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Mechanisms of muscle inflammation and clinical manifestations in patients polymyositis and dermatomyositis
Studýnková-Tomasová, Jana ; Vencovský, Jiří (advisor) ; Bartůňková, Jiřina (referee) ; Hrnčíř, Zbyněk (referee)
Idiopathic inflammatory myopathies (IIM) is a heterogeneous group of acquired diseases with varying course and prognosis nehnisavým caused by inflammation of striated muscle. Clinically they are characterized primarily by proximal muscular weakness. On the basis of specific clinical, histopathological, immunological and demographic features of the breakers can be divided into three subgroups dermatomyositis (DM), polymyositis (PM) and inclusion bodies with myositis (IBM). The aetiology of these diseases is unknown and there is also rooted difficulties with their treatment. The common objective of the project was to try to map out the mechanisms leading to inflammatory infiltration of muscles, muscle tissue edema and tissue damage, and subsequently to clinical manifestations of disease in patients with PM and DM.
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Periprosthetic osteolysis
Veigl, David ; Vavřík, Pavel (advisor) ; Vencovský, Jiří (referee) ; Koudela, Karel (referee)
Periprosthetic osteolysis remains the leading complication of total hip arthroplasty. It often results in aseptic loosening of the implant with a requirement for a revision surgery. Wear-generated particular debris is the main cause of initiating this destructive process. The most important cellular target for wear debris is a macrophage, which responds to particle challenge by activatig proinflamatory signals, which contribute to increased bone resorption. The activation of the RANKL/RANK/OPG system is considered to be a likely cause of periprosthetic osteolysis leading to implant failure. The aim of this study was to examine the possible correlation between the clinical extent of osteolysis, the number of wear particles and the expression of the osteoclastic mediator RANKL in the tissues around aseptically loosened cemented and non-cemened total hip replacements. Periprosthetic tissues were harvested from 59 patients undergoing revision hip replacement for aseptic loosening. We had observed RANKL-positive cells in 23 of our 59 patients, their presence was noted predominantly in tissues with a loosened cemented endoprosthesis. We have shown that RANKL is present only in the tissues with a large amount of wear debris and predominantly in the cases involving lacunar type of osteolysis. Key words:...
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Relation of Soluble Factors of Immune System to Fenotype of Idiopathic Inflammatory Myopathies
Klein, Martin ; Vencovský, Jiří (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Idiopathic inflammatory myopathies (myositis, IIM) are heterogeneous group of rare autoimmune systemic diseases, characterized particularly by proximal skeletal muscle weakness. Heretogeneity of myositis is based on different pathogenetic mechanisms which may be reflected by variable imunophenotypic response in individual subtypes. Objectives: The aim of this work was to explore the associations and influence of soluble factors of immune system in patient's sera on phenotypic characteristics and subtypes of IIM, to describe their expression in inflammed muscle tissue and study their eventual role in pathogenesis by analysis of effect on immune and muscle cells in vitro. Results: We have described prevalence and characteristics of joint involvement in myositis patients and its significant association with anti-Jo-1 autoantibody. Further we confirmed the relation of anti-HMGCR antibody to immune mediated necrotizing myopathy, its tight relation to statins and recent increase in incidence. We showed inverse association of IFNα serum levels with muscle activity detected on MRI. Clinical activity positively correlated with IFN type-I pathway activation in patients with dermatomyositis. We also show positive correlation of resistin levels and clinical activity and correlation of activity...
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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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BAFF (B-cell Activating Factor of the TNF Family) in patients with idiopathic inflammatory myopathieswith respect to autoantibody profile.
Kryštůfková, Olga ; Vencovský, Jiří (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Blažíčková, Stanislava (referee)
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of chronic muscle diseases with frequent extramuscular organ involvement that contributes to serious prognosis. The presence of autoantibodies and composition of muscle infiltrates both support autoimmune nature of the disease and pathogenic role of B lymphocytes. Besides the traditional diagnostic subgroups, autoantibody characterised phenotype subsets have been identified with presumed similar pathogenic mechanisms. The best known is the antisynthetase syndrome which is characterised by presence of myositis, antisynthetase autoantibodies (with anti-Jo-1 being the most frequent), interstitial lung disease and other extramuscular manifestations. BAFF (B cell-Activating Factor of the TNF Family) is a key factor in B cell homeostasis modulation. In high levels, it allows survival of autoreactive B cell clones and thus participates in the pathogenesis of autoimmune diseases. Its expression is induced by type I interferons (IFN-1). The aim of the PhD thesis was to explore the role of BAFF in pathogenesis of IIMs by analysis of its serum levels, the receptors for BAFF in muscle tissue, their associations to IFN-1 and expression of BAFF gene mRNA transcription variants in peripheral blood cells. Further aspect was to study a possible...
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Relation of Soluble Factors of Immune System to Fenotype of Idiopathic Inflammatory Myopathies
Klein, Martin ; Vencovský, Jiří (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Idiopathic inflammatory myopathies (myositis, IIM) are heterogeneous group of rare autoimmune systemic diseases, characterized particularly by proximal skeletal muscle weakness. Heretogeneity of myositis is based on different pathogenetic mechanisms which may be reflected by variable imunophenotypic response in individual subtypes. Objectives: The aim of this work was to explore the associations and influence of soluble factors of immune system in patient's sera on phenotypic characteristics and subtypes of IIM, to describe their expression in inflammed muscle tissue and study their eventual role in pathogenesis by analysis of effect on immune and muscle cells in vitro. Results: We have described prevalence and characteristics of joint involvement in myositis patients and its significant association with anti-Jo-1 autoantibody. Further we confirmed the relation of anti-HMGCR antibody to immune mediated necrotizing myopathy, its tight relation to statins and recent increase in incidence. We showed inverse association of IFNα serum levels with muscle activity detected on MRI. Clinical activity positively correlated with IFN type-I pathway activation in patients with dermatomyositis. We also show positive correlation of resistin levels and clinical activity and correlation of activity...
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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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