Trends in Immunology
OpinionAtherosclerosis as an autoimmune disease: an update
Section snippets
The heat-shock protein families
HSPs are expressed by prokaryotic and eukaryotic cells under physiological conditions or in response to stress (e.g. heat, toxins or mechanical stress). HSPs are classified into various families according to their molecular weight; the main families are the 100 kDa, 70 kDa, 60 kDa and low-molecular-weight families, which fulfill a wide variety of physiological functions in protein folding, cellular signaling and protein degradation. Under conditions of stress, some HSPs associate with other
Evidence for the pathogenic role of HSP60 in animal models
Immunization of normocholesterolemic rabbits with Freund's complete adjuvant (normally used to increase the immune response to a given antigen), consisting of mineral oil and heat-killed mycobacteria, leads to the development of atherosclerotic lesions at the known predilection sites in the aorta. The same effect can be observed after immunization with recombinant mHSP65 (Ref. 9), which forms a high percentage of the whole protein content of mycobacteria. Foam cells are still lacking at this
HSP60 and human atherosclerosis
Within the framework of the Bruneck Study, a prospective population-based survey on the pathogenesis of atherosclerosis, involving almost 900 men and women aged 40–80 years who have been followed for >10 years since 1990, we were able to show that – as expected owing to prior infections or vaccinations – all participants produced anti-bacterial (anti-mHSP65) antibodies (Abs) at levels that gave a significant positive correlation with the presence of sonographically visible atherosclerotic
HSP60 and in vitro experiments
We have shown that a given stressor (e.g. heat, TNF-α or oxygen radicals) induces the simultaneous expression of HSP60 and adhesion molecules [e.g. intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and endothelial–leukocyte adhesion molecule 1 (ELAM-1)] by ECs (Ref. 25). In this respect, it is important to emphasize that arterial ECs have a lower threshold than venous ECs for the effect of various stressors (i.e. classical atherosclerosis risk factors,
Local aspects of the arterial wall – immunohistochemical studies
In fully blown atherosclerotic lesions, granular Ig deposits with co-distributed complement components 32, as well as an increased expression of C3b receptors (CR1) and C3bi receptors (CR3) on macrophages, can be demonstrated 33. In contrast to the current dogma 34, 35, T cells, rather than macrophages, are the prevailing mononuclear cells in the intima infiltrate at the first stage 2, 36, 37. A considerable percentage of these T cells is activated (HLA-DR+CD25+) 38. CD4+ T cells prevail over
Conclusion
Fig. 2 summarizes our concept of an autoimmune, inflammatory pathogenesis of the earliest stages of atherosclerosis. Microorganisms (bacteria, viruses and parasites) display a variety of antigens, including HSP60, which shows a high degree of evolutionary conservation. All animals and humans have humoral and cellular immunity against microbial HSP60 that – together with the immune response against non-HSP60 antigens – confers protection against infection. Therefore, induction of tolerance
Acknowledgements
We acknowledge the cooperation of all the authors from our and collaborating groups whose work is cited in the present review. This work was supported by grants from the Austrian Science Fund (#P-12213 and #P-14741). H.P. is a recipient of a PhD fellowship from the Austrian Academy of Sciences.
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