LDL-CONTAINING IMMUNE-COMPLEXES AND ATHEROSCLEROSIS IN DIABETES

It has been proposed that both humoral and cellular mechanisms partici pate in the onset and/or progression of atherogenesis. The role of aut oantibodies and immune complexes (ICs) in this process has recently re ceived a considerable amount of support, Modified lipoproteins, partic ularly different forms of oxidized LDL, have been reported to elicit h umoral immune responses in both experimental animals and humans, In di abetes, the effects of glycation and oxidation are interwoven, and inc reased glycation results not only in increased susceptibility of LDL t o oxidation but also in increased formation of glycoxidation products or advanced glycosylation end products, Modified LDL triggers the form ation of autoantibodies, and both modified LDL and antibodies against modified LDL have been detected in circulation and in atheromatous pla ques, Also, ICs containing modified LDL have been isolated from the se rum of diabetic and nondiabetic patients,vith manifestations of athero sclerosis, In addition, it has been demonstrated that in vitro-formed LDL-IC and IC isolated from patients are taken up mainly through Fc(ga mma) receptors and cause intracellular accumulation of cholesterol est ers (CEs) in macrophages and smooth muscle cells, The accumulation of CEs in macrophages exposed to LDL IC is unique to this type of IC; it is associated with a paradoxical increase in LDL receptor expression a nd with overexpression of scavenger receptors, LDL-containing ICs are also responsible for stimulating the release by human macrophages of i ncreased amounts of superoxide radicals as well as inducing increased synthesis and release of interleukin-1 beta and tumor necrosis factor alpha. The release of cytokines in the subendothelial space has, among other effects, the ability to induce endothelial cell damage directly or indirectly, increase expression of adhesion molecules, promote the interaction of endothelial cells with mononuclear cells, and induce s mooth muscle cell proliferation, It seems very likely, therefore, that humoral autoimmunity plays a significant role in the pathogenesis of atherosclerosis in diabetes.