hirteen Nobel prizes awarded for research on the structure, conformation, synthesis and receptor cell biology of cholesterol and related molecules has prompted the comment that 'cholesterol is the most highly decorated small molecule in biology' 1 . The discovery of the low-density lipoprotein (LDL) receptor-mediated pathway for cholesterol homeostasis by Brown and Goldstein has led to an armamentarium of successful drugs and drug strategies aimed at lowering LDL, very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) cholesterol levels by inhibiting cholesterol biosynthesis and upregulating LDL receptor expression [1][2][3][4] . An ambitious goal has now been set for the elimination of coronary disease early in the next century 5 . Despite the panoply of cholesterol-lowering drugs, the achievement of this goal is a challenge that could still benefit from further theoretical and therapeutic insights 6,7 .
Could immunological mechanisms play a role in cholesterol metabolism? In this article we propose that a specific immunological mechanism, opsonization of LDL, VLDL and IDL cholesterol by the binding of naturally occurring antibodies to cholesterol, results in activation of complement (C) and binding of C split products (mainly C3b) to the lipoprotein. Uptake of the circulating lipoprotein-anticholesterol-C3b immune complexes by cells expressing C3b receptors then affects the normal turnover and distribution of LDL cholesterol in the plasma (Fig. 1). It is likely that most of the initial uptake occurs through binding to complement receptor type 1 (CR1) molecules on erythrocytes 8,9 , which bind immune complexes containing C3b through the phenomenon known as immune adherence, after which the immune complexes are shuttled by erythrocytes to macrophages 9 . Erythrocytic CR1 is a major site, both for removal of circulating immune complexes in primates and for downregulation of further C activation 9 . The current theory predicts that immunomodulation of cholesterol is specific to LDL, VLDL and IDL (lipoproteins containing 'bad' cholesterol) rather than to highdensity lipoprotein (HDL) cholesterol ('good' cholesterol) because the anticholesterol antibodies do not bind HDL cholesterol 10 . Experimental evidence supporting a natural role for immunomodulation of LDL cholesterol is provided below.