ATHEROSCLEROSIS AND AUTOIMMUNITY

The possible involvement of immunological mechanisms in the pathogenes is of atherosclerosis has been suggested intermittently since the earl y 1970s. Both humoral and cellular mechanisms have been proposed to pa rticipate in the onset and/or progression of atheromatous lesions, but the theories postulating the involvement of autoantibodies and immune complexes have met with considerable experimental support. Modified l ipoproteins, particularly different forms of oxidized LDL, have been r eported to elicit humoral immune responses in both experimental animal s and humans. Oxidized LDL has been demonstrated in atheromatous lesio ns, anti-oxidized LDL antibodies have been detected in circulation and in atheromatous plaques, and immune complexes formed with LDL and ant i-LDL have been isolated from the serum of patients with manifestation s of atherosclerosis. In addition, in vitro-formed LDL-IC and IC isola ted from patients have been demonstrated to cause intracellular accumu lation of cholesteryl esters (CE) in human macrophages and fibroblasts . The accumulation of CE in macrophages exposed to LDL-IC is unique to this type of IC and is associated with a paradoxical overexpression o f the native LDL receptor and with increase synthesis and release of i nterleukin 1 and TNF-alpha. The release of these cytokines in the sube ndothelial space may have a significant role in promoting the interact ion of endothelial cells with mononuclear cells, causing endothelial c ell damage directly or indirectly, and also in inducing smooth muscle cell proliferation. Thus, several lines of evidence suggest that humor al autoimmunity may play a significant role in the pathogenesis of ath erosclerosis. (C) 1994 Academic Press, Inc.