Review articleRegulatory T Cells and the Control of Modified Lipoprotein Autoimmunity-Driven Atherosclerosis
Section snippets
Autoimmunity Against Antigens Induced by Hypercholesterolemia Promotes Atherosclerosis
The first evidence for involvement of autoimmune responses in atherosclerosis was discovered more than 20 years ago when Jonasson et al. (1985) demonstrated expression of MHC class II antigen as well as the presence of activated T cells in human atherosclerotic plaques. Findings from initial studies with the use of hypercholesterolemic mice deficient in all lymphocytes (resulting from Rag or SCID gene mutations) were not entirely conclusive and suggested a role for immunity primarily in animals
Oxidized LDL is a Major Autoantigen in Atherosclerosis
The circumstance that the experimental studies describing the pathogenic role of Th1 immunity in atherosclerosis were based on induction of disease by hypercholesterolemia suggests that the relevant autoantigen is a lipoprotein or possibly a protein modified by lipids. Most attention has focused on the role of oxidized LDL in these processes. Antibodies against oxidized LDL are common in humans (Hulthe 2004). Oxidized LDL, as well as oxidized LDL autoantibodies, has also been isolated from
Immune-Modulation as a Novel Therapeutic Approach for Prevention of Atherosclerosis
The finding that atheroprotective immune responses could be activated by immunization with oxidized LDL pointed to the fascinating possibility of developing an atherosclerosis vaccine. Several laboratories initiated studies to reveal the active antigens in oxidized LDL and to characterize mechanisms involved in the protective effect. The result of these studies demonstrated the presence of multiple antigens related either to peptide fragments of B-100 (Fredrikson et al. 2003a) or to oxidized
Tregs Control Autoimmunity
The most important function of the immune system is to recognize and eliminate infectious microorganisms. In doing so, it is vital that the immune system can differentiate these pathogens from self-antigens. However, a complete deletion of all autoreactive T cells would impair the effectiveness of the infectious defense because some self-antigens share structural similarities with foreign pathogens. As a result, a fraction of moderately self-reactive T cells escapes deletion in the thymus; and
Tregs and Atherosclerosis
Several lines of evidence have implicated dysregulation of Treg function in atherosclerosis (Mallat et al. 2007). Atherosclerotic plaques contains relatively few FoxP3-positive Tregs (1%–5% of all T cells) as compared with normal arterial tissue or inflammatory skin lesions, where Tregs constitute about 25% of all T cells, suggesting that local tolerance protection is impaired in atherosclerotic plaques (de Boer et al. 2007). Regulatory T cell numbers are lower in old, atherosclerotic ApoE−/−
Therapeutic Targeting of Tregs
The identification of Tregs as an important protective factor in atherosclerosis has focused the attention on these cells as possible targets for intervention. As discussed above, there is accumulating evidence that the rate of progression of the disease is determined by the balance between proinflammatory Th1 and anti-inflammatory Treg responses against modified vascular antigens. The possibility to modulate this balance toward a predominance of Tregs represents an attractive therapeutic
Future Perspectives
The emerging recognition of the role of plaque antigen autoimmunity in atherosclerosis has focused attention on the possibility of developing immune-modulating therapy for prevention of cardiovascular disease. A first generation of such therapies is now approaching clinical testing, and phase I safety studies of an apo-B-peptide-based atherosclerosis vaccine are expected to be initiated during 2010. However, the relatively incomplete understanding of the mode of action of these novel therapies,
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