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Mechanisms of antigen presentation in the etiopathogenesis of celiac disease
Hudec, Michael ; Černá, Marie (advisor) ; Hrdý, Jiří (referee) ; Slavčev, Antonij (referee)
1 ABSTRACT Celiac disease (CeD) is a chronic autoimmune disease that develops as a response of the immune system to the presence of gluten in the small intestine. CeD is manifested not only by classic intestinal symptoms: abdominal pain, constipation or diarrhea, as well as complex less common symptoms: anemia, osteoporosis, psychiatric disorders or menstrual cycle disorders. HLA risk alleles predisposing to origin of celiac disease are HLA-DQ2 (DQA1*05:01 / DQB1*02:01) and HLA-DQ8 (DQA1*03:01 / DQB1*03:02). There are other celiac disease-associated polymorphisms outside of HLA locus (6p21.3) that are located in 5q32 and 19p13 regions with unclear connection to CeD development. HLA class II glycoproteins are expressed on antigen presenting cells (APC) that include dendritic cells, macrophages and B cells. Monocytes are one of several possible dendritic cell precursors that circulate in the bloodstream. Deviations in the frequency of intermediate monocytes are directly associated with autoimmune disorders such as Crohn's disease or rheumatoid arthritis. It is known that the monocytes of CeD patients show pro-inflammatory reaction in the presence of gluten. It means that, in the context of CeD, the response to gluten arises earlier than the activation of gluten-specific T cells. The conventional way of direct...
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Identification of new regulators of proinflammatory signaling pathways
Dráberová, Helena ; Štěpánek, Ondřej (advisor) ; Krulová, Magdaléna (referee) ; Funda, David (referee)
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...
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Targeting IRAK4 kinase in autoimmune diseases and cancer
Synáčková, Alžběta ; Dráber, Peter (advisor) ; Brdička, Tomáš (referee)
Immune system provides host protection against invading pathogens. However, aberrant activation can lead to development of autoimmune diseases or cancer. Understanding the mechanisms of inflammation and immune responses is crucial for treatment of such conditions and reestablishing immune balance. Toll-like receptors and interleukin-1 family receptors are a key component of the innate immune system. Their downstream molecules, MyD88 and IRAK4, are essential for receptor signaling as their deficiency causes host susceptibility to infection. On the other hand, overactivation of this pathway was shown to be able to promote autoimmunity and cancer. The main focus of this text will be to summarize current knowledge about the mechanism of IRAK4 signaling and how it can be exploited in the development of therapeutics. Keywords IRAK4, MyD88, Toll-like receptors, IL-1 receptor, cytokines, autoimmunity, cancer
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Autoantibodies against calreticulin in patients with dilated and hypertrophic cardiomyopathy
Sánchez, Daniel ; Tlaskalová - Hogenová, Helena (advisor) ; Javorková, Eliška (referee)
Distinct cellular level of the Ca2+ binding chaperone calreticulin (CRT) is essential for cardiac development and postnatal function. However, CRT is also a potential autoantigen eliciting formation of antibodies (Ab), whose role is not yet clarified. Immunization with CRT leads to cardiac injury, and overexpression of CRT in cardiomyocytes induces dilated cardiomyopathy (DCM) in experimental animals. Hence, we analysed levels of anti-CRT Ab and calreticulin in the sera of patients with idiopatic DCM and hypertrophic cardiomyopathy (HCM). ELISA and immunoblot using human recombinant CRT and Pepscan with synthetic, overlapping decapeptides of CRT were used to detect anti-CRT Ab. Significantly increased levels of anti-CRT Ab of IgA (P<0.001) and IgG (P<0.05) isotypes were found in patients with both DCM (12/34 seropositive for IgA, 7/34 for IgG) and HCM (13/38 seropositive for IgA, 11/38 for IgG) when compared with controls (2/79 for IgA, 1/79 for IgG). Titration analysis in seropositive DCM and HCM patients documented anti-CRT Ab detected at 1/1600 dilution for IgG and 1/800 for IgA (and IgA1) and at least at 1/200 dilution for IgA2, IgG1, IgG2 and IgG3. Pepscan identified several immunogenic CRT epitopes: EVKIDNSQVESGSLED, IDDPTDSKPE, DKAPEHIPDPDA and RKEEEEAEDKEDDAEDKDEDEEDE recognised by IgA and...
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Novel mechanisms of T cell-mediated intestinal autoimmunity to Paneth cells
Brabec, Tomáš ; Filipp, Dominik (advisor) ; Janečková, Lucie (referee)
(En) Paneth cells are one of the major player in the maintenance of the homeostatic relationship between intestinal microbiota and the immune system. This function is largely achieved by their production of bactericidal enteric α-defensins (ED) and other antimicrobials. Disruption of Paneth cell functions is associated with severe human disorders such as Crohn's disease (CD) and Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED). However, there is only a very limited information regarding the interactions and regulatory circuits operating between Paneth cells and intestinal immune system in either health or under pathological conditions. The previous study conducted in our laboratory described a new mechanism for the initiation and maintenance of Paneth cells targeted autoimmunity. The suggested model was that ED-specific T cells escape the selection in the thymus, infiltrate the intestine and diminish Paneth cell numbers through autoimmune destruction. This process also lead to the accumulation of inflammation- inducing bacteria, which were implied to exacerbate the inflammatory autoimmunity. Since this model of intestinal autoimmunity is of correlative nature, its intrinsic mechanism and functional relationships between immune system, Paneth cells and microbiota are largely...
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Immunogenetic and hormonal markers of predisposition to systemic rheumatic diseases particularly systemic lupus erythematosus
Fojtíková, Markéta ; Pavelka, Karel (advisor) ; Hrnčíř, Zbyněk (referee) ; Rovenský, Jozef (referee)
Fojtikova 2011 INTRODUCTION: Several factors like genetic susceptibility is required for systemic rheumatic diseases development. Immunomodulatory PRL effect supports autoimmunity. AIMS: 1. To detect the immunogenetic background (alleles HLA class I, II and microsatellite polymorphism of the transmembrane part exon 5 of MIC-A gene) of SLE and PsA. 2. To detect PRL serum and synovial fluid with regard to clinical and laboratory RA activity. 3. To find the role of the functional polymorphism -1149G/T SNP PRL of extrapituitary promoter of PRL gene in SLE, RA, PsA, SSc and inflammatory myopathies development. METHODS: Genetic analyses of pateints with SLE (n=156), RA (n=173), PsA (n=100), SSc (n=75), PM (n=47) a DM (n=68) and 123 healthy individuals: PCR-SSP (HLA clase I and II), PCR-fragment analysis (MIC-A) a PCR-RFLP (-1149 G/T SNP PRL). In 29 RA a 26 OA PRL serum and synovial fluid concentrations were detected using immunoradiometric assay. RESULTS: 1. The allele HLA-DRB1*03 (pc=0.008; OR 2.5) and haplotype HLA-DRB1*03-DQB1*0201 (pc <0.001; OR 4.54) were determined as risk immunogenetic markers for SLE in Czech population. In SLE versus controls allele MIC-A5.1 was increased (pc =0.005; OR 1.88). MIC-A5.1 together with HLA-DRB1*03 increases the risk for SLE development, pc <0.000001; OR 9.71....
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Immunointerventional therapy of autoimmune diabetes with recent oncet in NOD mice.
Vargová, Lenka ; Saudek, František (advisor) ; Štechová, Kateřina (referee) ; Mráz, Miloš (referee)
Introduction: Type 1 diabetes mellitus is a chronic metabolic disease caused by autoimmune destruction of pancreatic beta cells. The theory of the disease onset is derived from study of a disease course in non-obese diabetic (NOD) mice, in which the diabetes occurs due to a dysregulation of the immune system. Experimental and clinical studies showed that the autoimmunity may be abrogated by immune intervention, which if initiated early enough may at least slow down the ongoing beta cells lost and preserve residual insulin secretion. But immune intervention alone is not sufficient to restore normoglycemia in the majority of cases. Several interventional studies showed that stimulation of proliferation and/or regeneration of beta cells are necessary to restore normoglycemia in animal models. Aim of the study: To find out, if the combination of a potent immunosuppression (murine anti-thymocyte globulin (mATG), gusperimus) together with stimulation of islet regeneration (sitagliptin) will be able to slow down or reverse the course of the disease. Another aim is to identify the mechanism by which the substances act. Material and methods: All experiments were performed in female NODShiLtJ (H2g7 ) mice. The following parameters were examined at day 0, 7, 14 and 28: blood glucose, subpopulations of...
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Autoantibodies against calreticulin in patients with dilated and hypertrophic cardiomyopathy
Sánchez, Daniel
Distinct cellular level of the Ca2+ binding chaperone calreticulin (CRT) is essential for cardiac development and postnatal function. However, CRT is also a potential autoantigen eliciting formation of antibodies (Ab), whose role is not yet clarified. Immunization with CRT leads to cardiac injury, and overexpression of CRT in cardiomyocytes induces dilated cardiomyopathy (DCM) in experimental animals. Hence, we analysed levels of anti-CRT Ab and calreticulin in the sera of patients with idiopatic DCM and hypertrophic cardiomyopathy (HCM). ELISA and immunoblot using human recombinant CRT and Pepscan with synthetic, overlapping decapeptides of CRT were used to detect anti-CRT Ab. Significantly increased levels of anti-CRT Ab of IgA (P<0.001) and IgG (P<0.05) isotypes were found in patients with both DCM (12/34 seropositive for IgA, 7/34 for IgG) and HCM (13/38 seropositive for IgA, 11/38 for IgG) when compared with controls (2/79 for IgA, 1/79 for IgG). Titration analysis in seropositive DCM and HCM patients documented anti-CRT Ab detected at 1/1600 dilution for IgG and 1/800 for IgA (and IgA1) and at least at 1/200 dilution for IgA2, IgG1, IgG2 and IgG3. Pepscan identified several immunogenic CRT epitopes: EVKIDNSQVESGSLED, IDDPTDSKPE, DKAPEHIPDPDA and RKEEEEAEDKEDDAEDKDEDEEDE recognised by IgA and...
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Rehabilitation issues for patient with acute disseminated encephalomyelitis
Tyburcová, Marie ; Zumrová, Alena (advisor) ; Málková, Michaela (referee)
Acute disseminated encephalomyelitis (ADEM) is a serious neurological disease with a variable progression, which can have permanent consequences for the patient, despite medical advances. An irreplaceable element of complex treatment is rehabilitation which has in recent years become a sophisticated preventative therapeutic method, mainly based on the study of plasticity and of the possibilities of brain regeneration. This work presents a comprehensive theoretical overview of our current knowledge of a relatively rare autoimmune disease of the central nervous system (CNS) as well as current options and procedures for affecting the course of the disease and its consequences through physiotherapy. It was written based on the collection of theoretical data, questioning and observation of the physiotherapy of a patient with ADEM, who was hospitalised for five months in various wards of 2nd Faculty of Medicine in Prague. Physiotherapeutic procedures are divided and applied in both the theoretical and practical parts of the work according to the phase model. Theoretical knowledge, drawn from published case studies, as well as the course of the observed patient's disease and his following convalescence clearly illustrate that provided the timely commencement of intensive treatment and the continuation...
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