by Jacob George, Dror Harats, and Yehuda Shoenfeld (member of AARDA Scientific Advisory Board), of Tel Hashomer, Tel-Aviv University, Tel-Aviv, Israel Atherosclerosis is a histopathological term that refers to the narrowing of arterial blood vessels caused by fat deposition. The consequences of this process are limitation to blood flow, culminating in myocardial infarctions, stroke, and other end organ damages.
Atherosclerosis that was formerly considered an "inert" process is gradually perceived as a dynamic disorder in which immune system components appear to play a major role. Thus, T lymphocytes, macrophages (progenitors of the foam cells and fatty streaks), as well as MHC expressing cells (endothelial and smooth muscle cells) are present and functionally operate in the vicinity of the atherosclerotic plaque. These findings, combined with the ones showing the presence of other humoral mediators (cytokines, chemokines, and growth factors) with the atheroma, have led to the conceptual paradigm of atherosclerosis as an inflammatory condition initially coined by Russell Ross.
A further extension of this concept that has been developed by several laboratories in the past decade holds that autoimmunity to plaque components/molecules is capable of altering the "fate" of the plaque. This may well occur through classical mechanisms by which autoimmune diseases develop, such as altered self or molecular mimicry.
Modified forms of host lipoproteins constitute the initial example of the implementation of the autoimmune concept to the evolution of the plaque. Thus, when self-lipoproteins are being modified by processes such as oxidation, they result in tolerance breakdown by the host and a subsequent establishment of autoimmunity (altered self). Anti-oxidized LDL antibodies are a "signature" of this tolerance breakdown, and clinical trials have shown their association with atherosclerosis and their positive predictive value with respect to development of atherosclerotic complications. Interestingly, however, induction of anti-oxLDL antibodies in atherosclerosis-prone animals by active immunization with oxLDL have been shown to be associated with reduced plaque formation. These findings that were recently reported by several groups, including ours, suggests that anti-oxLDL antibodies may stand as active participants rather than innocent bystanders.
Heat shock protein 60/65 is an additional example of candidate triggering autoantigen. These highly conserved proteins, initially programmed to afford host protection, can, under certain conditions, result in autoimmunity. Thus, it is thought that infectious borne HSPs result in a respective immune response by the host, which becomes autoimmune as it turns around to target self-HSPs due to the structural resemblance of host to foreign proteins. Here, molecular mimicry is the mechanism by which autoimmunity is operable. Indeed, support for this hypothesis is provided by studies from G. Wick laboratory as well as ours, showing that immunization of rabbits and mice with recombinant HSP65 results in enhanced atherogenesis.
We have recently pointed to an additional autoantigen which may well influence plaque size and composition by a mechanism that is likely to resemble HSPs. B2-glycoprotein I (B2GPI) is a native self-protein that has been found to evoke humoral autoimmunity in lupus patients and subclassify a distinct patient population with procoagulant tendency. These patients are referred to as having the antiphospholipid syndrome and indeed suffer from premature atherosclerosis. By immunization of mice against this protein and raising a respective immune response, we have proposed that B2GPI autoimmunity is likely to play a role in atherogenesis. the resultant accelerated atherosclerosis is transferable by lymphocytes reactive with B2GPI, providing a solid evidence for the operability of autoimmune mechanisms in atherogenesis.
In conclusion, the candidate autoantigens that are likely to play a role in influencing atherosclerotic plaque formation are probably larger than yet recognized. Other than aiding in understanding the natural progression of the atheroma and predicting its rate of progression, this concept opens the door for a line of novel means of selective immunomodulation which may represent additional treatment strategies.
Researchers may address correspondence and reprint requests to Yehuda Shoenfeld, M.D., Department of Medicine B, Sheba Medical Center Tel-Hashomer 52621, Israel. Or contact AARDA by phone at 586-776-3900 or e-mail at aarda@aarda.org
