Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids - Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein
Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids - Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein
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DOI：
10.1172/jci118854
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发表时间：
1996-08-01
影响因子：
15.9
通讯作者：
Witztum, JL
中科院分区：
文献类型：
--
作者：
Horkko, S;Miller, E;Witztum, JL
抗磷脂抗体综合征（APS）患者的最佳临床治疗方案尚不明确，因为缺乏一个基本假设来解释为什么抗磷脂自身抗体（aPL）会针对像磷脂（PL）这样普遍存在的化合物产生。在本文中，我们证明，许多（如果不是大多数的话）aPL实际上是针对氧化磷脂（FL）的新表位，或者是针对氧化磷脂的分解产物与相关蛋白质之间形成加合物所产生的新表位。每个心磷脂（CL）分子含有四个不饱和脂肪酸，极易被氧化，尤其是在暴露于空气中时。然而，标准的抗心磷脂抗体（aCL）免疫测定通常是通过在4℃下将乙醇溶剂过夜蒸发，使CL结合到微量滴定板的孔中。我们使用多种技术证明，当CL被铺板并暴露于空气中时会迅速发生氧化。载脂蛋白E缺陷型小鼠的血清对氧化低密度脂蛋白具有高自身抗体滴度，其与暴露于空气中时间逐渐增加的CL的结合呈现出显著的时间依赖性增加。从载脂蛋白E缺陷型小鼠中克隆的针对氧化低密度脂蛋白的单克隆抗体也与氧化的CL结合。APS患者的血清以及亲和纯化的aCL - IgG随着CL被氧化，与CL的结合逐渐增加。然而，来自载脂蛋白E缺陷型小鼠的单克隆抗体，或者APS患者的血清或aCL - IgG并不与不能发生过氧化的还原型CL类似物结合。这些数据表明，许多aPL是针对氧化磷脂的新表位，并提示氧化事件在APS的病理生理学中可能很重要。这进而提示了新的治疗策略，可能包括强化抗氧化治疗。
The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized FL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 degrees C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity-purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy.