Trends in Immunology
Volume 22, Issue 12, 1 December 2001, Pages 665-669
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Atherosclerosis as an autoimmune disease: an update

https://doi.org/10.1016/S1471-4906(01)02089-0Get rights and content

Abstract

Immunoinflammatory processes are discussed increasingly as possible pathogenic factors for the development of atherosclerosis. Here, we summarize the data on which we have built our immunological hypothesis of atherogenesis. This concept is based on the observation that almost all humans have cellular and humoral immune reactions against microbial heat-shock protein 60 (HSP60). Because a high degree of antigenic homology exists between microbial (bacterial and parasitic) and human HSP60, the ‘cost’ of immunity to microbes might be the danger of cross-reactivity with human HSP60 expressed by the endothelial cells of stressed arteries. Genuine autoimmunity against altered autologous HSP60 might trigger this process also.

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.

References (46)

  • G. Schett

    Macrophage-lysis mediated by autoantibodies to heat-shock protein 65/60

    Atherosclerosis

    (1997)
  • Q. Xu

    Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks and atherosclerotic plaques in young and aged human specimens

    Clin. Immunol. Immunopathol.

    (1990)
  • G. Millonig

    Analysis of the cellular composition of the arterial intima with modified en face techniques

    Lab. Invest.

    (2001)
  • W. Born

    Recognition of heat-shock proteins and γδ-cell function

    Immunol. Today

    (1990)
  • G. Wick

    The multi-factorial pathogenesis of autoimmune disease

    Immunol. Lett.

    (1987)
  • G. Wick

    Atherosclerosis, autoimmunity and vascular-associated lymphoid tissue

    FASEB J.

    (1997)
  • J. Buchner

    Supervising the fold: functional principles of molecular chaperones

    FASEB J.

    (1996)
  • A.D. Johnson

    Differential distribution of 70 kD heat-shock protein in atherosclerosis. Its potential role in arterial SMC survival

    Arterioscler. Thromb. Vasc. Biol.

    (1995)
  • Q. Xu

    Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat-shock protein 65

    Arterioscler. Thromb. Vasc. Biol.

    (1992)
  • J. George

    Enhanced fatty-streak formation in C57BL/6J mice by immunization with heat-shock protein 65

    Arterioscler. Thromb. Vasc. Biol.

    (1999)
  • M. Mayr

    Endothelial cytotoxicity mediated by serum antibodies to heat-shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat-shock proteins as a possible link between infection and atherosclerosis

    Circulation

    (1999)
  • Q. Xu

    Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis: clinical significance determined in a follow-up study

    Circulation

    (1999)
  • M. Mayr

    Atherogenic effects of chronic infections: the role of heat-shock protein 60 in autoimmunity

    Isr. Med. Assoc. J.

    (1999)
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