Induction of Early Atherosclerosis in LDL-Receptor–Deficient Mice Immunized With β 2 -Glycoprotein I

Abstract

Background —Immunization with β 2 -glycoprotein I (β2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of β2GPI immunization on the progression of atherosclerosis. Methods and Results —In the first experiment, 3 groups of LDL receptor–deficient (LDL-RD) mice (n=15 per group) were immunized with either β2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All β2GPI-immunized mice developed high titers of anti-β2GPI antibodies as well as a specific lymph node proliferation to β2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the β2GPI-immunized mice (mean aortic lesion, 26 000±5700 μm 2 ) in comparison with their ovalbumin-immunized (mean, 3000±1099 μm 2 ; P <0.01) and nonimmunized (mean, 2250±700 μm 2 ; P <0.01) littermates. The average lesion size in the β2GPI-immunized mice fed an atherogenic diet (mean, 98 000±8305 μm 2 ) was larger than the ovalbumin-immunized mice (mean, 81 250±12 933 μm 2 ; P =NS) or the nonimmunized controls (mean, 75 625±7281 μm 2 ; P =NS). The atherosclerotic plaques in the β2GPI-immunized mice appeared to be more mature, and denser infiltration of CD4 lymphocytes was present in the subendothelium of the aortic sinuses from this group of mice. Conclusions —The results of the present study provide the first direct evidence for the proatherogenic effect of β2GPI immunization and establish a new model for immune-mediated atherosclerosis.