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Studies of Atherosclerosis in Systemic Lupus Erythematosus

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Studies of Atherosclerosis in Systemic Lupus Erythematosus
Shelton, Kathryn
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of anti-nuclear autoantibodies, a wide spectrum of clinical signs, and a striking 9:1 female to male disparity in disease incidence attributed to the SLE disease promoting effects of estrogen. Estrogen increases susceptibility to loss of immune tolerance, increases autoantibody production, increases disease activity in women and accelerates the SLE phenotype in mice. A major cause of death and disability in women with SLE is accelerated lupus-associated atherosclerosis (ALAA). The overarching hypothesis of this study is that the pro-inflammatory immune dysregulation characteristic of SLE is the underlying mechanism for ALAA. The goal was to further understanding of these underlying mechanisms through the following aims: 1) create a nonhuman primate model of SLE, 2) determine the effect of estrogen on atherosclerosis development in a mouse model of SLE and atherosclerosis (Sle/LDLr-/- mice) compared to placebo, and 3) determine the effect of SLE on B6.Sle1.2.3 macrophage function and determine the impact of estrogen treatment on those functions. For aim one, we treated four cynomolgus macaques with a subcutaneous regimen of IFNalpha, TLR7 agonists, and U1-snRNP. After 23 weeks, all the monkeys developed positive anti-RNP antibody titers and one monkey developed moderate multifocal degenerative joint disease. For aim two, we treated Sle/LDLr-/- mice with 5.6 µg/day of 17beta -estradiol or placebo for 10 weeks. We found that that estrogen treatment resulted in decreased atherosclerotic plaque size without improvement of plasma lipoprotein concentrations and acceleration of the SLE phenotype. For aim three, we used bone marrow derived macrophages from B6.Sle1.2.3 mice and found that while there was no in vitro difference in foam cell formation or clearance of apoptotic cells, there was increased TNFalpha, IL-12p40, IL-6, MCP-1, and IL-10 gene expression in response to six hours of 100 ng/ml of LPS treatment independent of 1 x 10 ^ -9 M 17beta-estradiol treatment. Our findings indicate that some cynomolgus macaques may be susceptible to the development of a less well defined form of systemic autoimmune disease such as undifferentiated mixed connective tissue disease secondary to anti-RNP antibody development. Our findings also indicate that estrogen treatment is atheroprotective within the context of active SLE disease in mice and that a macrophage hyper-inflammatory response to TLR4 stimulation may contribute to the development of ALAA. These data improve understanding of ALAA pathogenesis and suggest that despite their accelerated course of atherosclerosis, premenopausal women with SLE are benefiting from atheroprotective effects of estrogen.
Cline, Mark (committee chair)
Alexander-MIller, Martha (committee member)
Parks, John (committee member)
Register, Thomas (committee member)
Wagner, Janice (committee member)
2013-01-09T09:35:11Z (accessioned)
2012 (issued)
Molecular Pathology (discipline)
forever (terms)
10000-01-01 (liftdate)
http://hdl.handle.net/10339/37649 (uri)
en (iso)
Wake Forest University

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