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.