Anticardiolipin Antibodies and Oxidized Phospholipids

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Patients with the antiphospholipid antibody syndrome (APS) have autoantibodies to certain phospholipids (aPL) such as cardiolipin and/or the lupus anticoagulant and clinically experience recurrent venous or arterial thrombosis, history of fetal death and autoimmune thrombocytopenia. Increased aPL also appear to predict increased risk of stroke and myocardial infarction in otherwise healthy men as well. However, controversy exists about the target antigens of aPL, and even university laboratories cannot agree who has elevated aPL titers. In turn, clinical management is hampered by lack of an underlying hypothesis to explain why antibodies should form to such ubiquitous compounds as PL. We have developed the novel hypothesis that many aPL are directed against epitopes of oxidized PL (OxPL) and/or against covalent adducts of OxPL and associated PL binding proteins, such as beta2GPI. Our hypothesis suggests that states of enhanced lipid peroxidation, as occurs in inflammation or atherosclerosis, leads to oxidation of PL (such as in LDL or in membranes of apoptotic or dying cells) which creates neo self-determinants and immunogenic epitopes. The resultant autoantibodies can then target such neoepitopes in many tissues, and may have a variety of biological consequences. Cardiolipin (CL) is the most common PL used to test for aPL. We have shown that APS plasma bind exclusively to OxCL, or to OxCL adducts with beta2GPI, and not to native CL. We propose to further test our hypothesis by determining if antibodies to other OxPL are also present in sera from patients and mice with lupus- like syndromes. We will generate a panel of such aOxPL murine monoclonals from (NZWxBXSB) F1 males. Similar Fab and scFv antibodies will be generated from a human phage-display library. We will determine the epitopes to which they bind and their impact on in vitro and in vivo coagulation, with an emphasis on the Protein C pathway. We will treat lupus-prone mice with potent antioxidants to see if changes in aPL titers and/or other clinical parameters occur. Understanding the etiology of even some of the aPL should lead not only to development of more standardized assays, which should improve our ability to detect high risk individuals, but also to consideration of new therapeutic modalities for patients with aPL and APS (e.g. aggressive anti-inflammatory and/or antioxidant interventions).