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，绝经前狼疮妇女患心肌梗死的风险是正常人的50倍。风险增加的潜在机制尚不清楚，并且由于缺乏反映人类加速动脉粥样硬化和狼疮等效的动物模型，研究受到阻碍。我们通过将狼疮易感、B6.Sle1.2.3基因或C57Bl/6对照骨髓转移到LDLr-/-小鼠（LDLr）来解决这一问题。Sle和LDLr。B6,分别)。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，但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。LDLr。然而，Sle小鼠CD4+ T细胞的活化和凋亡增加，B细胞增殖增加，抗氧化LDL和心磷脂的抗体产生增加。LDLr。Sle小鼠的病灶CD4+ T细胞也增加了三倍，炎症标志物的表达也增加了。因此，本研究的长期目标是阐明SLE介导加速动脉粥样硬化的遗传、细胞和免疫调节成分。为了验证免疫功能障碍加速动脉粥样硬化的假设，我们将使用我们的新动物模型来确定(1)通过研究LDLr-/-小鼠狼疮易感基因间隔的生物同质性来确定参与加速动脉粥样硬化的免疫调节因子；2)通过从B6转移淋巴细胞群加速动脉粥样硬化所必需的细胞成分。Sle小鼠对淋巴细胞缺陷Rag-/- ldlr -/-小鼠的影响3)失调的T细胞凋亡和/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；4)通过非清髓性细胞转移纠正自身免疫是否可以停止或逆转动脉粥样硬化。这项研究与公共卫生的相关性，特别是对妇女的相关性，在于其对SLE中过早的、通常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狼疮和心血管疾病治疗方法的改进。

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.