Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 18, Pages 7018-7023Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602311103
Keywords
autoimmunity; congenic mice
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Funding
- NHLBI NIH HHS [HL65709, R01 HL065405, HL53989, R01 HL053989, R01 HL057986, HL57986, HL65405, R01 HL065709] Funding Source: Medline
- NICHD NIH HHS [5 K12 HD043483-04, K12 HD043483] Funding Source: Medline
- NIDDK NIH HHS [DK59637-01, U24 DK059637] Funding Source: Medline
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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.S/e1.2.3 congenic or C57BL/6 control donors (LDLr.S/e and LDLr.B6, respectively). LDLr.5/e mice developed a lupus-like disease characterized by production of double-stranded DNA autoantibodies and renal disease. When fed a Western-type diet, LDLr.S/e chimeras had increased mortality and atherosclerotic lesions. The plaques of LDLr.5/e mice were highly inflammatory and contained more CD3(+) T cells than controls. LDLr.S/e 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.
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