Autoimmunity to heat shock proteins in atherosclerosis

Based on data obtained from animal experiments and investigations in man, we have developed a new "immunological" hypothesis for the development of atherosclerosis. This concept proposes that the first stage of this disease is of an inflammatory, immunological type. Humoral and cellular immune reactions against certain types of stress proteins, the so-called heat shock proteins (hsp) 65/60 seem to play an important initiating role in atherogenesis. Stress proteins are phylogenetically highly conserved. Thus, a homology at the DNA and protein level of over 50% exists between hsp 65 of Mycobacterium tuberculosis, hsp 60 of Escherichia coli (GroEl) and the mammalian homologue hsp 60. Immune reactions against bacterial hsp 60 are essential to protect an organ ism from infection, This protection has, however, to be "paid for" with the risk of cross-reactions to autologous hsp 60. Hsp 60 and adhesion molecules are expressed by endothelial cells at those sites of the arterial vascular tree that are subject to major haemodynamic stress (e.g., the aortic arch and the branching of larger vessels). Pre-existing hsp 65/60-reactive T cells and antibodies, respectively, are able to react with these stressed endothelial cells and mediate the initial lesion. Protracted influence of these risk factors, especially high blood pressure and chemically modified (e.g., oxidized) low-density lipoproteins then lead to the development of classical atherosclerotic lesions, ranging from fatty streaks to fully blown plaques. Immunization of normocholesterolemic rabbits with recombinant hsp 65 leads to mononuclear cell infiltration at these predilection sites that can progress to classical atherosclerotic lesions (including foam cells) if the animals receive, in addition, a cholesterol-rich diet.