THE EPITOPES FOR SOME ANTIPHOSPHOLIPID ANTIBODIES ARE ADDUCTS OF OXIDIZED PHOSPHOLIPID AND BETA(2) GLYCOPROTEIN-1 (AND OTHER PROTEINS)

Circulating autoantibodies to phospholipids (aPLs), such as cardiolipi n (CL), are found in patients with antiphospholipid antibody syndrome (APS). We recently demonstrated that many aPLs bound to CL only after it had been oxidized (OxCL), but not to a reduced CL analogue that cou ld not undergo oxidation, We now show that the neoepitopes recognized by some aPLs consist of adducts formed between breakdown products of o xidized phospholipid and associated proteins, such as beta(2) glycopro tein 1 (beta(2)GP1). Addition of human beta(2)GP1, polylysine, native low-density lipoprotein, or apolipoprotein AI to OxCL-coated wells inc reased the anticardiolipin antibody (aCL) binding from APS sera that f irst had been diluted so that no aCL binding to OxCL could be detected , No increase in aCL binding was observed when these proteins were add ed to wells coated with reduced CL. The ability of beta(2)GP1, polylys ine, or low-density lipoprotein to be a ''cofactor'' for aCL binding t o OxCL was greatly reduced when the proteins were methylated, Incubati on of beta(2)GP1 with oxidized -palmitoyl-2-linoleyl-[1-C-14]-phosphat idylcholine (PC), but not with dipalmitoyl-[1-C-14]-PC, led to formati on of covalent adducts with beta(2)GP1 recognized by APS sera, These d ata suggest that the reactive groups of OxCL, such as aldehydes genera ted during the decomposition of oxidized polyunsaturated fatty acids, form covalent adducts with beta(2)GP1 (and other proteins) and that th ese are epitopes for aCLs. Knowledge that the epitopes recognized by m any aPLs are adducts of oxidized phospholipid and associated proteins, including beta(2)GP1, may give new insights into the pathogenic event s underlying the clinical manifestations of APS.