The Journal of Experimental Medicine
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Published 6 December 2004. doi:10.1084/jem.20031763
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 11, 1359-1370
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Apoptotic Cells with Oxidation-specific Epitopes Are Immunogenic and Proinflammatory

Mi-Kyung Chang1, Christoph J. Binder1, Yury I. Miller1, Ganesamoorthy Subbanagounder3, Gregg J. Silverman2, Judith A. Berliner3, and Joseph L. Witztum1

1 Division of Endocrinology and Metabolism and 2 Department of Medicine, Division of Rheumatology, University of California, San Diego, La Jolla, CA 92093
3 Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095

Address correspondence to Mi-Kyung Chang, Dept. of Medicine, Div. of Endocrinology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Phone: (858) 534-4407; Fax: (858) 534-2005; email: m7chang{at}ucsd.edu

Oxidation of low density lipoprotein (LDL) generates a variety of oxidatively modified lipids and lipid-protein adducts that are immunogenic and proinflammatory, which in turn contribute to atherogenesis. Cells undergoing apoptosis also display oxidized moieties on their surface membranes, as determined by binding of oxidation-specific monoclonal antibodies. In the present paper, we demonstrated by mass spectrometry that in comparison with viable cells, membranes of cells undergoing apoptosis contain increased levels of biologically active oxidized phospholipids (OxPLs). Indeed, immunization of mice with syngeneic apoptotic cells induced high autoantibody titers to various oxidation-specific epitopes of oxidized LDL, including OxPLs containing phosphorylcholine, whereas immunization with viable thymocytes, primary necrotic thymocytes, or phosphate-buffered saline did not. Reciprocally, these antisera specifically bound to apoptotic cells through the recognition of oxidation-specific epitopes. Moreover, splenocyte cultures from mice immunized with apoptotic cells spontaneously released significant levels of T helper cell (Th) 1 and Th2 cytokines, whereas splenocytes from controls yielded only low levels. Finally, we demonstrated that the OxPLs of apoptotic cells activated endothelial cells to induce monocyte adhesion, a proinflammatory response that was abrogated by an antibody specific to oxidized phosphatidylcholine. These results suggest that apoptotic cell death generates oxidatively modified moieties, which can induce autoimmune responses and a local inflammatory response by recruiting monocytes via monocyte–endothelial cell interaction.

Key Words: apoptosis • lipid peroxidation • autoimmunity • inflammation • oxidized LDL

M.-K. Chang and C.J. Binder contributed equally to this work.

Abbreviations used in this paper: aPL, antiphospholipid antibody; LC/MRM, liquid chromatography multiple reaction monitoring; LDL, low density lipoprotein; lyso-PC, 1-palmitoyl-2-lyso-sn-glycero-3-PC; MDA, malondialdehyde; OxLDL, oxidized LDL; OxPL, oxidized phospholipid; PAEC, porcine aortic endothelial cell; PC, phosphorylcholine; PEIPC, 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-PC; POVPC, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-PC; SLE, systemic lupus erythematosus.


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