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 probl...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-05, Vol.103 (18), p.7018-7023
Main Authors: Stanic, Aleksandar K., Stein, Charles M., Morgan, Adam C., Fazio, Sergio, Linton, MacRae F., Wakeland, Edward K., Olsen, Nancy J., Major, Amy S.
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Antiphospholipid - blood
Atherosclerosis
Atherosclerosis - immunology
Atherosclerosis - pathology
B lymphocytes
Biological Sciences
Blood vessels
Bone marrow
Bone Marrow Transplantation
Cellular biology
Chimeras
Diet
Humans
Immune system
Immune System - physiology
Lesions
Low density lipoprotein receptors
Lupus
Lupus Erythematosus, Systemic - genetics
Lupus Erythematosus, Systemic - immunology
Medical research
Mice
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Radiation Chimera
Receptors, LDL - genetics
Receptors, LDL - metabolism
Rodents
Spleen - cytology
Spleen - immunology
Systemic lupus erythematosus
T lymphocytes
Thymus Gland - cytology
Thymus Gland - immunology
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Summary: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) receptordeficient ($LDLr^{-/-}$) 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0602311103