Immune mechanisms of atherosclerosis in diabetes mellitus.
It was recently proposed that the increased levels of modified lipoproteins in diabetic patients may be responsible for the accelerated development of macrovascular complications associated with the disease. Modified lipoproteins are believed to induce the transformation of macrophages into foam cells and, in some cases, to induce endothelial cell damage. In addition, modified lipoproteins trigger an immune response leading to the formation of antibodies and then to the formation of LDL-containing immune complexes. In this review, we summarize the evidence linking LDL glycation and oxidation with intracellular accumulation of cholesterol esters and foam-cell formation, and we discuss their potential for inducing an autoimmune response and the formation of lipoprotein-containing immune complexes. The formation of LDL-ICs seems particularly significant, because these ICs are avidly taken up by macrophages through their Fc receptors and induce not only massive intracellular accumulation of CE but also a paradoxical increase in LDL-receptor expression. Our experimental data suggest that the uptake of LDL-IC is facilitated by RBC adsorption, in agreement with the role of RBC in the adsorption of circulating IC and their delivery to phagocytic cells. In addition, macrophages are activated when ingesting LDL-IC and release IL-1 beta and TNF-alpha, which can contribute to the initiation and progression of an atheromatous lesion by several mechanisms. Although it is difficult to envisage how LDL-IC could initiate an endothelial lesion, it is easy to speculate about their role as cofactors in the initiation and progression of the atherosclerotic process.
Lopes-Virella
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MF
Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina.
Virella
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G
D000936:Antigen-Antibody Complex / Q000502:physiology; D001161:Arteriosclerosis / Q000276:immunology*; D003925:Diabetic Angiopathies / Q000276:immunology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000276:immunology; D008262:Macrophage Activation / Q000502:physiology
D000936:Antigen-Antibody Complex; D008077:Lipoproteins, LDL