Immunity to HSP60 in incipient atherosclerosis

Cardiovascular diseases are still the killer number one in the developed world. Among these diseases, atherosclerosis is the most prominent representative leading to fatal consequences such as stroke, myocardial infarction and peripheral vascular occlusion. It has long been considered as a dogma that whitish cushion-like lesions (fatty streaks) in the innermost layer of arteries (intima) constitute the earliest stages of atherosclerosis that later proceed into complicated advanced lesions, so-called atherosclerotic plaques, when atherosclerosis risk- factors continue to be present. However, in recent years it has become clear that the earliest stages of atherosclerosis are of an inflammatory-immunologic nature consisting of mononuclear cell infiltrations in the intima. Direct evidence from animal experiments and indirect conclusions from investigations in human patients suggested that antibodies and T cells reacting against the stress protein heat shock protein 60 (HSP60) are instrumentally initiating atherosclerosis. The phylogenetically highly conserved HSP60 molecule shows a high degree of sequence homology from pro- to eukaryontes. Since every healthy person has protective humoral and cellular immunity against microbial HSP60 as well as against biochemically altered autologous HSP60 released upon cellular damage the expression of HSP60 by stressed ECs may have to be "paid for" by danger of an immunologic crossreactivity entailing the early inflammatory atherosclerotic lesions. We have shown for most classical atherosclerosis risk-factors that they act as endothelial stressors and thus inducers of HSP60 expression in the earliest stages of atherogenesis. The immunisation of rabbits or mice with HSP60 leads to the development of atherosclerosis the severity of which is increased by additional high serum cholesterol levels. Passive transfer of HSP60-specific T cells and antibodies in the murine system have been shown to lead to the development of atherosclerosis especially if accompanied by high serum cholesterol levels. Furthermore, induction of oral tolerance against HSP60 can prevent the development of atherosclerosis in HSP60 immunised mice. T cells extracted from advanced human atherosclerotic lesions have a preferential reaction with HSP60, significantly higher than that of T cells obtained from the peripheral blood. The present project is aimed at providing a definitive answer to the question if T cells in the earliest, clinically still inapparent inflammatory stage of atherosclerosis in human patients react against HSP60 and if they already display a restricted T cell receptor repertoire at this stage that we have demonstrated for late, complicated lesions. The answer to this question would provide a crucial basis for a new evidence-based concept for the prevention and treatment of atherosclerosis.

Cardiovascular diseases are still the killer number one in the developed world. Among these diseases, atherosclerosis is the most prominent representative leading to fatal consequences such as stroke, myocardial infarction and peripheral vascular occlusion. It has long been considered as a dogma that whitish cushion-like lesions (fatty streaks) in the innermost layer of arteries (intima) constitute the earliest stages of atherosclerosis that later proceed into complicated advanced lesions, so-called atherosclerotic plaques, when atherosclerosis risk- factors continue to be present. However, in recent years it has become clear that the earliest stages of atherosclerosis are of an inflammatory-immunologic nature consisting of mononuclear cell infiltrations in the intima. Direct evidence from animal experiments and indirect conclusions from investigations in human patients suggested that antibodies and T cells reacting against the stress protein heat shock protein 60 (HSP60) are instrumentally initiating atherosclerosis. The phylogenetically highly conserved HSP60 molecule shows a high degree of sequence homology from pro- to eukaryontes. Since every healthy person has protective humoral and cellular immunity against microbial HSP60 as well as against biochemically altered autologous HSP60 released upon cellular damage the expression of HSP60 by stressed ECs may have to be "paid for" by danger of an immunologic crossreactivity entailing the early inflammatory atherosclerotic lesions. We have shown for most classical atherosclerosis risk-factors that they act as endothelial stressors and thus inducers of HSP60 expression in the earliest stages of atherogenesis. The immunisation of rabbits or mice with HSP60 leads to the development of atherosclerosis the severity of which is increased by additional high serum cholesterol levels. Passive transfer of HSP60-specific T cells and antibodies in the murine system have been shown to lead to the development of atherosclerosis especially if accompanied by high serum cholesterol levels. Furthermore, induction of oral tolerance against HSP60 can prevent the development of atherosclerosis in HSP60 immunised mice. T cells extracted from advanced human atherosclerotic lesions have a preferential reaction with HSP60, significantly higher than that of T cells obtained from the peripheral blood. The present project is aimed at providing a definitive answer to the question if T cells in the earliest, clinically still inapparent inflammatory stage of atherosclerosis in human patients react against HSP60 and if they already display a restricted T cell receptor repertoire at this stage that we have demonstrated for late, complicated lesions. The answer to this question would provide a crucial basis for a new evidence-based concept for the prevention and treatment of atherosclerosis.