RNAs, S100 proteins and autoantibodies. In the theoretical part, I sum up the current knowledge on their biogenesis, function and the role in rheumatology. In the investigative part, I present six original publications and one review on the role of those molecules in development of rheumatoid arthritis (RA) and idiopathic inflammatory myositis (IIM). One of the main studies was focused on expression of PIWI-interacting RNAs (piRNAs) in RA synovial fibroblasts (SF). piRNAs are small regulatory RNAs which in complex with PIWIL proteins regulate gene expression and silence transpozoms. piRNA expression was considered to be limited to germline and cancer cells. We have found 267 PIWI-interacting RNAs to be expressed...
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The role of S100 proteins in the pathogenesis of rheumatic diseases
Andrés Cerezo, Lucie ; Šenolt, Ladislav (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Recent findings and better understanding to the pathogenesis of rheumatic diseases contributed to the development of biological therapies targeting cytokines and immune cells. Several S100 proteins exert cytokine-like effects and participate in the regulation of the inflammatory process. The aim of this work was to study the role of selected S100 proteins in the activity and in the pathogenesis of the rheumatic diseases. Results: Our data show for the first time an association of S100A4 proteinwith RA disease activity and decrease of the bioactive form, but not the total amount of S100A4, after aplication of tumour necrosis factor (TNF) blocking biologic therapy in patients with RA. We demonstrated that in vitro S100A4 acts as a potent pro-inflammatory mediator inducing production of TNFα, interleukin (IL)-1β and IL-6 in PBMCs via Toll-like receptor 4 (TLR-4), transcription factor NFκB and tyrosine kinases erk1/2 and p38. Moreover, S100A4 can play an important role in the pathogenesis of inflammatory myopathies. S100A4 is present in the inflammatory infiltrate of the affected muscles and in the regenerating muscles and may act as a cytokine-like factor indirectly promoting muscle fiber damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines. We...
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