Enhanced immune system activation and arterial inflammation accelerates atherosclerosis in lupus-prone mice.
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.


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 gld-->Ldl-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.
Gautier
Emmanuel L
EL
INSERM Unit 551, UPMC-Paris 6, Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris, France.
Huby
Thierry
T
Ouzilleau
Betty
B
Doucet
Chantal
C
Saint-Charles
Flora
F
Gremy
Guilaine
G
Chapman
M John
MJ
Lesnik
Philippe
P
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000097:blood; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D050197:Atherosclerosis / Q000276:immunology* / Q000503:physiopathology*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D007107:Immune System / Q000502:physiology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011336:Probability; D011828:Radiation Chimera; D012016:Reference Values; D012680:Sensitivity and Specificity
D017152:Antibodies, Antiphospholipid; D016207:Cytokines; D008074:Lipoproteins