S. Bhakdi

Institute of Medical Microbiology, University of Mainz

e-mail: makowiec@mail.uni-mainz.de

We present a novel explanation for the pathogenesis of atherosclerosis that obviates the need to search for a causative infectious agent and moreover indicates that oxidative processes are not decisive [1]. We show that LDL stranded in the subendothelium is transformed by enzymatic, nonoxidative modification to yield an entity that binds C-reactive protein, thus activating complement [2-5]. Degraded LDL simultaneously becomes a ligand for scavenger receptors, so that monocytes attracted to the lesions engulf the lipoprotein and transform to foam cells. HDL serves an essential role since it initiates the reverse cholesterol Transport from the foam cells out of the vessel wall. When LDL-deposition exceeds a critical limit, overactivation of complement and macrophages ensues, and this results in a chronic inflammation [6-8]. Atherosclerosis is thus a special form of an immunopathological disease that is triggered by activation of the archaic components of the immune system by altered self. We contend that tissue-deposited LDL is the sole cause of atherosclerosis; circumstances that promote insudation and trapping of the lipoprotein (e.g. hypertension, diabetes, homocysteinenemia) are risk factors. Several predictions arise. 1) Immune inhibition will counteract atherogenesis; 2) Immune overactivation will promote atherogenesis; 3) Antioxidants and antibiotics will not effectively prevent atherosclerosis; 4) Reduction of plasma LDL levels will prevent and even heal atherosclerosis. These predictions are essentially being fulfilled.

[1] Bhakdi, Ann. Med. 30: 503, 1998. [2] Seifert et al., J. Exp. Med. 172: 547, 1990. [3] Bhakdi et al., J. Exp. Med. 182: 1959, 1995. [4] Torzewski et al., Arterioscl. Thromb. Vasc. Biol. 18: 369, 1998. [5] Bhakdi et al., Arterioscl. Thromb. Vasc. Biol. 1999, in press. [6] Klouche et al., Arterioscl. Thromb. Vasc. Biol. 18: 1376, 1998. [7] Schmiedt et al., Arterioscl. Thromb. Vasc. Biol. 18: 1790. 1998. [8] Klouche et al., Arterioscl. Thromb. Vasc. Biol. 19: 784, 1999.