Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Hypercholesterolaemia and Autoimmunity Interact in a Mouse Model of Systemic Lupus Erythematosus To Enhance Both Atherosclerosis and Renal Inflammation, but by Distinct Mechanisms.
Lewis2, Myles J., Malik2, Talat H., Fossati-Jimack2, Liliane M., Carassiti2, Daniele, Cook2, Terence H., Haskard1, Dorian O., Botto1, Marina
Although SLE is known to accelerate atherosclerosis, the underlying mechanisms are not known. We explored the hypothesis that hypercholesterolaemia and autoimmunity interact in driving both arterial wall and renal pathology through immune-complex deposition.
Atherosclerosis prone low density-lipoprotein receptor deficient mice (Ldlr-/-) were crossed with B6.129-Sle16 congenic autoimmune mice, which develop high titres of lupus autoantibodies, and studied on low fat (LF) and high fat (HF) diets at 22 weeks of age.
The Sle16 locus significantly increased atherosclerosis in Ldlr-/- mice, as measured by en face aortic lesion area (LF p<0.0001; HF p<0.002) and by aortic root lesion analysis (LF p<0.05; HF p<0.0001). Unexpectedly, aortic root lesions in Sle16.Ldlr-/- mice had significantly less complement C3 than those in Ldlr-/- mice, but similar IgG deposition. The Sle16 locus caused a reduction in serum C3, associated with renal immune-complex deposition. Sle16.Ldlr-/- mice showed augmented renal inflammation, with enhanced glomerular C3 deposition compared to B6.129-Sle16 mice, but again no difference in glomerular IgG deposits.
The data suggest that hypercholesterolaemia enhances immune complex-mediated renal damage by amplifying complement activation, but do not support a role for arterial wall immune complex deposition and complement activation in accelerated atherosclerosis. On the contrary, systemic complement depletion by immune-complexes may contribute to atherogenesis by reducing the protective role of complement in disposal of apoptotic debris. The results predict that aggressive treatment of hyperlipidaemia in SLE may reduce lupus nephritis, as well as reduce accelerated atherosclerosis.
To cite this abstract, please use the following information:
Lewis, Myles J., Malik, Talat H., Fossati-Jimack, Liliane M., Carassiti, Daniele, Cook, Terence H., Haskard, Dorian O., et al; Hypercholesterolaemia and Autoimmunity Interact in a Mouse Model of Systemic Lupus Erythematosus To Enhance Both Atherosclerosis and Renal Inflammation, but by Distinct Mechanisms. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :430