EFFECT OF AUTOANTIBODIES ON LIPOPROTEIN METABOLISM IN MOUSE MODEL OF SLE

抗心磷脂抗体(ACL)是一种抗磷脂 针对心磷脂和心磷脂复合体的自身抗体 载脂蛋白H，又称β2-糖蛋白I(beta2-GPI)。这个 存在高滴度的这些自身抗体，通常在自身免疫中发现 系统性红斑狼疮(SLE)等疾病是致病和 与抗磷脂抗体综合症有关。研究 已表明ACL与冠状动脉血管炎的发生有关 以及冠状动脉疾病在自身免疫小鼠模型中的作用。此外， ACL的存在也与脂蛋白的改变有关 在MRL/LPR×BALB/CJ杂交小鼠中。系统性红斑狼疮患者处于 早发冠状动脉疾病的风险增加，而ACL一直是 被认为是一个促成因素。他们可以通过的机制 发挥这种作用是未知的，但它们可能通过改变做出贡献。 脂蛋白水平，一个重要的心血管危险因素。基于 先前使用近亲交配的自身免疫小鼠品系的遗传学研究结果， 该提案假设ACL直接导致了 脂蛋白水平，并且β2-GPI基因对ACL和 脂蛋白水平。这一假设将通过检验效果来检验。 自身免疫背景和ACL对脂蛋白清除和合成的影响 率，并通过测试与ACL和ARC连锁的Beta2-GPI位点 MRL/LPR×BALB/CJ杂交小鼠脂蛋白水平的研究如果有证据证明 发现β2-GPI与ACL和脂蛋白水平有关，然后 将对Beta2-GPI基因进行分子表达研究。如果 这些表型与Beta2-GPI关联的证据在 MRL/LPR X BALB/CJ杂交小鼠，β2-GPI基因座和 剩余的基因组将在年内进行与这些表型的关联测试 利用QTL分析产生高AL效价的NZW×BxSB杂交种 在NZW和BxSB(Yaa+)亲本菌株的杂交上。这个 这些研究的长期目标是开始识别基因 对ACL开发的贡献，以及这些贡献对 脂蛋白代谢。预计这将提供更多的理解 探讨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.