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.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease affecting people of various ages across the globe. Treatment for the disease is in the form of immunosuppressive drugs. Due to either the treatment of the disease or the disease itself, SLE patients have been shown to have abnormal immune function. This dysfunction accounts for an increased rate of infections in this population. Reactivation of the varicella zoster virus (VZV), herpes zoster (HZ), has been shown to occur in the SLE population at higher rates than the general, healthy population. Recently a vaccine for HZ was approved by the Food and Drug Administration for individuals 50 years of age and older. STUDY: In this study we examined the safety and immunogenicity of the HZ vaccine, Zostavax, in a small sample of SLE patients. This study was a case-control with a ratio of 1:1, SLE patients to healthy controls. The total sample size was 20 with an average age of 57.9. All study participants were seen in a clinical setting at the Oklahoma Medical Research Foundation and signed informed consents. Subjects were seen for an initial baseline visit, and were administered the vaccine. Follow-up visits were scheduled at 2, 6 and 12 weeks. RESULTS: The notable finding of this study is a lack of significant differences between SLE patients and healthy individuals with one exception. At the 6-week point a significant difference was found (P=0.03) between SLE patients and healthy controls, with regards to the number of VZV-specific cells stimulated to produce interferon gamma. No vaccine-induced illness was evident and there was no sign of an increase in SLE disease activity in patients.

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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

Wigging Out, a memoir, chronicles my first chemotherapy treatment which began in 2008 for the autoimmune disease Lupus. The primary focus is on how identity is affected by disability. Each symptom of my disease and side effect from my medications prompted a reevaluation of my identity as I felt a change both in myself and in the way others perceived me. In order to maintain a sense of control, I tried several techniques to pass and cover my disabled status, including the use of prosthetic hair pieces. Ultimately, the use of prosthetics made accepting my situation more difficult as it encouraged holding onto a former identity rather than creating a new one. It was not until I stopped using prosthetics as a form of denial and instead adopted them as part of a new identity that I was finally able to achieve the confidence necessary to fight for my life. / by Jeanette Moffa. / Thesis (M.F.A.)--Florida Atlantic University, 201?. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

From this series of studies, we conclude that microalbuminuria may represent a novel risk factor in SLE, and lupus patients are more susceptible to endothelial dysfunction caused by hyperhomocysteinemia. The use of antimalarial agents is beneficial for lupus patients with active disease on corticosteroid, and antioxidant vitamins are useful in lowering the oxidative stress markers but do not affect the endothelial function. The results highlight the importance of targeting the known modifiable risk factors in order to prevent premature atherosclerosis in SLE patients. / My first step was to elucidate the prevalence and metabolic abnormalities in SLE patients with microalbuminuria. Twenty percent of patients were found to have microalbuminuria, which was associated with higher mean arterial pressure, total plasma antioxidant and homocysteine levels. / Next, we recruited 12 SLE patients and 15 controls and gave them oral methionine loading to achieve acute hyperhomocysteinemia. After oral methionine loading, von Willebrand factor (vWF) levels increased significantly in both groups. The increase in vWF was apparently more pronounced in SLE (20%) compared to controls (8%). Fibrinogen binding to platelets increased significantly only in SLE patients. / Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of unknown cause which can affect any organs. Studies have reported an increased prevalence of cardiovascular disease (CVD) in these patients. We performed a series of studies to elucidate the interaction between microalbuminuria, dyslipidaemia, hyperhomocysteinemia, oxidative stress and immune dysregulation from the underlying disease in order to understand the accelerated atherosclerotic process in SLE. / We then evaluated the effects of long-term antioxidant vitamins. The plasma malondialdehyde level was significantly decreased after treatment in the vitamin group. Other oxidative stress markers and antioxidant levels and endothelial function remained unchanged in both groups. / We then proceeded to study the relative effect of antimalarial agents on fasting lipid fractions in patients with active SLE. Total cholesterol, very low-density lipoprotein cholesterol, and low density lipoprotein cholesterol levels were significantly lower in patients taking antimalarial agents, particularly for those patients taking concomitant prednisone. In the last study, we demonstrated that hydroxychloroquine had no significant effect on the serum lipid profile in these lupus patients with mild or inactive disease. / Tam Lai Shan. / Adviser: Edmund K. Li. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1550. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 178-214). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.