Immunoglobulin M Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Abstract

Immunoglobulin M (IgM) natural antibodies bind oxidatively-modified low-density lipoprotein (LDL) and apoptotic cells and have been implicated as being important for protection against atherosclerosis. We have directly investigated the requirement for IgM by studying the effects of IgM deficiency in LDL receptor-deficient (Ldlr(-/-)) mice. Mice deficient in serum IgM (sIgM) or complement C1q were crossed with Ldlr(-/-) mice and studied on both low-fat and high-fat semisynthetic diets. On both diets, en face and aortic root atherosclerotic lesions in sIgM.Ldlr(-/-) mice were substantially larger and more complex, with accelerated cholesterol crystal formation and increased smooth muscle cell content in aortic root lesions. Combined C1q and IgM deficiency had the same effect as IgM deficiency alone. Increased apoptosis was observed in aortic root lesions of both sIgM.Ldlr(-/-) and C1qa.Ldlr(-/-) mice. Because lesions were significantly larger in IgM-deficient mice than in the absence of C1q, IgM protective mechanisms appear to be partially independent of classical pathway activation and apoptotic cell clearance. Levels of IgG antibodies against copper-oxidized LDL were lower in sIgM.Ldlr(-/-) mice fed a high-fat diet, suggesting compensatory consumption of IgG in the absence of IgM. This study provides direct evidence that IgM antibodies play a central role in protection against atherosclerosis. The mechanism appears to be at least partly independent of classical pathway complement activation by C1q.