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¹ Molecular Cardiology, Whitaker Cardiovascular Institute
² Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118
³ Department of Anatomy and Cellular Biology, Program in Cellular, Molecular, and Developmental Biology, Tufts University School of Medicine, Boston, MA 02111
⁴ Institut d'Hématologie et d'Immunologie, Faculté de Médecine, Université Louis Pasteur, 67085 Strasbourg et Institut National de la Santé et de la Recherche Médicale, U143, 94276 Le Kremlin-Bicetre, France

Address correspondence to Kenneth Walsh, Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany St., W611, Boston, MA 02118. Phone: (617) 414-2392; Fax: (617) 414-2391; email: kwalsh{at}world.std.com

To clarify the link between autoimmune disease and hypercholesterolemia, we created the gld.apoE^–/– mouse as a model of accelerated atherosclerosis. Atherosclerotic lesion area was significantly increased in gld.apoE^–/– mice compared with apoE^–/– mice. gld.apoE^–/– mice also displayed increases in lymphadenopathy, splenomegaly, and autoantibodies compared with gld mice, and these effects were exacerbated by high cholesterol diet. gld.apoE^–/– mice exhibited higher levels of apoptotic cells, yet a reduced frequency of engulfed apoptotic nuclei within macrophages. Infusion of lysophosphatidylcholine, a component of oxidized low density lipoprotein, markedly decreased apoptotic cell clearance in gld mice, indicating that hypercholesterolemia promotes autoimmune disease in this background. These data suggest that defects in apoptotic cell clearance promote synergy between atherosclerotic and autoimmune diseases.

Key Words: atherosclerosis • autoimmunity • macrophages • lysophosphatidylcholine • lymphoproliferation

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