Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids: Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein

Sohvi Hörkkö, Elizabeth Miller, Eric Dudl, Peter Reaven, Linda K. Curtiss, Nathan J. Zvaifler, Robert Terkeltaub, Silvia S. Pierangeli, D. Ware Branch, Wulf Palinski, Joseph L. Witztum

Research output: Contribution to journalArticle

316 Scopus citations

Abstract

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 PL 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°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 ape 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.

Original languageEnglish (US)
Pages (from-to)815-825
Number of pages11
JournalJournal of Clinical Investigation
Volume98
Issue number3
DOIs
StatePublished - Aug 1 1996

Keywords

  • antiphospholipid antibody syndrome
  • atherosclerosis
  • autoantibodies
  • cardiolipin
  • oxidized lipoproteins

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids: Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein'. Together they form a unique fingerprint.

  • Cite this

    Hörkkö, S., Miller, E., Dudl, E., Reaven, P., Curtiss, L. K., Zvaifler, N. J., Terkeltaub, R., Pierangeli, S. S., Branch, D. W., Palinski, W., & Witztum, J. L. (1996). Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids: Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. Journal of Clinical Investigation, 98(3), 815-825. https://doi.org/10.1172/JCI118854