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| This article will appear in a forthcoming issue of Trends in Immunology. | |
Abstract
Atherosclerosis as an infectious disease
Of the many infectious agents claimed to affect AS plaque deposition, Chlamydia pneumoniae probably has the strongest association (S. Gupta, London, UK). A close relationship exists between infection, antibody titers, heat shock protein (HSP)-60 production, and MI, CVA and peripheral vascular disease (PVD). T-cell reactivity to the C. pneumoniae antigens found in AS plaques has been demonstrated. Other major AS-associated pathogens include Helicobacter pylori, Epstein-Barr virus and cytomegalovirus. Pathogenic mechanisms have been established for some of these, for example, cytomegalovirus gene proliferation in smooth-muscle cells. It is suggested that any infectious agent, and especially multiple chronic infections (e.g. chronic bronchitis or periodontitis), could result in accelerated AS formation, as confirmed recently by experimental animal models. S.E. Epstein (Washington, WA, USA) suggested that chronic infections could contribute to the acceleration of AS development, either by nonspecific [hypercoagulability, increased adhesion molecule and elevated C-reactive protein (CRP) levels] or specific (induction of HSP-60 expression and resultant anti-HSP-60 antibody production) mechanisms.
Atherosclerosis as an Inflammatory Disease
It was noted by P. Libby (Boston, MA, USA) that high serum CRP levels correlate with an increased risk of AS and thus, an increased incidence of MI, CVA, PVD and ultimately mortality. CRP might mediate its pathogenic role through the induction of expression of adhesion molecules and chemokines (e.g. macrophage chemoattractant protein-1), resulting in an attractive milieu for the recruitment of circulating monocytes to the arterial wall (E.T.H. Yeh, Houston, TX, USA). Thus, the efforts of pharmaceutical companies are being directed towards discovering compounds that lower CRP levels. Other acute phase proteins (e.g. serum amyloid protein, fibrinogen, troponin and soluble adhesion molecules) might also play a part in the acceleration of AS plaque formation.
Atherosclerosis as an Autoimmune Condition
AS fulfills the four Witebsky and Rose criteria for an autoimmune condition (Box 1), and several autoantigens and their respective autoantibodies are considered to be associated with AS (D. Harats, Tel-Hashomer, Israel) [2].
Oxidized LDL
Oxidized (ox) LDL is the prime candidate for an autoantigen. It is incriminated in foam-cell generation through uptake by the unregulated scavenger receptors on macrophages, and antibody titers correlate not only with MI, CVA and predictions of progression of coronary AS, but also with the restenosis of angioplastic vessels (T. Koike, Hokkaido, Japan). Anti-oxLDL antibodies also enhance oxLDL uptake by monocytes. However, repeated immunizations of rabbits and mice with oxLDL resulted in the generation of anti-oxLDL antibodies but a reduction in AS. The differences between protective and pathogenic antibodies have yet to be elucidated (J.L. Witztum, San Diego, CA, USA).
HSP-60
G. Wick et al. (Innsbruck, Austria) was the first to claim that HSP-60 is involved in AS (reference 3). In carotid ultrasound studies, anti-HSP-60 antibody titers correlate with the degree of AS. The increase in antibody titre could result from turbulence damage to bifurcated arteries or infectious agents (e.g. C. pneumoniae) releasing immunogenic HSP-60. T-cell lines cultured from plaques proliferate when exposed to HSP-60, and both autoantibodies and autoantigens can be found in the plaque. Finally, the active immunization of rabbits and apolipoprotein-E or low-density lipoprotein (LDL)-receptor knockout mice with HSP-60 leads to accelerated plaque formation.
β-2-glycoprotein-I
β-2-glycoprotein-I (β2GPI) is a normal anti-coagulant glycoprotein synthesized by the liver that behaves as an anti-atherogenic agent. It is found in AS plaques (J. George, Tel-Aviv, Israel), and is the target antigen in APS, another condition intimately associated with AS (M. Khamashta, London, UK). Antibodies to β2GPI can be found in SLE and APS, and post-infection (O. Vaarala, Helsinki, Finland), and their titer correlates with the extent of AS. In in vitro studies they enhance the uptake of oxLDL by macrophages by preventing the β2GPI-mediated inhibition of oxLDL uptake by scavenger receptors. In a recent classical study [4], accelerated AS plaque formation was induced in LDL-receptor-deficient mice by the passive transfer of lymphocytes from the lymph nodes and spleens of mice actively immunized with β2GPI.
Treatment Strategies
AS is an infectious and inflammatory condition, involving both humoral and cellular autoimmune mechanisms in the accelerated formation of the AS plaque It seems that autoimmune-accelerated AS is caused by various autoantigenic stimuli as a result of multiple humoral and cellular infections. Not surprisingly, this process can be manipulated very effectively by immune modulation (Y. Shoenfeld, Tel-Hashomer, Israel). In many patients, the disease can be treated by long-term antibiotic intake (i.e. azythromycin) or statin therapy. The latter has been found to affect AS beyond the known cholesterol-reducing ability of statins (F. Mach, Geneva, Switzerland); decreased MHC class II and adhesion molecule expression on the vascular wall is thought to be important. AS is also reduced by CD3+ lymphocyte depletion and anti-CD40 antibody therapy. Similarly, intravenous Ig (IVIg) therapy leads to a 40% reduction in the extent of plaque formation. It is probable that IVIg therapy acts in part by anti-idiotypic antibodies against oxLDL, nonspecific blockade of macrophages and infusion of natural protective anti-oxLDL antibodies. In the near future, various vaccines, tolerance-induction protocols and immunomodulators should be routinely incorporated into the prevention and therapy of cardiovascular diseases.
Immunity, Atherosclerosis and Cardiovascular Disease - a report of the British Society for Immunology meeting held in Harrogate, U.K., on December 7, 2000. From Trends in Immunology, 2001, 22:4:180-181.
Infection and Heart Disease: The Current Situation - a short review of how infectious diseases might promote heart disease. From Trends in Molecular Medicine, 2001, 7:2:43-44.
The Role of Chlamydia pneumoniae in Atherosclerosis - Recent Evidence From Animal Models - a review of recent studies that have focused on the use of animal models to examine the putative role of C. pneumoniae infection. From Trends in Microbiology, 2000, 8:6:255-257.
Atherosclerosis and the Immune System - Editor's Correspondence from the February 8, 1999 issue of Archives of Internal Medicine, 159: 315-315.
Two recent papers in The Scientist focus on Atherosclerosis: The Biological Basis for Atherosclerosis and Hot Papers in Heart Disease.
Arteriosclerosis, Thrombosis, and Vascular Biology - a journal from the American Heart Association, now available online.
National Heart, Lung, and Blood Institute - offers extensive information for both the public and health professionals.
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