Immunity to Low-Density Lipoprotein
Animal experiments, epidemiological studies and clinical investigations all show that high levels of plasma low-density lipoprotein (LDL) promote atherosclerotic cardiovascular disease [1]. LDL particles contain epitopes that trigger cellular and humoral
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21.1
Low-Density Lipoprotein Initiates Vascular Inflammation
Animal experiments, epidemiological studies and clinical investigations all show that high levels of plasma low-density lipoprotein (LDL) promote atherosclerotic cardiovascular disease [1]. LDL particles contain epitopes that trigger cellular and humoral immune responses. Autoimmunization during the course of atherosclerosis generates proinflammatory T cell responses whereas vaccination with LDL components can lead to atheroprotective immunity. Mechanisms underlying these responses are discussed in the present review. As a consequence of its subendothelial retention, LDL particles are trapped within the intima where they may undergo oxidative modifications due to enzymatic attack by myeloperoxidase and lipoxygenases, or by reactive oxygen species such as HOCl, phenoxyl radical intermediates or peroxynitrite (ONOO ) generated within the intima in inflammation and atherosclerosis [4]. Lipid peroxidation generates reactive aldehydes as well as modified phospholipids such as lysophosphatidylcholine and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3phosphocholine (ox-PAPC), which can initiate innate inflammatory responses [5]. These lipids activate endothelial cells and macrophages to produce adhesion molecules and chemokines. The mechanisms mediating this response involve activation of the early growth response-1 (Egr-1) [6] and Jak-STAT [7] pathways and the unfolded protein response [8].
G.K. Hansson (*) Department of Medicine, Karolinska Institute, Stockholm, Sweden Center for Molecular Medicine, Karolinska University Hospital L8:03, SE-17176 Stockholm, Sweden e-mail: [email protected] G. Wick and C. Grundtman (eds.), Inflammation and Atherosclerosis, DOI 10.1007/978-3-7091-0338-8_21, # Springer-Verlag/Wien 2012
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Oxidized LDL is found in several other tissues in addition to the arterial intima and also in peripheral blood. For instance, oxLDL particles have been identified in synovial fluid and peripheral blood of patients with rheumatoid arthritis [9, 10]. Their presence in blood is surprising since blood contains powerful antioxidants and cells with scavenger receptors rapidly internalize these particles. However, several studies report detectable levels in blood and have suggested that oxLDL levels may reflect increased risk for cardiovascular disease [11]. OxLDL and components thereof have also been reported to activate innate immunity by binding to Toll-like receptors (TLR) [12], and cholesterol crystals were recently reported to trigger inflammasome activation, leading to secretion of interleukin-1b [13]. Activation of innate immunity through any of these mechanisms may indirectly impact also on adaptive immunity, for example by modulating the function of antigen-presenting cells or T cells.
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T Cells: Key Components of Adaptive Immunity in Atherosclerosis
Components of adaptive immunity are present in human lesions throughout the course of atherosclerosis, and several studies point to an im
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