ANTICARDIOLIPIN ANTIBODIES AND OXIDIZED PHOSPHOLIPIDS

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DESCRIPTION (Adapted from Investigator's Abstract): Patients with the antiphospholipid syndrome (APS) have autoantibodies to certain phospholipids such as cardiolipin and/or the lupus anticoagulant and clinically experience recurrent venous or arterial thrombosis, history of fetal death and autoimmune thrombocytopenia. Patients with increased antiphospholipid antibodies (aPL) have increased risk of stroke and of myocardial infarction. However, diagnosis of elevated aPL has been frustrated by marked variation in assay results even between expert laboratories, and clinical management has been hampered by lack of an underlying hypothesis to explain why antibodies should form to such ubiquitous compounds as phospholipids, much less that aPL should occur in a variety of settings. A novel hypothesis is put forth that explains the etiology of some, if not most, aPL antibodies. It is proposed that aPL antibodies are directed against epitopes of oxidized phospholipids and/or against covalent adducts between breakdown products of oxidized phospholipids and associated proteins. A corollary is that most aPL are not directed to native, unmodified phospholipids. The hypothesis suggests that enhanced lipid peroxidation in vivo, either localized or generalized, leads to oxidation of phospholipids which creates new immunogenic epitopes. The resultant autoantibodies than have a variety of biological consequences. To test these hypotheses, a panel of aPL murine monoclonals directed at cardiolipin and phosphatidylserine using the spleens of apoE-deficient mice, which have a high titer of autoantibodies to both oxidized LDL and cardiolipin will be generated. These antibodies to epitopies of oxidized phospholipids will be used to determine the epitipes to which they bind and whether they act as lupus antiboagulants or induce altered biologic behavior. Finally this information and understanding will be used to develop more standardized assays which will be applied to selected patient populations. Validation of these hypotheses could lead not only to improved ability to detect high-risk individuals, but would suggest explanations for the etiology of these antibodies and possibly new therapeutic modalities (e.g., anti-inflammatory and/or antioxidant interventions).