Physicians' Academy for Cardiovascular Education

The autoimmune concept of atherosclerosis

Literature -

The autoimmune concept of atherosclerosis

Grundtman et al, Current Opinion in Lipidology 2011, 22:000–000

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.


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).


Key points

  • All classical atherosclerosis risk factors can act as endothelial stressors provoking the simultaneous surface expression of HSP60 and adhesion molecules at known arterial predilection sites.
  • HSP60 can then act as a ‘danger signal’ for the immune system recognized by pre-existing innate and adaptive anti-HSP60 immunity.
  • T cells predominate over macrophages in early atherosclerotic lesions. An increased number of vascular-associated dendritic cells can be found in areas of hemodynamic stress and they may play a role in early tolerization against autoantigens.
  • oxLDL exert relatively low levels of stress on endothelial cell but are nevertheless the most common risk factor for atherosclerosis. oxLDL lead to foam cell formation at sites of primary inflammation/immunological reaction.
  • The importance of cholesterol and oxLDL in atherogenesis may be because of the fact that from an evolutionary viewpoint, people currently considered ‘normocholesterolemic’ are in fact hypercholesterolemic.


The authors concluded that their hypothesis that from an evolutionary viewpoint, plasma cholesterol levels currently is considered ‘normal’ are far too high in the majority of humans. Cholesterol – even as a relatively mild adhesion molecule and HSP60-inducing endothelial cell stressor – is a ubiquitous risk factor. If true, irrespective of their primary risk factor(s), most members of developed societies are at risk of developing fatty streaks and even atherosclerotic plaques, because of the presence of intimal inflammatory foci arising from pre-existing anti-HSP60 immunity.

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