EFFECT OF AUTOANTIBODIES ON LIPOPROTEIN METABOLISM IN MOUSE MODEL OF SLE

抗心磷脂抗体（Anti-cardiolipin antibodies，简称Anti-cardiolipin antibodies，简称Anti-cardiolipin antibodies）是一种抗磷脂抗体。 抗心磷脂复合物的自身抗体， 载脂蛋白H，也称为β 2-糖蛋白I（β 2-GPI）。的 这些自身抗体的高滴度的存在，通常在自身免疫性疾病中发现， 疾病如系统性红斑狼疮（SLE）是致病性的， 与抗磷脂抗体综合征有关。研究 已经显示出冠状动脉炎的发生与冠状动脉炎的发生有关 和冠状动脉疾病。而且 脂蛋白的改变也与脂蛋白的存在有关 在MRL/lpr × BALB/cJ杂交小鼠中。SLE患者处于 过早患冠状动脉疾病的风险增加， 被认为是一个促成因素。通过这种机制， 发挥这种影响是未知的，但他们可能有助于通过改变 脂蛋白水平，一个重要的心血管危险因素。基于 先前使用近交自身免疫小鼠品系的遗传研究结果， 该提案假设， 脂蛋白水平，β 2-GPI基因有助于ACL， 脂蛋白水平这一假设将通过检验 自身免疫性背景和胰岛素对脂蛋白清除和合成的影响 率，并通过测试β 2-GPI基因座与ACL的连锁， MRL/lpr × BALB/cJ杂交小鼠的脂蛋白水平。如果有证据表明 发现β 2-GPI与ACL和脂蛋白水平的联系， 将对β 2-GPI基因进行分子表达研究。如果 这些表型与β 2-GPI的联系的证据缺乏， MRL/lpr X BALB/cj互交小鼠，然后是β 2-GPI基因座和MRL/lpr X BALB/cj互交小鼠。 基因组的其余部分将被测试与这些表型的联系， 通过进行QTL分析， 在NZW和BxSB（Yaa+）亲本菌株之间的互交上。的 这些研究的长期目标是开始确定遗传 对ACL开发的贡献，以及这些贡献如何影响 脂蛋白代谢预计这将提供更多的了解 加速性冠状动脉疾病的发病机制， SLE患者。

Anti-cardiolipin antibodies (ACLs) are a type of anti-phospholipid autoantibody directed against the complex of cardiolipin and apolipoprotein H, also known as beta2-glycoprotein I (beta2-GPI). The presence of high titers of these autoantibodies, often found in autoimmune diseases such as systemic lupus erythematosus (SLE), are pathogenic and have been associated with the anti-phospholipid antibody syndrome. Studies have shown an association of ACLs with the develop of coronary vasculitis and coronary artery disease in mouse models of autoimmunity. Moreover, the presence of ACLs has also been associated with alterations of lipoproteins in the MRL/lpr X BALB/cJ intercross mice. Individuals with SLE are at an increased risk for premature coronary artery disease, and ACLs have been suggested as a contributing factor. The mechanism through which they may exert this effect is unknown, but they may contribute through alterations in lipoprotein levels, an important cardiovascular risk factor. Based upon previous results of genetic studies using inbred autoimmune mouse strains, this proposal hypothesizes that ACLs directly contribute to alterations in lipoprotein levels, and that the gene for beta2-GPI contributes to ACL and lipoprotein levels. This hypothesis will be tested by examining the effect of autoimmune background and ACLs on lipoprotein clearance and synthesis rates, and by testing the beta2-GPI locus for linkage to ACL and lipoprotein levels in MRL/lpr X BALB/cJ intercross mice. If evidence for linkage of beta2-GPI to ACL and lipoprotein levels is found, than molecular expression studies on the beta2-GPI gene will be performed. If evidence for linkage of these phenotypes to beta2-GPI is a lacking in the MRL/lpr X BALB/cj intercross mice, then the beta2-GPI locus and the remainder of the genome will be tested for linkage to these phenotypes in the high AL titer producing NZW x BxSB hybrid by performing a QTL analysis on an intercross between the NZW and BxSB(Yaa+) parental strains. The long-term goal of these studies to begin identifying the genetic contributions to ACL development, and how these contributions impact upon lipoprotein metabolism. This is expected to provide greater understanding into the pathogenesis of the accelerated coronary artery disease in patients with SLE.