Immune reactions against oxidatively modified low density lipoproteins in patients with atherosclerosis and healthy individuals

Abstract

Immune-inflammatory mechanisms are involved in the development of atherosclerosis, and immune reactions against oxidatively modified LDL have received special interest. In the present study, we have investigated the effect of oxLDL on the stimulation of peripheral blood mononuclear cells (PBMC) to increased DNA-synthesis and cytotoxicity and the nature and the prevalence of antibodies against oxLDL in healthy individuals and in patients with atherosclerosis.

Human PBMC exposed to low concentrations of oxLDL secrete factors that stimulate endothelial cells to the expression of the cellular adhesion molecules ICAM- 1, VCAM- 1 and ELAM- 1, whereas native LDL had no such effect. Exposure of endothelial cells directly to oxLDL did not influence the expression of adhesion molecules. Incubation of endothelial cells with conditioned medium from PBMC grown in the presence of oxLDL resulted in a three-fold increase in the binding of the monocytoid cell line U937.

T-cells are activated by oxLDL to increased DNA-synthesis and expression of HLA-DR and CD25. This activation is dependent on antigen presenting cells and is MHC class II restricted. Human peripheral T-cells are also activated to a specific cytotoxic response against autologous PHA activated PBMC which have been pre-incubated with oxLDL. The cytotoxic reaction is mainly exerted by CD8+ enriched cells and is inhibited by monoclonal antibodies against HLA class I.

When PBMC are incubated in autologous serum with oxLDL, the cells from healthy individuals are activated to increased DNA-synthesis whereas cells from patients with CAD are not. Incubation of cells from patients in serum from healthy individuals partly reversed this inhibition and sera from patients could transfer the inhibition to cells from healthy individuals. The inhibitory factor present in patients sera was localised to the LDL fraction. Inhibition was antigen specific and PPD-induced stimulation was not impaired.

Antibodies against oxLDL are present in both patients with atherosclerosis and healthy individuals. The type of antibodies is IgG2, IgG3, IgA and/or IgM. The antibodies have a high affinity for antigen and increase the uptake of oxLDL in the monocytoid cell line U937. The level of antibodies is related to the risk of developing myocardial infarction. In a prospective study, 50 years old healthy men were followed for 20 years. The levels of IgG and IgA antibodies were related to future myocardial infarction and death.

A retrospective study of patients with premature peripheral vascular disease showed that patients had increased levels of antibodies against oxLDL. The levels of antibodies was the variable that discriminated best between patients and controls. There was a tendency for higher levels of antibodies against oxLDL in patients with more extensive atherosclerotic lesions.