published_or_final_version / Paediatrics / Master / Master of Philosophy

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No description available.

Thesis (M.S.)--Ball State University, 2009. / Title from PDF t.p. (viewed on June 08, 2010). Includes bibliographical references (p. 39-42).

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with chronic inflammation affecting multiple organ systems, as well as accelerated atherosclerosis as a major complication. Prior studies by our lab have shown beneficial effects of PPARgamma agonists towards preventing SLE in two different mouse models: the well-established lupus mouse model, MRL.lpr, and the gld.apoE^-/- model of accelerated lupus and atherosclerosis. Retinaldehyde is a retinoic acid precursor that has recently been shown to inhibit PPARgamma signaling in adipose tissue. We proposed that abnormal accumulation of retinaldehyde in lupus promotes autoimmunity by inhibition of PPARgamma signaling. We measured the serum retinaldehyde levels in both lupus mouse models using reversed-phase high-performance liquid chromatography. We also examined the mRNA expressions of genes involved in retinaldehyde metabolism and PPARgamma signaling in white adipose tissues using real-time quantitative PCR. We observed a higher level of circulating retinaldehyde in the MRL.lpr mouse model on a chow diet. The circulating retinaldehyde levels in both .gld.apoE^-/- and C57 increased when maintained on a high-cholesterol Western diet. Within visceral and subcuntaneous adipose tissue, we saw several changes to expression of the genes responsible for retinaldehyde synthesis and catabolism, however further study is required to definitively assess the role of these genes. Importantly, the expression levels of genes involved in PPARgamma signaling decreased in the subcutaneous fat of gld.apoE^-/- mice on a Western diet. Our data suggest that retinaldehyde may play a role in SLE pathogenesis and could be a potential therapeutic target for SLE.

OBJECTIVE: Atherosclerotic disease progression is mediated in part, by immunological mechanisms. In recent years, interest has increased towards the prospect of modulating these immune mechanisms through vaccination to ameliorate the course of disease. Patients with lupus are at a significantly higher risk for accelerated atherosclerosis and related complications. The goal of this study was to assess the outcome of immunization in mouse models of lupus, and lupus with accelerated atherosclerosis. MATERIALS/METHODS: Atherosclerosis-prone apoE^-/- mice and autoimmune gld mice were previously crossed to generate the gld.apoE^-/- mouse. Mice were treated with an apoB-100-derived vaccine, Alum (adjuvant control), or PBS control. The antibody response was determined by quantifying the amount of circulating anti-apoB100. Serum triglyceride and cholesterol levels were analyzed. Kidney tissue from gld and gld.apoE^-/- mice was processed and histologically analyzed, using glomerular tuft size as a measure of renal disease and by extension, autoimmune disease severity. Results: Immunization led to a pronounced initial antibody response that was decreased by the endpoint of the study. No significant differences in serum triglyceride or cholesterol were observed regardless of treatment. Similarly, no significant differences were observed in glomerular tuft size. Conclusion: The data suggests that immunization with an apoB-100- derived vaccine neither improves nor worsens autoimmune disease severity in the gld.apoE^-/- mouse model. It also appears that immunization is tolerated in the autoimmune background. While further study is necessary to determine the efficacy of immunization in reducing atherosclerotic disease in this model, this may be a possible therapy to lower incidence of atherosclerosis in lupus patients.

No description available.

No description available.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and the production of auto-antibodies which target various nuclear components. There is a 9:1 women to men ratio among lupus patients, indicating differing mechanisms of lupus pathogenesis between the sexes. Although lupus patients may develop many different manifestations, lupus nephritis (LN) remains to be one of the most devastating manifestations and an indicator of poor prognosis. Although both sexes develop LN, the nephritis in males often develops more rapidly and is more severe. Necrotic cell death is a characteristic of lupus nephritis and contributes to the exacerbation of the inflammatory immune response within the glomeruli. Previously our laboratory found that absence or pharmacological inhibition of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme involved in necrotic cell death, results in milder nephritis, reduced necrotic lesions, and higher survival rates only among males. Although RIPK3-mediated necrosis was a likely candidate for inducing necrosis during female LN, murine models of glomerulonephritis revealed that the development of LN occurs independently of RIPK3. In addition, during LN, there is no crosstalk between the RIPK3- and PARP-1 mediated pathways to induce necrotic cell death. The sex bias in SLE indicates sex hormones may play a role in pathogenesis. Interestingly, estrogen receptor alpha (ERα) in the renal tissue is highly expressed and the renal specific estrogen-induced gene activation is second only to that of reproductive organs. The absence of estrogen receptor alpha protects female mice from developing nephritis, despite the presence of immune complexes in the kidneys and production of pro-inflammatory cytokines. Analysis of gene expression changes during LN progression indicate the protection seen in ERKO females may be due to alterations in metabolic pathways, including PPAR and retinol metabolism. These results demonstrate the complexity of lupus nephritis. Despite the presence of necrosis in LN, this manifestation occurs in a RIPK3-independent manner, which leaves the pathway responsible for necrosis in female kidneys to still be investigated. In addition, lupus nephritis occurs in an ER-dependent manner in females, demonstrating the significant impacts sex-hormone environments play in the pathogenesis of immune-mediated nephropathies. / Biomedical Sciences