The autoimmune concept of atherosclerosis

Abstract

Purpose of review: This review summarizes the recent data on the 'Autoimmune Concept of Atherosclerosis', according to which the first stage of this disease is due to an autoimmune reaction against arterial endothelial cells expressing heat shock protein 60 (HSP60) and adhesion molecules when stressed by classical atherosclerosis risk factors. Special emphasis is put on oxidized low-density lipoproteins as early endothelial stressors.

Recent findings: Plasma cholesterol and LDL levels considered 'normal' by the medical community are possibly too high from an evolutionary viewpoint. The proinflammatory milieu at sites of early atherosclerotic lesions could be conducive to oxidation of LDL in situ. LDL oxidation can also take place at nonvascular sites or in the circulation under general proinflammatory conditions explaining its proatherosclerotic role in 'normocholesterolemic' individuals.

Summary: We hypothesize that the plasma cholesterol and LDL levels currently considered normal are evolutionarily too high. Cholesterol and/or oxidized low-density lipoprotein, even as a mild HSP60-inducing endothelial stressor, function as a ubiquitous risk factor. If this hypothesis is true, most members of developed societies might be at risk to develop atherosclerotic plaques at anti-HSP60-immunity-triggered intimal inflammatory foci, irrespective of the primary risk-factor(s).

Figure 1. The ‘autoimmune concept of atherosclerosis’ is based on the well proven fact that all healthy human beings develop protective immunity against microbial (bacterial and parasitic) heat shock protein 60 as well as bona fide physiological autoimmunity against biochemically modified autologous HSP60 produced by and released from stressed and/or disintegrated cells

Heat shock protein 60 (HSP60) of various bacterial species displays over 95% sequence homology, and there is over 50% homology at the DNA and protein levels between prokaryotic and eukaryotic (including human) HSP60. When arterial endothelial cells are stressed by classical atherosclerosis risk factors, they simultaneously express HSP60 and adhesion molecules (ICAM-1, VCAM-1, and ELAM-1) on their surface, making them target cells for pre-existing beneficial cellular and humoral anti-HSP60 immunity. HSP60-reactive T cells invade the arterial intima and initiate the first inflammatory stage of atherosclerosis, which is followed by monocytes/macrophages and vascular smooth muscle cells. Anti-hHSP60 (auto)antibodies accelerate and perpetuate the disease. This first inflammatory stage of atherosclerosis is still reversible. However, in the continued presence of risk factors, severe advanced atherosclerosis (plaques) develops with deleterious consequences, such as myocardial infarction, stroke, and claudication. Thus, atherosclerosis is ‘the price we pay for pre-existing anti-HSP60 immunity’ if we maltreat our arteries by exposing them to classical risk factors. , HSP60; , altered HSP60; , cell-specific proteins; , adhesion molecules; , T cell; , anti-hHSP60 antibody. Partly adapted from Servier Medical Art.

Figure 2. All classical atherosclerosis risk factors studied in our laboratory so far act as endothelial cell stressors leading to the simultaneous surface expression of heat shock protein 60 and adhesion molecules (ICAM-1, VCAM-1, and ELAM-1)

An approximate ranking of the respective stressor potential on protein and/or RNA levels is given. All data in the figure relate to the in-vitro treatment of human umbilical vein endothelial cells (HUVECS). The invivo effects of mechanical stress and bacterial lipopolysaccharide (LPS) have been shown in rats and rabbits, respectively. In several instances, comparative results were obtained with human arterial vs. venous endothelial cells showing a higher susceptibility of the former for the stressor effect of risk factors.

Figure 3. Compared with venous endothelial cells, arterial endothelial cells are exposed to higher mechanical stress because of the arterial blood pressure and flow conditions

This is especially true at branching points subjected to an increased turbulent hemodynamic shear stress predisposing these sites for the development of atherosclerotic lesions. (1–2) Classical atherosclerosis risk factors first act as endothelial stressors leading to the simultaneous expression of heat shock protein 60 (HSP60) and adhesion molecules. (3) HSP60-reactive T cells adhere to stressed endothelial target cells and transmigrate into the intima with its pre-existing network of Langerhans-like dendritic cells that act as antigen-processing and antigen-presenting cells similar to the situation in the skin. Whether sensitization of T cells attracted to these sites occurs in situ or in the draining lymph nodes remains to be seen. (4–6) Whether LDL oxidation occurs already in the circulation or in the mononuclear cell infiltrate in the intima by oxidative stress is still a matter of debate. It is, however, well proven that oxLDL itself acts as an endothelial stressor leading to HSP60 expression. Furthermore, activated platelets can bind LDL in the circulation, adhere to endothelial cells, and mediate monocyte attachment. Monocytes (loaded or not with LDL) can then migrate into the primary T-cell-dominated inflammatory intima where they can differentiate into macrophages. In a further step, smooth muscle cells (SMCs) from the media are attracted into the intima. Macrophages, dendritic cells, and vascular SMCs possess scavenger receptors, which enable them to take up oxLDL and transform into foam cells. (7) T cells initiate the disease, and local immune reaction creates a microenvironment with an altered balance of pro-inflammatory and anti-inflammatory mediators. (8) (Auto)antibodies accelerate and perpetuate the disease. (9) Continuing presence of risk factors led to endothelial damage. Partly adapted from Servier Medical Art.