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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1625.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Enhanced Immune System Activation and Arterial Inflammation Accelerates Atherosclerosis in Lupus-Prone Mice

Emmanuel L. Gautier; Thierry Huby; Betty Ouzilleau; Chantal Doucet; Flora Saint-Charles; Guilaine Gremy; M. John Chapman; Philippe Lesnik

From INSERM Unit 551, UPMC-Paris 6, Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris, France.

Correspondence to Dr Philippe Lesnik, INSERM U551, Hôpital de la Pitié, 83 Bd de l’hôpital, 75651 Paris 13, France. E-mail lesnik{at}chups.jussieu.fr

Objective— Premature atherosclerosis is a characteristic feature of systemic lupus erythematosus, a prototypic autoimmune disease. The principle cellular and molecular mechanisms which underlie such accelerated atherosclerosis are indeterminate.

Methods and Results— The pathophysiology of lupus-mediated atherogenesis was evaluated in a novel animal model involving transplantation of bone marrow cells from the lupus prone strain gld into Ldl-r^–/– mice. Diet-induced atherogenesis in lethally-irradiated Ldl-r^–/– mice transplanted with gld bone marrow cells resulted in accelerated atherosclerosis (+65%) as compared with control mice transplanted with wild-type marrow cells. Enhanced atherogenesis was associated with enhanced activation of both B and T lymphocytes and with arterial inflammation involving endothelial cell activation, monocyte recruitment, and accumulation of apoptotic debris, macrophages, and CD4 T cells, but was independent of plasma lipid levels and renal function.

Conclusions— Our data support the contention that despite the absence of both disturbed cholesterol homeostasis and renal dysfunction in autoimmune gldLdl-r^–/– mice, lupus disease induces enhanced activation of the immune system and acts locally on the vasculature to induce inflammation, together with accumulation of apoptotic debris, macrophages, and CD4 T cells, thereby accelerating plaque progression.

Premature atherosclerosis is a feature of autoimmune disease but the mechanisms that underlie such accelerated atherosclerosis are indeterminate. Our experimental findings highlight enhanced immune system activation, aortic inflammation, and lesional accumulation of apoptotic cells, macrophages, and CD4 T cells as central mechanisms in the progression of atherosclerosis in autoimmune mice.

Key Words: atherosclerosis • lupus • arterial inflammation • immune system • apoptotic cells