The role of heat shock proteins in atherosclerosis

Key Points

  • Humoral and cellular immunity against bacterial and parasitic heat shock protein (HSP)60 is normal, but bona fide autoimmunity is also possible against chemically altered autologous HSP60 released by damaged or dying cells

  • Phylogenetically highly conserved microbial and mammalian HSP60 shows 55% sequence homology and, therefore, is potentially cross-reactive in people with pre-existing HSP60 immunity

  • In experimental models, immunization of normocholesterolaemic animals with bacterial HSP60 leads to atherosclerosis, and this process can be aggravated by increasing blood cholesterol levels

  • Lifelong arterial stress owing to higher blood pressure and different flow conditions compared with veins lowers the threshold for HSP60 expression upon exposure to any classic risk factor for atherosclerosis

  • HSP60 and adhesion molecules expressed by arterial endothelial cells can be used as a target for molecular imaging of early atherosclerotic lesions

  • Immunological tolerance induced by oral or nasal application of HSP60 protects against atherosclerosis; identification of HSP60-derived potentially atherogenic epitopes in mice and humans could lead to the development of vaccines

Abstract

Atherosclerosis is a chronic, multifactorial disease that starts in youth, manifests clinically later in life, and can lead to myocardial infarction, stroke, claudication, and death. Although inflammatory processes have long been known to be involved in atherogenesis, interest in this subject has grown in the past 30–40 years. Animal experiments and human analyses of early atherosclerotic lesions have shown that the first pathogenic event in atherogenesis is the intimal infiltration of T cells at arterial branching points. These T cells recognize heat shock protein (HSP)60, which is expressed together with adhesion molecules by endothelial cells in response to classic risk factors for atherosclerosis. Although these HSP60-reactive T cells initiate atherosclerosis, antibodies to HSP60 accelerate and perpetuate the disease. All healthy humans develop cellular and humoral immunity against microbial HSP60 by infection or vaccination. Given that prokaryotic (bacterial) and eukaryotic (for instance, human) HSP60 display substantial sequence homology, atherosclerosis might be the price we pay for this protective immunity, if risk factors stress the vascular endothelial cells beyond physiological conditions.

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Figure 1: The autoimmune concept of atherosclerosis.
Figure 2: HSP60-induced atherosclerosis.
Figure 3: Important HSP60 epitopes identified in human atherosclerosis.
Figure 4: PET–CT in vivo molecular imaging of endothelial HSP60 expression.
Figure 5: Plaque formation after immunization with mycobaterial HSP65 in mice prone to atherosclerosis.

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Acknowledgements

The authors acknowledge funding from: the European Union FP7Large-Scale Integrated Project, Novel Approaches to Reconstitute Normal Immune Function at Old Age (TOLERAGE HEALTH-F4-2008-202156), coordinated by G.W. and C.G.; the Austrian Research Fund (FWF) Grant P198810-B05 to G.W.; the Medizinische Forschungsförderung Innsbruck MFI (Project 9443) to M.C.W.; the Lore and Udo Saldow-Donation to G.W. and B.J.; the Tiroler Wissenschaftsfonds Project “The role of Vascular Associated Lymphoid Tissue (VALT) in the Development of Atherosclerosis–Inside Out or Outside In” to B.J.; and the Translational Research Project “T-Oral” to G.W. and M.B.

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All the authors researched data for the article, provided substantial contributions to discussions of its content, wrote the article, and reviewed/edited the manuscript before submission.

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Correspondence to Georg Wick.

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Supplementary information

Supplementary Table 1

Amino acid sequence of heat shock proteins and their reactive T-cell and B-cell epitopes from human samples (DOCX 86 kb)

Supplementary Table 2

Induction and tolerization of atherosclerosis with heat shock proteins and their reactive T-cell epitopes in experimental animals (DOCX 38 kb)

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Wick, G., Jakic, B., Buszko, M. et al. The role of heat shock proteins in atherosclerosis. Nat Rev Cardiol 11, 516–529 (2014). https://doi.org/10.1038/nrcardio.2014.91

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