Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus.
Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis. The underlying mechanisms are poorly understood, and investigations have been hampered by the absence of animal models that reflect the human condition of generalized atherosclerosis and lupus. We addressed this problem by transferring lupus susceptibility to low-density lipoprotein (LDL) receptor-deficient (LDLr-/-) mice, an established model of atherosclerosis, creating radiation chimeras with NZM2410-derived, lupus-susceptible, B6.Sle1.2.3 congenic or C57BL/6 control donors (LDLr.Sle and LDLr.B6, respectively). LDLr.Sle mice developed a lupus-like disease characterized by production of double-stranded DNA autoantibodies and renal disease. When fed a Western-type diet, LDLr.Sle chimeras had increased mortality and atherosclerotic lesions. The plaques of LDLr.Sle mice were highly inflammatory and contained more CD3+ T cells than controls. LDLr.Sle mice also had increased activation of CD4+ T and B cells and significantly higher antibody to oxidized LDL and cardiolipin. Collectively, these studies demonstrate that the lupus-susceptible immune system enhances atherogenesis and modulates plaque composition.
Stanic
Aleksandar K
AK
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6300, USA.
Stein
Charles M
CM
Morgan
Adam C
AC
Fazio
Sergio
S
Linton
MacRae F
MF
Wakeland
Edward K
EK
Olsen
Nancy J
NJ
Major
Amy S
AS
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000097:blood; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D004032:Diet; D006801:Humans; D007107:Immune System / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D011973:Receptors, LDL