Accelerated Atherosclerosis and system lupus erythematosus

描述(由申请人提供)：系统性红斑狼疮(SLE)患者有加速的动脉粥样硬化，这是经典危险因素无法预测的。受影响最大的是女性，她们占SLE患者总数的90%。据估计，绝经前患有狼疮的女性患心肌梗死的风险是后者的50倍。风险增加的潜在机制尚不清楚，由于缺乏反映人类等同于加速的动脉粥样硬化和狼疮的动物模型，研究一直受到阻碍。我们通过将狼疮易感的B6.Sle1.2.3同源基因或C57BL/6对照骨髓转移到LDLR-/-小鼠(分别为LDLr.Sle和LDLr.B6)来解决这个问题。当喂食高脂肪食物时，LDLr.Sle小鼠的死亡率和动脉粥样硬化病变增加，而血清胆固醇或甘油三酯没有增加，也没有与血清肌酐或尿素水平直接相关。然而，LDLr.Sle小鼠确实增加了CD4+T细胞的激活和凋亡，增加了B细胞的增殖和抗氧化型低密度脂蛋白和心磷脂抗体的产生。LDLr.Sle小鼠的病变CD4+T细胞也增加了三倍，炎症标志物的表达也增加了。因此，这项建议的长期目标是阐明SLE的遗传、细胞和免疫调节成分，这些成分介导了加速的动脉粥样硬化。为了验证免疫功能障碍加速动脉粥样硬化的假说，我们将使用我们的新动物模型来确定(1)通过研究狼疮易感基因间隔的LDLR-/-小鼠生物同源基因，参与加速动脉粥样硬化的免疫调节因素；2)通过将淋巴细胞群体从B6转移到淋巴细胞缺乏的RAG-/-LDLR-/-小鼠，加速动脉粥样硬化所需的细胞成分；3)T细胞凋亡异常和/或巨噬细胞对凋亡细胞的清除不足是否是加剧早期动脉粥样硬化病变的机制；以及4)通过非清髓细胞转移纠正自身免疫是否可以阻止或逆转动脉粥样硬化的形成。这项研究与公共卫生的相关性，特别是对妇女的相关性，是对SLE过早发生、往往是致命的心血管事件的潜在机制的追求。这些研究的完成将最终导致改善治疗狼疮和心血管疾病的疗法。

DESCRIPTION (provided by applicant): Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis that is not predicted by classical risk factors. Most affected are women, who make up 90% of the SLE patient population. It is estimated that premenopausal women with lupus are at 50 times greater risk of suffering from myocardial infarction. The underlying mechanisms for increased risk are poorly understood, and investigations have been hampered by the absence of animal models reflecting the human equivalent of accelerated atherosclerosis and lupus. We addressed this by transferring lupus-susceptible, B6.Sle1.2.3 congenic or C57Bl/6 control bone marrow to LDLr-/- mice (LDLr.Sle and LDLr.B6, respectively). When fed high fat diet, LDLr.Sle mice had increased mortality and atherosclerotic lesions without enhances in serum cholesterol or triglycerides or direct correlation with serum creatinine or urea levels. The LDLr.Sle mice did, however, have increased activation and apoptosis of CD4+ T cells and increased B cell proliferation and antibody production against oxidized LDL and cardiolipin. LDLr.Sle mice also had a three-fold increase in lesional CD4+ T cells and increased expression of inflammatory markers. Therefore, the long-term objective of this proposal is to elucidate the genetic, cellular and immunoregulatory components of SLE that mediate accelerated atherosclerosis. To test the hypothesis that immune dysfunction accelerates atherosclerosis we will use our novel animal model to determine (1) the immune regulatory factors involved in accelerated atherosclerosis by studying LDLr-/- mice biocongenic for lupus-susceptibility gene intervals; 2) the cellular components necessary for accelerated atherosclerosis by transferring lymphocyte populations from B6.Sle mice to lymphocyte-deficient Rag-/-LDLr-/- mice; 3) whether dysregulated T cell apoptosis and/or deficient clearance of apoptotic cells by macrophages is a mechanism to exacerbate early atherosclerotic lesions and 4) if correction of autoimmunity by nonmyeloablative cell transfer can cease or regress atherogenesis. The relevance of this research to public health, especially to women, is steeped in its pursuit of underlying mechanisms for premature, often fatal, cardiovascular events in SLE. The completion of these studies will ultimately lead to improved therapeutics to treat both lupus and cardiovascular disease.