Thesis (Ph.D.)--Aberdeen University, 2008. / Title from web page (viewed on June 15, 2009). Includes bibliographical references.

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliography.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Factors regulating the induction and development of B cell–mediated autoimmunity are not well understood. Here, we report that targeted deletion in murine B cells of X-linked Cosmc, encoding the chaperone required for expression of core 1 O-glycans, causes the spontaneous development of autoimmune pathologies due to a breakdown of B cell tolerance. BC-CosmcKO mice display multiple phenotypic abnormalities, including severe weight loss, ocular manifestations, lymphadenopathy, and increased female-associated mortality. Disruption of B cell tolerance in BC-CosmcKO mice is manifested as elevated self-reactive IgM and IgG autoantibodies. Cosmc-deficient B cells exhibit enhanced basal activation and responsiveness to stimuli. There is also an elevated frequency of spontaneous germinal center B cells in BC-CosmcKO mice. Mechanistically, loss of Cosmc confers enhanced B cell receptor (BCR) signaling through diminished BCR internalization. The results demonstrate that Cosmc, through control of core 1 O-glycans, is a previously unidentified immune checkpoint gene in maintaining B cell tolerance.

Rheumatoid arthritis (RA) is a systemic and inflammatory disease that has been associated with an increased morbidity and mortality in cardiovascular disease (CVD). Low aerobic capacity is one of the strongest independent risk factors for CVD and all-cause mortality in the general population. In patients with longstanding RA, low aerobic capacity has been related with a worse cardiovascular profile and an increased risk of CVD mortality. As a consequence of this, low aerobic capacity might provide an additional risk factor for CVD in patients with RA. The aim of this thesis was to describe the associations between aerobic capacity and risk factors for CVD as well as disease activity in patients with early RA, and also the effects of intensive exercise therapy on traditional risk factors for CVD and disease activity in patients with longstanding RA. Paper I, a cross-sectional study including 67 patients with early RA, mean (SD) age 53.1 (14.4), assessments of aerobic capacity, CVD risk factors, disease activity and functional ability were taken. Data were analysed for the associations between aerobic capacity and CVD risk factors and disease activity. In paper II, an intervention study, including 13 patients with RA, median age (Q1-Q3) 57 (44-64) years, aerobic capacity, pulse wave analysis (PWA), CVD risk factors, and disease activity were analysed for changes after 10 weeks of intensive exercise therapy. Additional follow-up was made after 25 weeks. In paper I, the mean (SD) aerobic capacity was 31.6 (8.7) ml O2/kg/min. CVD risk factors and disease activity were all in favour of patients with higher aerobic capacity. In a multiple regression model, adjusted for age and sex, aerobic capacity was significantly associated with percent body fat (β=-0.502, 95%CI=-0.671;-0.333) and triglycerides (β=-2.365, 95%CI=-4.252;-0.479). In paper II, intensive exercise over ten weeks was shown to be a feasible method to significantly improve aerobic capacity (p=≤0.05), systolic blood pressure (p=≤0.01) and the number of tender joints (p=≤0.05). No detrimental effect on disease activity was recorded. This thesis adds further knowledge of aerobic capacity and its associations with CVD risk factors and disease activity in patients with RA. Also, intensive exercise therapy was a feasible intervention to improve CVD risk factors. To include assessment of aerobic capacity in regular clinical practice may improve patient management as well as patient outcome in patients with RA. / Bakgrund: Reumatoid artrit (RA, ledgångsreumatism) är en kronisk inflammatorisk sjukdom som i första hand angriper leder, men kan även påverka inre organ. Typiska symptom är ledsvullnad, smärta, morgonstelhet och nedsatt funktion i lederna. Patienter med RA har visat sig ha en ökad risk att insjukna i och avlida i hjärt- och kärlsjukdom. I den allmänna befolkningen har låg syreupptagningsförmåga (kondition) visat sig vara en av de starkaste riskfaktorerna för att insjukna i eller att avlida i hjärt- och kärlsjukdom. Tidigare studier har visat att patienter med RA kan ha låg kondition vilket kan utgöra en riskfaktor för hjärt- och kärlsjukdom även vid RA. Syfte: Syftet med denna avhandling var att beskriva sambanden mellan kondition och riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet. Ett annat syfte var att studera hur intensiv cykelträning påverkar kondition, traditionella riskfaktorer och sjukdomsaktivitet hos patienter med RA. Metod: Studie I är en tvärsnittsstudie, bestånde av 67 patienter med tidig RA, som hade en medelålder på 53 år. De undersöktes avseende; kondition, riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet för att analysera samband mellan dessa. Studie II är en träningsstudie, bestående av 13 patienter med RA, med en medianålder på 57 år. Kondition, riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet analyserades för att se förändringar efter tio veckors intensiv cykelträning samt vid en uppföljning efter 25 veckor. Resultat: I studie I visade den studerade gruppen ett konditionsmedelvärde på 31.6 mL. Sambandsanalyser visade att högre kondition var relaterad till lägre grad av riskfaktorer för hjärt- och kärlsjukdom, samt lägre 10 års risk för hjärt- och kärlsjukdom och sjukdomsaktivitet. I studie II fann vi att tio veckors intensiv cykelträning kan vara en användbar metod för att förbättra kondition, blodtryck och antalet ömma leder. Ingen ökad sjukdomsaktivitet noterades. Slutsatser: Dessa studier bidrar med kunskap om samband mellan kondition och riskfaktorer för hjärt- och kärlsjukdom samt sjukdomsaktiviteten hos patienter med RA. De visar också att intensiv cykelträning kan vara en effektiv metod att förbättra kondition och blodtryck hos patienter med RA.

The promoter region of interferon regulatory factor 5 (IRF5) contains the rs2004640 T or G single nucleotide polymorphism (SNP) and a CGGGG indel. Both of these polymorphisms have been implicated as genetic risk factors for several autoimmune diseases, including systemic lupus erythematosus, whose pathology involves altered apoptosis and cytokine signaling. The polymorphisms' overall effect is to increase IRF5 levels. IRF5 is a transcription factor of several cytokines, including interferon, and is pro-apoptotic. Thus an alteration of cytokine levels and apoptosis signaling due to high IRF5 levels is the proposed source of autoimmune risk. Each of IRF5's four first exons (1A, 1B, 1C, 1D) has its own promoter and responds to specific stimuli. rs2004640 is a T or G polymorphism; T is the risk allele. The SNP creates a sequence-specific recognition site for the spliceosome, making exon 1B spliceable. Analysis of the 1B promoter showed putative p53 binding site. IRF5 and p53 are pro-apoptotic transcription factors, and the p53 site may provide a positive feedback loop. Apoptosis levels were altered in cells with the rs2004640 risk T/T allele when treated with DNA damaging agents (extrinsic apoptosis), but not when activating death receptors (intrinsic apoptosis). The 1B promoter was the only one to activate expression after inducing DNA damage in a luciferase reporter assay, and this activation was abolished after mutating the p53 site. The exon 1A promoter contains either three or four copies (4X) of CGGGG; the 4X variant is the risk allele. The 1A promoter is constitutively active and is responsive to the Toll-like receptor 7 agonist imiquimod. RNA folding analysis revealed a hairpin encompassing exon 1B. Mutational analysis showed that the hairpin shape decreased translation five-fold in a luciferase reporter assay. Cells with the CGGGG or rs2004640 risk allele exhibited higher levels of IRF5 mRNA and protein, but demonstrated no change in mRNA stability. Quantitative PCR in cell lines with either risk polymorphism demonstrated decreased usage of exons 1C or 1D, although no other correlated splicing events were observed. Also, several mRNA splice variants of IRF5 were sequenced. The risk polymorphisms altered cytokine signaling as well. Expression of interferon, Toll-like receptor, and B cell receptor pathways were affected by a risk haplotype which includes the rs2004640 SNP. The CGGGG polymorphism decreased the levels of CC-chemokine receptor 7. Specific transcription factor binding sites define promoter activity and thus first exon usage and transcription levels. Translation levels are affected by mRNA folding. Overall, the rs2004640 SNP and the CGGGG indel cause high levels of IRF5. High IRF5 expression causes altered cytokine and apoptosis signaling, and may bias the immune system toward autoimmunity.

There is a role for environmental factors in the pathogenesis of autoimmune diseases in humans and animals. Correlations have been made between mercury (Hg) exposure and the prevalence human autoimmune diseases. The rodent model of Hg-induced autoimmunity is useful for the analysis of systemic autoimmunity that is both environmentally and genetically modulated. In susceptible mice, Hg treatment induces both polyclonal activation of B cells, as well as the production of highly specific autoantibodies targeting the nucleolar protein fibrillarin. Tim proteins are a family of immune cell surface molecules that have been implicated in modulation of autoimmune diseases in both humans and animals. Tim-3, originally reported as a Th1 specific molecule, is expressed on T cells of various subsets, as well as antigen presenting cells and granulocytes. Tim-3 and its known ligand galectin-9 play a role in the down-regulation of immune responses, including experimental autoimmune encephalomyelitis and autoimmune conjunctivitis. Tim-3-Ig fusion protein, as well as blocking and stimulating anti-Tim-3 antibodies, were employed in vivo to modulate the Tim-3-galectin-9 pathway during Hg-induced autoimmunity. Results have shown an increase in Th1 manifestations and decrease in Th2 manifestations when the pathway is inhibited by Tim-3-Ig. Blockade of the pathway using a Tim-3 directed antibody resulted in an increase of all disease manifestations, including Th2-driven IgE production; a stimulating antibody had the opposite effect on IgG and no effect on IgE. In addition to studying the regulation of Hg-induced autoimmunity, a goal of immunologists is to understand the genesis of this disease model. Apoptosis, although anti-inflammatory, has been proposed as a source of autoantigen in autoimmune diseases. Interest in events occurring at the site of Hg injection has prompted us to perform in vitro studies of Hg-induced cell death. Treatment of murine lung epithelial cells or Jurkat T cells with doses of Hg similar to those present at the injection site results in a death process that is morphologically and biochemically distinct from apoptosis. We have observed peripheral movement of the nucleolar protein fibrillarin via confocal microscopic study of Hg-induced cell death. As cells die, there is extrusion of fibrillarin from the nucleus and exposure at the cell surface. Such cell death may allow recognition of fibrillarin by the immune system thereby promoting the formation of anti-nucleolar antibodies. / Microbiology and Immunology

Thesis (Ph. D.)--West Virginia University, 2000. / Title from document title page. Document formatted into pages; contains x, 185 p. : ill. Includes abstract. Includes bibliographical references.

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