Atherosclerosis is a principal cause of death in the Westernized world. Previously, it was thought to be a disease primarily involving lipid accumulation in the arterial walls. The inflammatory cells found at the sites of fatty streaks as well as in the more advanced lesions were not considered to be principally responsible for the disease. A different view of atherosclerosis has emerged subsequently. Current concepts of this disease include involvement of the immune system and chronic inflammation as crucial elements in the initiation of endothelial cell dysfunction, in fatty streak formation, and in development of advanced lesions and eventual vessel rupture (for a recent review, see ref. 1). Atherosclerosis can now be viewed as a problem of wound healing and of chronic inflammation. Numerous reports in the past few years have demonstrated clearly that migratory immune cells, including monocytes and T lymphocytes, are key cellular elements at all stages of atherosclerosis. Most exciting and relevant to atherosclerosis as a disease of chronic inflammation are papers by Schönbeck et al.(2) and Lutgens et al.(3) appearing in this issue of PNAS. These research groups clearly show that disruption of the CD40–CD40 ligand (L) system, a key mediator of cell communication in the immune system, prevents progression of established atherosclerotic lesions to more advanced unstable lesions. This evidence, coupled with recent studies showing that disruption of the CD40–CD40L system can retard the initiation of arterial plaque formation, provides compelling evidence for the role of chronic inflammation and elements of the immune response in atherosclerosis. Moreover, these investigations identify CD40–CD40L as key regulators of this process and recognize them as potentially important therapeutic targets.

CD40 is a cell membrane-spanning protein of 50 kDa that was found originally on B lymphocytes (see ref. 4 for review). It is responsible for B lymphocyte activation and serves several key functions. Engagement of B lymphocyte CD40 by its ligand (commonly called CD40L but offi-