1.
Atherosclerosis as a paradigmatic disease of the elderly: role of the immune system.
Knoflach, M, Mayrl, B, Mayerl, C, Sedivy, R, Wick, G
Immunology and allergy clinics of North America. 2003;(1):117-32
Abstract
When a new hypothesis about the etiology and pathogenesis of a disease is developed, there is always the danger that it will be presented as the only acceptable explanation for the occurrence of a given pathologic condition. In view of the well-proven multifactoral pathogenesis of atherosclerosis, we would like to emphasize that we are not postulating that immunity to HSP60 is the only cause of atherogenesis, especially in the later stages where there are clinically-apparent sequelae, such as myocardial infarction, stroke, and other atherosclerosis-dependent symptoms. In this article, we summarized some of the experimental and clinical data that we and others have collected in support of the concept that atherosclerosis is a good example of pleotropic antagonism, and postulated that age-dependent diseases are the price we pay for genetic traits established by natural selection to assure maximum survival until the age of reproduction, the effects of which may, however, become deleterious later in life. In the present case, the cost we pay for protective immunity to microbial and altered autologous HSP60 is the risk of cross-reactivity with HSP60 expressed by arterial endothelial cells that are subjected to stress factors already known as classical atherosclerosis risk factors. We showed that the first inflammatory stage of atherosclerosis starts early in life, long before it becomes clinically apparent. More severe lesions that lead to atherosclerosis-dependent organ-specific or systemic symptoms will only occur if classical atherosclerosis risk factors, especially those involving the cholesterol metabolism, remain present.
2.
Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis.
Choy, JC, Granville, DJ, Hunt, DW, McManus, BM
Journal of molecular and cellular cardiology. 2001;(9):1673-90
Abstract
The high turnover of endothelial cells (EC) in atherosclerosis suggests that an increase in the frequency of both cell proliferation and cell death is important in the pathogenesis of this common disorder. Further, increased apoptosis of EC, smooth muscle cells (SMC) and immune cells has been observed in atheromatous plaques. Many pro-atherogenic factors, including oxidized low-density lipoproteins, angiotensin II and oxidative stress, can induce EC apoptosis. Such damage to the endothelium may be an initiating event in atherogenesis since EC apoptosis may compromise vasoregulation, increase SMC proliferation, SMC migration and blood coagulation. In addition, EC overlying vascular lesions have been shown to increase their expression of pro-apoptotic proteins, such as Fas and Bax, while decreasing levels of anti-apoptotic factors. Therefore, understanding EC apoptotic pathways that are altered in atherosclerosis may enable a greater understanding of disease pathogenesis and foster the development of new therapies. The present discussion outlines the biochemical characteristics of EC apoptosis and the role that altered regulation of apoptosis plays in vasculopathy.
3.
Unregulated inflammation shortens human functional longevity.
Brod, SA
Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 2000;(11):561-70
Abstract
Systemic inflammation, represented in large part by the production of pro-inflammatory cytokines, is the response of humans to the assault of the non-self on the organism. Three distinct types of human ailments - namely autoimmunity, presenile dementia (Alzheimer's disease), or atherosclerosis - are initiated or worsened by systemic inflammation. Autoimmunity is unregulated hyperimmunity to organ-specific proteins, inducing rapid turnover of antigen-specific T cells of the acquired immune system with ultimate exhaustion and loss of acquired immunity IL-2 and IFN-gamma production and proliferative decline, conforming to the limited capacity of clonal division (Hayflick phenonmenon). In Alzheimer's disease (AD), the primary degenerative process of amyloid-beta (AJ3) protein precedes a cascade of events that ultimately leads to a local "brain inflammatory response". Unregulated systemic immune processes are secondary but important as a driving-force role in AD pathogenesis. Atherosclerosis, an underlying cause of myocardial infarction, stroke, and other cardiovascular diseases, consists of focal plaques characterized by cholesterol deposition, fibrosis, and inflammation. The presence of activated T lymphocytes and macrophages indicate a local immunologic activation in the atherosclerotic plaque that may be secondary to unregulated pro-inflammatory cytokines too. The premature hyperimmunity of autoimmunity, the local "brain inflammatory response" to A/3 protein in AD, and the immune response to fatty changes in vessels in atherosclerosis all signal the critical importance of unregulated systemic inflammation to common neurological and cardiovascular disease that shortens the nominal longevity of humans.