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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
61

Systemic lupus erythematosus and rheumatoid arthritis : analyses of candidate genes involved in immune functions, for susceptibility and severity

Johansson, Martin January 2010 (has links)
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with systemic manifestations characterized by auto-antibodies directed against different parts of the cell nucleus including DNA, histones and ribosomes. The systemic inflammation can cause damage to multiple organs, e.g., kidneys, skin, heart, lungs and the nervous system. Rheumatoid arthritis (RA) is another autoimmune rheumatic disease characterized by auto-antibodies, mainly directed against the Fc-part of immunoglobulin G (rheumatoid factor (RF)) but also against citrullinated peptides/proteins (ACPAs). The inflammation in RA primarily involves the joints resulting in inflamed synovial tissue and destruction of cartilage. The aetiology of both SLE and RA is unclear but there is a genetic contribution predominantly of genes involved in inflammation. The diseases are believed to be multifactorial, or complex, meaning that multiple genes interact with environmental, infectious and hormonal factors, thus increasing the risk of developing disease. The aim of this study was to investigate different candidate genes involved in functions of the immune system and their relationship with SLE and RA susceptibility and severity. The patients and controls were from the four northernmost counties of Sweden, which is a fairly homogenous population well suited for genetic studies. Two single nucleotide polymorphisms (SNPs) in the oestrogen receptor α (ESR1) gene were analysed in SLE. No association was found between the SNPs and SLE per se however the minor alleles (PvuII C and XbaI G) were associated with skin manifestations and later disease onset, thus representing a milder form of the disease. A SNP in the programmed cell-death 1 (PDCD1) gene, which codes for PD-1, an inhibitory molecule involved in T-cell activation, was studied. No association was seen between the risk allele (PD-1.3A) and SLE susceptibility but a strong association was found with renal disease. A risk allele of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene that codes for a protein called Lyp which acts as a negative regulator of T-cell receptor (TCR) signalling was significantly associated with SLE in three different case-control sets across Sweden. Both PDCD1 and PTPN22 were independently associated with renal disease. The PTPN22 gene has been associated with numerous autoimmune diseases and was evaluated in another auto-antibody producing disease, RA. From the Medical Biobank of northern Sweden samples donated before the development of symptoms of RA were identified. In these individuals, who subsequently developed RA, the 1858T risk allele in combination with ACPAs gave a high relative risk (>132) for developing RA. The association between PTPN22 and RA was confirmed in a larger material of patients with early RA. The 1858T allele, of the three SNPs investigated, was shown to be the true risk allele associated with auto-antibody positive RA. A functional role of PTPN22 in TCR-mediated activation of T cells from patients with SLE and RA was not demonstrated. In conclusion, minor alleles of two SNPs in the ESR1 gene were associated with a milder form of SLE. The risk allele in the PDCD1 gene was associated with renal disorder in SLE. The risk allele 1858T of the PTPN22 gene was associated with SLE, particularly with renal disease. The 1858T allele in combination with auto-antibodies was a risk factor for developing RA. In early diagnosed RA, the 1858T allele was highly associated with RA and in particular with auto-antibody positive RA.
62

Alternativ splicing i mänsklig sjukdom

Edin, Joel January 2010 (has links)
Exoner är de sekvenser i DNA vilka rymmer koden för proteiner i människan och i alla andra organismer. Intronerna, vilka utgör utrymmet mellan exoner, består av ickekodande sekvenser och kontrollelement. Exoner tillhörande en gen måste inte alltid inkluderas i den slutliga mRNA produkten, alternativ splicing tillåter exkludering av vissa sekvenser och gör att en gen kan ha mer än en mRNA produkt, därigenom kan en gen koda för flera olika proteiner. Alternativ splicing är ett fält som snabbt utvecklas och dess relevans för många sjukdomar har blivit uppenbar. Detta arbete går igenom ett flertal av dessa sjukdomar för att sammanställa ny forskning och tydliggöra rollen av alternativ splicing i dem. De sjukdomar som undersökts är cystisk fibros, ärftlig frontotemporal dementia, systemisk lupus erythematosus, aniridi, myotonisk dystrofi, amyotrophic lateral sclerosoch familial dysautonomia. Dessa sjukdomar har involvering av alternativ splicing, de genetiska processerna bakom dem är dock mycket olika och kan visa på de många sätt alternativ splicing kan påverka cell och kroppsfunktion. Målet med arbetet är en översiktlig bild av framstegen som gjorts och vilken forskning som nu bedrivs.
63

The effects of acute muscle damage and autoimmune disease on vascular function : the potential role of inflammation

Barnes, Jill Nicole 14 October 2009 (has links)
Inflammation has been implicated in the development of cardiovascular disease and a potential underlying mechanism in the pathogenesis of impaired vascular function. Two different but complementary approaches were utilized to determine the role of inflammation on vascular function. First, to evaluate the effect of acute inflammation, we induced muscle damage to both small and large muscle mass and measured vascular function every 24 hours for up to 5 days of recovery. Eccentric exercise-induced muscle damage, in both small and large muscle mass, resulted in a transient increase in central arterial stiffness. Next, patients with systemic lupus erythematosus (SLE) were studied as a model of chronic inflammation. Measurements of vascular function were compared in habitually-exercising and sedentary SLE patients, and age-matched healthy controls. Individuals with SLE demonstrated lower vascular function than healthy controls. When SLE patients were grouped by exercise status, habitually-exercising SLE patients exhibited similar vascular function to healthy controls, and lower overall disease activity compared with sedentary SLE patients, supporting the beneficial effect of regular exercise in this population. Inflammatory biomarkers were associated with measures of macro- and microvascular function. In conclusion, acute muscle damage and chronic disease-related inflammation have a potent effect on measures of vascular function, suggesting that inflammation plays a role in the pathogenesis of vascular dysfunction and is an important biomarker for cardiovascular risk. / text
64

Follicular dendritic cell Fc gamma RIIB prevents survival of less-developed B cells: single cell sequence analysis from autoreactive germinal centers

Macaulay, Charles 03 July 2018 (has links)
BACKGROUND: Previous work has shown that follicular dendritic cells (FDCs) play an important role in selecting B cells such that antigens are responded to in a specific manner. FcγRΙΙB (CD32) is an antibody constant-region receptor found on FDCs and mutation of this receptor in humans is associated with Systemic Lupus Erythematosus (SLE). In addition, previous work has demonstrated that autoreactive germinal centers are the product of expression of interferon alpha (ΙFNα) by FDCs, so FcγRIIB signaling may involve modulation of IFNα signaling. OBJECTIVE: Because FcγRIIB mutation is associated with SLE and FDCs have been shown to be important in orchestrating B cell responses, understanding FcγRIIB on FDCs helps characterize B cell repertoire development in response to antigen—whether the antigen is foreign or self, as is the case in autoimmunity. Better characterization of the role of FcγRIIB could have consequences for autoimmune and cancer therapy. This study seeks to determine the role of FcγRΙΙB on FDCs in germinal center B cell selection dynamics within single, autoreactive germinal centers. METHODS: This study compares transplanted wild-type (B6) B cells—that are driven to be autoimmune by simultaneously transplanted autoimmune B cells—in two stromal cell settings: first, in germinal centers containing wild-type FDCs and second, in germinal centers containing FcγRIIB-knockout FDCs. Transplanted B6 B cell populations express photoactivatable protein, which allows for sorting of B cells from individual germinal centers. B cell sequences from single germinal centers were analyzed to determine how focused each germinal center response was and how the B cells differ in maturity and affinity for antigen. Finally, mice expressing a lineage-tracing system were treated with IFNα in order to observe the cytokine’s effect on B cell selection. RESULTS: Cells sorted from germinal centers containing FcγRIIB-knockout FDCs contain a distinguished population of less-developed B cells, as quantified by population-based analysis of their variable heavy chain genes. Overall, the IgM sequences from B cells sorted from germinal centers (GCs) containing FcγRIIB-knockout follicular dendritic cells displayed lower levels of somatic hypermutation (SHM) (p<.05) and shorter hypervariable regions (CDR3) (p<.05) compared to other B cell populations. Values computed to summarize how many different B cell lineages were present in a GC—its “clonality”—did not vary between the two mouse populations, although FcγRIIB-knockout FDC germinal centers displayed a correlation between clonality and immunoglobulin (Ig) isotype expression (R2= .85). Finally, lineage tracing mice receiving injections of interferon alpha (IFNα) displayed no difference in GC clonality compared to those receiving vehicle and assays of IFNα downstream signaling genes also displayed no change. CONCLUSIONS: FcγRIIB encourages more stringent selection of immature B cells in germinal centers as evidenced by survival of less developed B cells as defined by degree of somatic hypermutation and CDR3 length in GCs comprising FcγRIIB-knockout FDCs. In spite of this, sequence-based measures of germinal center clonality as completed here may fail to capture the functional results of B cell selection. In addition, the link between FcγRIIB and IFNα requires further investigation. / 2019-07-03T00:00:00Z
65

Expressão de proteínas reguladoras do complemento CD55/CD59 em células de sangue periférico de pacientes com lúpus eritematoso sistêmico

Alegretti, Ana Paula January 2008 (has links)
CD55 e CD59 são proteínas de membrana ancoradas pela glicosilfosfatidilinositol que apresentam propriedades reguladoras da ativação da cascata do complemento. Esta regulação ocorre através da inibição da C3 convertase e prevenção da etapa final de polimerização do complexo de ataque à membrana, respectivamente. Pacientes com Lúpus Eritematoso Sistêmico com anemia hemolítica e linfopenia parecem apresentar uma deficiência adquirida de CD55 e CD59. Contudo, os mecanismos que modulam essa diminuída expressão continuam desconhecidos e o seu impacto nas manifestações do Lúpus Eritematoso Sistêmico necessita ser melhor estudado. / CD55 and CD59 are glycosylphosphatidylinositos-anchored proteins with complement inhibitory properties, which inhibit formation of the C3 convertases and prevent the terminal polymerization of the membrane attack complex, respectively. Systemic Lupus erythematosus patients seem to have an acquired deficiency of CD55 and CD59 proteins associated with secondary autoimmune hemolytic anemia and lymphopenia. But the mechanisms remain unknown and its impact on the clinical manifestation of Systemic Lupus erythematosus needs to be more explored.
66

Expressão de proteínas reguladoras do complemento CD55/CD59 em células de sangue periférico de pacientes com lúpus eritematoso sistêmico

Alegretti, Ana Paula January 2008 (has links)
CD55 e CD59 são proteínas de membrana ancoradas pela glicosilfosfatidilinositol que apresentam propriedades reguladoras da ativação da cascata do complemento. Esta regulação ocorre através da inibição da C3 convertase e prevenção da etapa final de polimerização do complexo de ataque à membrana, respectivamente. Pacientes com Lúpus Eritematoso Sistêmico com anemia hemolítica e linfopenia parecem apresentar uma deficiência adquirida de CD55 e CD59. Contudo, os mecanismos que modulam essa diminuída expressão continuam desconhecidos e o seu impacto nas manifestações do Lúpus Eritematoso Sistêmico necessita ser melhor estudado. / CD55 and CD59 are glycosylphosphatidylinositos-anchored proteins with complement inhibitory properties, which inhibit formation of the C3 convertases and prevent the terminal polymerization of the membrane attack complex, respectively. Systemic Lupus erythematosus patients seem to have an acquired deficiency of CD55 and CD59 proteins associated with secondary autoimmune hemolytic anemia and lymphopenia. But the mechanisms remain unknown and its impact on the clinical manifestation of Systemic Lupus erythematosus needs to be more explored.
67

Expressão de proteínas reguladoras do complemento CD55/CD59 em células de sangue periférico de pacientes com lúpus eritematoso sistêmico

Alegretti, Ana Paula January 2008 (has links)
CD55 e CD59 são proteínas de membrana ancoradas pela glicosilfosfatidilinositol que apresentam propriedades reguladoras da ativação da cascata do complemento. Esta regulação ocorre através da inibição da C3 convertase e prevenção da etapa final de polimerização do complexo de ataque à membrana, respectivamente. Pacientes com Lúpus Eritematoso Sistêmico com anemia hemolítica e linfopenia parecem apresentar uma deficiência adquirida de CD55 e CD59. Contudo, os mecanismos que modulam essa diminuída expressão continuam desconhecidos e o seu impacto nas manifestações do Lúpus Eritematoso Sistêmico necessita ser melhor estudado. / CD55 and CD59 are glycosylphosphatidylinositos-anchored proteins with complement inhibitory properties, which inhibit formation of the C3 convertases and prevent the terminal polymerization of the membrane attack complex, respectively. Systemic Lupus erythematosus patients seem to have an acquired deficiency of CD55 and CD59 proteins associated with secondary autoimmune hemolytic anemia and lymphopenia. But the mechanisms remain unknown and its impact on the clinical manifestation of Systemic Lupus erythematosus needs to be more explored.
68

Loewner chains and evolution families on parallel slit half-planes / 平行截線半平面上のレヴナー鎖および発展族

Murayama, Takuya 23 March 2021 (has links)
京都大学 / 新制・課程博士 / 博士(理学) / 甲第22977号 / 理博第4654号 / 新制||理||1669(附属図書館) / 京都大学大学院理学研究科数学・数理解析専攻 / (主査)教授 日野 正訓, 教授 泉 正己, 准教授 楠岡 誠一郎 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DFAM
69

A Protein Coding Variant in IRF7 is associated with SLE Risk and Affects Production of Type IIinterferon

Fjellman, Ellen V. F. 05 October 2021 (has links)
No description available.
70

Körperliche Aktivität bei Patienten mit systemischem Lupus erythematodes

Lipovskiy, Lev 01 July 2021 (has links)
Der systemische Lupus erythematodes (SLE) ist eine chronische Autoimmunerkrankung aus dem rheumatischen Formenkreis, deren Begleitsymptome ein potentielles Risiko für reduzierte körperliche Aktivität (KA) darstellen. Allerdings existieren gegenwärtig nur wenige Daten über die Prävalenz der alltäglichen KA bei SLE, Faktoren, die KA verringern, und die gegenseitige Beeinflussung von Krankheitssymptomen und KA. Außerdem wurde eine Assoziation zwischen KA und einem niedrigeren Inflammationsniveau in der SLE-Population geprüft. Insgesamt wurden Daten von 99 Patienten erfasst. Krankheitsaktivität, krankheitsbedingten Organschäden, Medikamentenanamnese und Labordaten wurden anhand der Patientenakte erhoben. Schmerzsymptome, Lebensqualität, Fatigue und psychologisches Allgemeinbefinden wurden durch standardisierten Fragebogen erfasst. Die KA wurde in Hinsicht auf berichtete alltägliche Betätigung (IPAQ-Fragebogen) sowie objektive körperliche Leistung (2- und 6-Minuten-Gehtest) gemessen. Aus 73 Serumproben wurde der Interleukinstatus bestimmt. Bei einem relativ hohen subjektiven Niveau der KA konnte eine relativ niedrige objektive körperliche Leistung beobachtet werden. Ein niedrigeres subjektives Niveau der KA war mit neuropsychiatrischer Beteiligung sowie psychologischen Auffälligkeiten, Fatigue und reduzierter Lebensqualität assoziiert. Pulmonale Beteiligung, Diabetes mellitus und ein höherer Body-Mass-Index standen in Zusammenhang mit einer schlechteren Gehleistung. Als weiteres Ergebnis stellte sich eine Assoziation zwischen einem größeren Unterschreiten von normativen Referenzwerten in dem 2- und 6-Minuten Gehtest und höherer IL-6 Konzentration ein. Gleichzeitig war ein höherer IL-6 Spiegel mit größerem Bauchumfang und Adipositas assoziiert.:Inhaltsverzeichnis 1 Abbildungsverzeichnis 3 Tabellenverzeichnis 4 Abkürzungsverzeichnis 7 Bibliographische Beschreibung 9 1. Einführung 11 1.1 Systemischer Lupus erythematodes 11 1.1.1 Definition der Erkrankung 11 1.1.2 Epidemiologie 11 1.1.3 Ätiologie und Pathogenese 12 1.1.4 Klinisches Bild und Diagnostik 15 1.1.5 Therapie des SLE 22 1.2 Körperliche Aktivität 23 1.2.1 Gesundheitliche Vorteile von körperlicher Aktivität für die Allgemeinbevölkerung 23 1.2.2 Körperliche Aktivität bei rheumatischen Erkrankungen und SLE 26 1.3 Messung der körperlichen Aktivität 28 1.3.1 Subjektive Erfassung der alltäglichen körperlichen Aktivität 28 1.3.2 Objektive Messung der körperlichen Leistung 29 1.4 Zielsetzung und Fragestellung 30 2. Methoden 32 2.1 Patienten 32 2.2 Fragebogensammlung und standardisierte Scores 33 2.3 Messung der körperlichen Leistung 41 2.3.1 Ausschlusskriterien für den Zwei- und Sechs-Minuten-Gehtest 41 2.3.2 Durchführung des Zwei- und Sechs-Minuten-Gehtestes 42 2.4 Bestimmung der IL-6 Plasmakonzentration 44 2.4.1 Blutentnahmen 44 2.4.2 Labormessung 44 2.5 Statistische Auswertung 45 3 Ergebnisse 46 3.1 Klinische Charakterisierung der Patienten 46 3.2 Subjektiv erfasste körperliche Aktivität 55 3.2.1 Subjektive Bewertung der Hürden für körperliche Aktivität 56 3.2.2 Klinische Parameter und subjektiv erfasste, alltägliche körperliche Aktivität 59 3.3 Ergebnisse der Messung körperlicher Leistung 69 3.3.1 Ergebnisse des Zwei-Minuten-Gehtests 69 3.3.1.2 Einfluss allgemeiner Faktoren auf den Zwei-Minuten-Gehtest 70 3.3.1.3 Vergleich mit Referenzgrößen für gesunde Erwachsene 71 3.3.1.4 Leistungsschwache versus leistungsstärkere Patienten 72 3.3.2 Ergebnisse des Sechs-Minuten-Gehtests 79 3.3.2.1 Einfluss der allgemeinen Faktoren auf den Sechs-Minuten-Gehtest 81 3.3.2.2 Vergleich mit Referenzgrößen für gesunde Erwachsene 81 3.3.2.4 Leistungsschwache versus leistungsstärkere Patienten 83 3.4 Vergleich der Methoden für die Erfassung der körperlichen Aktivität 90 3.4.1 Vergleich der selbstberichteten körperlichen Aktivität: IPAQ- vs. GPAQ-Fragebogen 90 3.4.2 Vergleich der Messergebnisse körperlicher Leistung: Zwei-Minuten- vs. Sechs-Minuten-Gehtest 93 3.4.3 Messung der körperlichen Aktivität: Fragebogen für alltägliche Aktivität vs. körperlichen Leistung 97 3.5 Risikofaktoren für reduzierte körperliche Aktivität 99 3.5.1 Risikofaktoren für eine niedrige subjektiv erfasste alltägliche körperliche Aktivität 99 3.5.2 Risikofaktoren für eine verminderte körperliche Leistung 104 3.6 Inflammationsparameter im Zusammenhang mit den in der aktuellen Arbeit erfassten Faktoren 106 3.6.1 Zusammenhänge zwischen IL-6 und klinischen Variablen 109 3.6.2 Risikofaktoren für einen erhöhten IL-6-Serumspiegel 114 4. Diskussion 117 4.1 Klinische Charakterisierung der Patienten 117 4.2 Subjektiv erfasste alltägliche körperliche Aktivität 118 4.3 Ergebnisse der Messung der körperlichen Leistung 120 4.4 Vergleich der Methoden für die Erfassung der körperlichen Aktivität 123 4.5 Risikofaktoren für eine niedrige körperliche Aktivität 126 4.6 Inflammationsparameter im Zusammenhang mit in dieser Arbeit erfassten Faktoren 128 5. Zusammenfassung der Arbeit 131 Literaturverzeichnis 135 Erklärung über die eigenständige Abfassung der Arbeit 145 Danksagung 146 Lebenslauf 147

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