Rethinking oxidized low-density lipoprotein, its role in atherogenesis and the immune responses associated with it.

Atherosclerosis is a chronic inflammatory disease, resulting from hyperlipidemia and a complex interplay of many environmental, metabolic, and genetic risk factors. The unregulated macrophage uptake of cholesterol and lipids through modified forms of low-density lipoprotein (LDL), such as "OxLDL", transforms macrophages into "foam cells" to form the initial morphological lesion (the fatty streak). The modification of LDL not only enhances its uptake by macrophages, but also changes the natural structures of these otherwise ubiquitous molecules to generate a variety of modified lipids and proteins that represent highly immunogenic neo-determinants. For example, in ApoE-/- mice, autoantibody titers to epitopes on OxLDL are correlated with the extent of atherosclerosis. Similarly, oxidative stress on cellular membranes could also give rise to "oxidation-specific" epitopes and common autoantibodies. However, OxLDL is not uniform, but rather contains complex structures, ranging from a small conformational change in surface lipids to the breakdown of the peptide chain. Therefore, the immune responses to the variety of OxLDL and their association to atherosclerosis progression are very different. For example, phosphorylcholine (PC) is a natural component of phospholipids and exists in LDL and plasma membranes. "Natural" antibodies against PC can distinctively react to PC on bacteria, OxLDL and apoptotic cells, but not to those on unoxidized phospholipids, native LDL and viable cells, which suggests the broader role of such autoantibodies in maintaining the homeostasis of the host. While malondialdehyde-modified structures resemble more the exogenous changes and associate with advanced stage of lesion, they are more likely to associate with adaptive immunity.