nomodulation of FcRs. 23 Some clues on how ICs may be atherogenic are emerging. Oxidized lipids and antibodies to oxidized low-density lipoproteins (LDLs) are elevated in SLE, 11, 12 and macrophages incubated with oxidized LDL IC demonstrate enhanced uptake, cholesteryl ester accumulation, and foam cell formation in vitro compared with native LDL. 24 Uptake through FcRs was associated with macrophage activation and release of cytokines, which are characteristics of atherosclerotic lesions. 25 The independent contribution of SLE and IgG ICs to the development of atherosclerosis is further supported by the observation that apolipoprotein E (ApoE) and Faslpr/lpr (lupus-prone mice) double-deficient B6 mice spontaneously develop lupus-like disease and develop far more atherosclerotic lesions than mice deficient in ApoE or Fas alone. Elevated anti–oxidized phospholipid IgG antibody levels in the double-deficient mice were associated with increased IgG deposition in the aorta intima and significantly correlated with atherosclerotic lesion area. 26 Together these data suggest that autoantibodies play a role in the pathogenesis of atherosclerosis.

Chronic systemic inflammation, endothelial dysfunction, and immune dysregulation observed in SLE and RA are known to also promote atherosclerosis. 11 Indeed, the cholesterol-lowering drug HMG-CoA reductase inhibitor simvastatin, also known for its antiinflammatory effects, reduced the atherosclerotic lesion area and proinflammatory cytokine production in mice with lupus-like features independently of effects on cholesterol levels. 27 LDL and cholesterol may not contribute differently in SLE patients and in normal controls, but disease duration, lack of aggressive treatment with immunosuppressants, 1 and the high levels of homocysteine2 contribute independently to early CVD. These clinical data point to an independent contribution of SLE immune features to the development of CVD. Consistent with this, studies in animal models show that transfer of bone marrow cells from B6. Sle1. 2.3 mice (which readily develop lupus and CVD) to the B6. LDLR/mice (an accepted model of atherosclerosis) increased the rate of formation of atherosclerotic lesions that were heavily infiltrated by CD3 cells. 28 In a human artery severe combined-immunodeficiency mouse chimera, adoptively transferred human T cells instigated arterial wall inflammation only when wall-embedded dendritic cells (DCs) were conditioned with Toll-like receptor (TLR) ligands. 29 If the transferred T cells produce tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), it may bind to DR5 (a TRAIL receptor) on the surface of smooth muscle cells and cause their apoptotic death. 30 Accordingly, activated T cells, probably displaying adhesion molecules, 31 present in patients with SLE may enter vessels in which the resident DCs have been activated and contribute significantly to the expression of vessel pathology in the form of atherosclerotic plaques. Macrophages may differentiate in the presence of lupus serum to DCs32 and may account for the increased presence of DCs in the vessel walls of SLE patients. Less well appreciated is the contribution of neutrophils to atherosclerotic lesion development in the context of autoimmunity. Neutrophils are abundant in joint lesions of RA patients and play a prominent role in RA development in mouse models. 33 Neutrophils are also present in renal tissue